Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1S([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=O)=O)([O-])=O.[C:26]1([C:32]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.SCC(O)=O.O.[OH-].[Li+].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[C:26]1([C:32]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([CH2:50][NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=4)=[CH:46][CH:45]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCc1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)CS
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (180 mg, 0.5 mmol), {4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (178 mg, 0.5 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in dichloromethane (5 mL) was added diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give a yellow oil. To a solution of the yellow oil and mercaptoacetic acid (100 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added lithium hydroxide monohydrate (80 mg, 1.9 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (120 mg, yield 48%, 2 steps) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][C:15]=1[C:20]([F:23])([F:21])[F:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Product: O=C(Nc1ccc(Cl)cc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 21.5 %

Procedure:
Using 5-chlorosalicylic acid and 4-chloro-2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[CH:1]([C:4]1[C:12]([C:13](=[O:15])[CH3:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc2ccccn2n1
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
2-Isopropyl-pyrazolo[1,5-a]pyridine (10.00 g, 66.7 mmol), acetic anhydride (100 ml), and concentrated sulfuric acid (10 drops) were combined and stirred for 3 hours at reflux. The reaction mixture was cooled to room temperature and poured into ice water (300 ml). The mixture was quenched with 2 N sodium hydroxide until the pH>10, and the quenched solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 40% ethyl acetate in hexanes) to give 11.8 g (87%) of 1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-ethanone. 1H-NMR (250 MHz, DMSO-d6) δ 8.47 (d, J=6.8 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 3.76 (sept, J=6.9 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.8 Hz, 6H); LC/MS 203.3 m/z (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[CH2:7]2.BrCC1C=C(C=CC=1CBr)[C:20]([O:22][CH3:23])=[O:21]>>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:20]([O:22][CH3:23])=[O:21])=[CH:11][C:6]=1[CH2:7]2
Reactant: O=C1C2CCC1Cc1ccccc1C2
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Product: COC(=O)c1ccc2c(c1)CC1CCC(C2)C1=O

Procedure:
Prepared using the procedure described for 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (Justus Liebigs Ann. Chem. 1961, 650, 115) using methyl 3,4-bis(bromomethyl)benzoate in place of 1,2-bis(bromomethyl)benzene.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21](=[O:27])(=[O:26])[NH:22][CH:23]([CH3:25])[CH3:24])[CH:19]=2)[NH:14][C:13]1=[O:28]>CO.[OH-].[Na+]>[CH:23]([NH:22][S:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:28])[C:12]2=[CH:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:29])=[O:2])(=[O:27])=[O:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccccc1NC=C1C(=O)Nc2ccc(S(=O)(=O)NC(C)C)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)C(=CNc1ccccc1C(=O)O)C(=O)N2
Temperature: 150 °C

Procedure:
A suspension of rpm335 (0.155 g, 0.3734 mmol) in methanol (1 mL) and NaOH 1M (1 ml) was heated in the microwave at 150° C. for 5 min. The reaction mixture was cooled to 0° C., and the solvent distilled under reduced pressure and HCl (aq 4M, 5 ml) added. The orange precipitate was collected by filtration, washed with water (10 ml) and dried, to give pure rpm336 (0.139 g, 0.346 mmol, 92%). MS (API-ES): m/z 402 (M+H)+; HRMS (API-ES) m/z Found: 402.1116 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(N(CC)CC)C.Cl[C:16](=[N:23]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-]>C(O)C.C(OCC)(=O)C>[CH3:5][C:4]1[O:6][N:23]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]=1[C:2](=[O:7])[CH3:1]
Reactant: ON=C(Cl)c1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of pentane-2,4-dione (13.23 g, 0.132 mol) and triethylamine (13.35 g, 0.132 mol) in ethanol was added α-chlorobenzaldehyde oxime (13.70 g, 0.088 mol) at room temperature. The reaction mixture was stirred overnight at room temperature. To the reaction was added ethyl acetate and saturated aqueous NaCl. The organic phase was washed with saturated aqueous NaCl (twice) and dried with MgSO4, and the organic solvent was removed under reduced pressure to provide 17.7 g of the title compound. The yield was 100%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:2]/[C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Acetyl-3-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridine-2-carbonitrile (65) (1.32 g, 5.71 mmol) was dissolved in dry toluene (30 mL). N,N-dimethylformamide dimethyl acetal (2.3 mL, 17.3 mmol) was added and the mixture was stirred at reflux for 5 hours. N,N-Dimethylformamide dimethyl acetal (5.0 mL, 37.6 mmol) was added and the mixture was stirred at reflux for 4 hours. The solution was cooled to rt and the solution left to stand at rt for 16 hours. The solvent was carefully decanted and the remaining reside triturated with Et2O (50 mL) followed by EtOAc (50 mL). The residual solvent was evaporated in vacuo. The title compound 66 was afforded as an orange solid (1.11 g, 68%); LCMS, Rt=1.98 min (MeOH-FA method), m/z 287 (MH+).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>C(O)C>[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[N:15]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Cn1ccc(N)n1
Solvent: CCO
Product: Cn1ccc(N2CCC(C(=O)O)C2=O)n1
Yield: 20.5 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 1-methyl-1H-pyrazol-3-amine (0.428 g; 4.41 mmol) in ethanol (3 mL). 1-(1-methyl-1H-pyrazol-3-yl)-2-oxopyrrolidine-3-carboxylic acid 0.063 g (21%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[O:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)(=O)=O.C(=O)([O-])[O-].O>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:1][C:2]2[C:3]([C:8]3[O:9][C:10]4[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:22]=1
Reactant: Oc1cccnc1-c1nc2c(o1)CCCC2
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccnc2-c2nc3c(o2)CCCC3)n1

