Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:26][C:27]([OH:29])=[O:28])[CH2:8][CH2:7]1>O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:26][C:27]([OH:29])=[O:28])[CH2:10][CH2:11][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:14][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]1
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=[Pt]=O
Product: COc1ccc(N)cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a nitrogen purged aqueous (50 ml) solution containing 50 mg of PtO2 was added 50 mg of 1-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid (prepared by the procedure of Example 23). After hydrogenating in a Parr bomb for one hour, the solution was filtered and the aqueous filtrate freeze-dried to give the aniline derivative as a tan solid (95 percent yield), MF>240° C. dec, and further characterized by:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][CH:7]3[CH2:11][C:10](=O)[NH:9][CH:8]32)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][CH:7]3[CH2:11][C:10](=[S:16])[NH:9][CH:8]32)=[CH:4][CH:3]=1
Reactant: O=C1CC2Cc3ccc(Cl)cc3C2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1CC2Cc3ccc(Cl)cc3C2N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 225.8 %

Procedure:
To a solution of 4.2 g of 7-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one in 100 ml of pyridine is added 2.2 g of diphosphorus pentasulfide, and the mixture is stirred at 90° C. for 1 hour. The reaction mixture is then cooled, poured into ice-cold water and extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and the solvent is distilled off. The residual oil is chromatographed over silica gel with chloroform eluant. The purified product is crystallized with isopropyl ether and recrystallized from the same solvent to give 2.5 g of 7-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-thione, melting at 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)OC(C)(C)C

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 1,1-dimethylethyl bromoacetate: MS (ESI) m/z 320 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>>[CH3:1][N:2]([CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:3]
Reactant: CNC
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Product: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 610.1 %

Procedure:
To a stirred solution of dimethyl amine (2.0M solution in tetrahydrofuran) (0.31 mL, 0.028 mmol) in tetradhyrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4R,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) and stirred at room temperature overnight. The solvent is evaporated in vacuo and the crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.072 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (S, 3H), 2.21 (s, 6H), 3.56 (s, 2H), 4.56-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H), 5.26 (d, J=3.76 Hz, 1H), 6.64 (t, J=52.36 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.59 (d, J=8.08 Hz, 2H), 7.78 (d, J=8.12 Hz, 2H), 8.07-8.09 (m, 1H), 8.81 (s, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:10]([CH2:9][CH2:8][CH2:7][OH:6])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)(=[O:13])=[O:12])=[C:25]([CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[CH:26]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO[Si](C)(C)C(C)(C)C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCCO)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To 8 g of N-(3-{[tertbutyl(dimethyl)silyl]oxy}propyl)-N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide in 80 ml of tetrahydrofuran at 0° C. are added 2.98 g of tetrabutylammonium fluoride trihydrate. After 40 minutes at 25° C., the reaction medium is concentrated and then chromatographed on a column of silica gel, eluting with dichloromethane, to give 3.28 g of the expected product.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:29][C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[CH:30]=[CH:31][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 60.9 %

Procedure:
Using the procedure described in Example 93, Part A, 4-anisoyl chloride (2.2 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 441 mg (61%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:18][CH2:19][C:20](Br)=[O:21]>C1COCC1.C(=O)=O.CC(C)=O>[Br:18][CH2:19][C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:21]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Br)CBr
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(CBr)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (4R)-4-phenyl-1,3-oxazolidin-2-one (100 g, 613 mmol) in THF (2 L) under a nitrogen atmosphere was cooled to −78° C. in dry ice-acetone bath. To the stirred solution was added n-BuLi (337 mL, 2 M solution in cyclohexane, 675 mmol) dropwise over a period of 30 min, followed by the addition of 2-bromoacetyl bromide (123.7 g, 613 mmol) over 15 min. The resulting solution was stirred at 25° C. for 2 h. The reaction was quenched with aqueous NH4Cl (500 mL), and the mixture was extracted three times with EtOAc (3×1 L). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a brown solid. The crude product was used directly in the next step.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[F:36]>>[Br:27][C:28]1[CH:33]=[C:32]([CH2:