Procedure:
0.12 g 2-(3-hydroxy-2-pyridyl)-4,5,6,7-tetrahydrobenzoxazole, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.21 g pottasium carbonate were suspended in 3 ml DMF, and the resulting suspension was subjected to a reaction for 2 hours at 60° C. After completing the reaction, the suspension reacted was added with water and then extracted with ethyl acetate. The extract was then washed with saturated saline solution. The organic layer obtained was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.18 g.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3CC[C@@H]12
Reaction time: 24 h
Yield: 54.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a waxy solid. FDMS: m/e=389. α[D]589 =+48.95 (c=0.96, chloroform).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1N

Procedure:
The title compound was prepared from (4-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A3) (32.54 g, 127 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light orange solid (25.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].[H-].[Na+].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>O1CCCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:22]2[CH:23]=[C:24]3[N:31]([CH3:32])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)=[CH:8][C:7]=1[F:14]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(3,4-dichlorophenoxy)-3-fluorophenyl)methanol (0.101 g, 0.350 mmol) in tetrahydrofuran (THF) (8 mL), sodium hydride (0.021 g, 0.525 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.065 g, 0.350 mmol) in DMF (1 mL).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[CH:11][N:12]=[C:6]2[N:5]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>Cl.O>[N:12]1[CH:11]=[CH:10][N:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[N:5][C:6]=12
Reactant: COC(OC)c1ccn2ccnc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccn2ccnc2n1
Temperature: 48 °C
Yield: 98.3 %

Procedure:
7-Dimethoxymethylimidazo[1,2-α]pyrimidine (1.00 g, 5.18 mmol) was dissolved in 3N hydrochloric acid and heated at 48° C. for 14 h. The solution was layered with ethyl acetate (30 ml) and solid sodium hydrogencarbonate (1.06 g, 12.6 mmol) was added in portions over 5 min. The mixture was diluted with water (6 ml) and extracted with dichloromethane (5×50 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give imidazo[1,2-α]pyrimidine-7-carbaldehyde (749 mg, 99%) as a yellow solid: δH (360 MHz, CDCl3) 7.53 (1H, d, J 7), 7.77 (1H, d, J 1), 8.10 (1H, d, J 1), 8.60 (1H, d, J 7), 10.05 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH2:15]I)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][O:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][N:22]([O:23][CH3:24])[C:20](=[O:21])[C:19]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:18]=3[F:17])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(C2(CI)CC2)c(Cl)c1
Reactant: CONC(=O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CON(CC1(c2ncc(C(F)(F)F)cc2Cl)CC1)C(=O)c1c(F)cccc1F
Temperature: 70 °C
Yield: 15.3 %

Procedure:
169 mg of 3-chloro-2-[1-(iodomethyl)cyclopropyl]-5-(trifluoromethyl)pyridine (step 3) and 110 mg of 2,6-difluoro-N-methoxy-benzamide were dissolved in dry dimethylsulfoxide under argon and 90 mg of potassium carbonate was added. The mixture was heated at 70° C. for 1 hour. Then ice water was added and the mixture was extracted with ether. The concentrated organic phase was purified on 30 g of silica gel, eluent hexane/ethyl acetate (4:1). Thus, 30 mg of N-[[1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropyl]methyl]-2,6-difluoro-N-methoxy-benzamide was obtained as a colorless resin. 1H-NMR (CDCl3): 8.70 ppm (s, 1H), 7.90 ppm (s, 1H), 7.32 ppm (m, 1H), 6.87 ppm (m, 2H), 4.24 ppm (s, 2H), 3.40 ppm (s, 3H), 1.19 ppm (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[C:3]([C:10]([F:12])([F:13])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: OCc1ccnc(C(F)(F)F)c1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-fluoro-2-trifluoromethyl-pyridin-4-yl)-methanol (0.620 g, 3.18 mmol) and activated MnO2 (3.20 g, 36.5 mmol) in CH2Cl2 was stirred at RT overnight. The solid was filtered off, washed with CH2Cl2, and the filtrate was concentrated under mildly reduced pressure to afford the title compound as a yellow liquid. MS (LC/MS): 212.0 [M+NH4]+, 226.0 [M+MeOH]+. tR (HPLC conditions c): 3.26 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.CN(C)C=O.[Cl:24]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:7]([Cl:24])=[N:6][C:5]([O:8][CH:9]([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(OC(C(F)(F)F)C(F)(F)F)ncc1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC(C(F)(F)F)C(F)(F)F)nc(Cl)c1N
Reaction time: 1 h
Yield: 44.4 %

Procedure:
1.0 g of 5-amino-4-methyl-2-(2,2,2-trifluoro-1-trifluoromethylethoxy)pyri dine was introduced to 10 ml of N,N-dimethyl formamide, and 0.56 g of N-chlorosuccinimide was added at room temperature. The temperature was elevated to 60° C., and the mixture was stirred for 1 hour and poured into water. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thus obtained residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=10:1) to give 0.50 g (yield 44%) of the title compound as a brown oil.
Reaction SMILES: [I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[NH:7]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.C(=O)(OC(C)(C)C)[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[N:7]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC12CCC(I)C(C1)NC2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(=O)C2(C)CCC(I)C1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-1-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c, (9.5 g, 35.8 mmol) in CH2Cl2 (100 mL) was added DMAP (0.2 g, 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at room temperature. The product was extracted into CH2Cl2 and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1.[H][H]>CO.O=[Pt]=O>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=2)=[C:2]([F:1])[CH:22]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Yield: 80.6 %

Procedure:
A solution of tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate (11 mg, 0.031 mmol) in MeOH (2 mL) was treated with PtO2 and the reaction mixture was stirred under a blanket of hydrogen (from a latex balloon) for 2 h. The catalyst was filtered off and the filtrate concentrated to give tert-butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate (8 mg, 81%). 1H NMR (DMSO-d6) δ 10.62 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 8.36 (dd, 1H, J=9.8, 2.5 Hz), 8.36 (dd, 1H, J=9.8, 2.5 Hz), 8.20-8.17 (m, 1H), 7.71 (dd, 1H, J=8.8, 8.8 Hz), 7.49 (s, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.[C:23]([O:27][C:28](OC([O-])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OC([O-])=O)(=O)[O-]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])OC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (27.7 g, 94.8 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) in dry methanol (300 mL) was added t-butylpyrocarbonate (25.0 g, 114 mmol). Shortly after the addition of the pyrocarbonate, a clear solution was formed. The solution was stirred at ambient temperature for 1 h, resulting in formation of a white precipitate. The solid was collected by filtration, washed with a 1:1 mixture of diethyl ether:pentane, and dried in vacuo to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([O:17][CH3:18])[CH:3]=1.Cl[C:20]1[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]3[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)=[CH:22][CH:21]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C
Yield: 94 %

Procedure:
To a microwave vial was added 2-(4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (535 mg, 2.12 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 500 mg, 1.77 mmol), potassium phosphate (1.5 g, 7.07 mmol), Pd2(dba)3 (162 mg, 0.18 mmol), and SPhos (72.6 mg, 0.18 mmol), followed by addition of 1,4-dioxane (3.7 mL)/H2O (0.7 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 100° C. in the microwave for one hour. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueous solution, loaded on an SCX column and washed with methanol, then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 6-(4-fluoro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (620 mg) MS [M+H+]=373.3.
Reaction SMILES: C1(C[C@H]2COC(=O)N2[C:14](=[O:23])[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:17]1([CH:15]([CH3:16])[CH2:14][OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)c1ccccc1
Reaction time: 0.47 h

Procedure:
A mixture of (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLI, Isomer I, 2.651 g, 8.57 mmol) in THF (10 ml) is added dropwise to a cooled slurry of lithium aluminum hydride (0.3518 g, 9.27 mmol) in THF (10 ml). After the mixture had stirred for 28 min at 0°, water (0.35 ml) is added and the mixture is stirred for 15 min. Sodium hydroxide (15% aqueous solution, 0.35 ml) is added and again the mixture is allowed to stir for 15 min. After the final addition of water (1.05 ml), the salts are removed by filtration and washed with ether. The combined filtrates are washed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate/hexane (15/85). The appropriate fractions are pooled and concentrated to give 2-phenylpropanol (XLIII, Isomer Ia), NMR (CDCl3) 1.28, 1.35, 2.95, 3.71 and 7.26 δ.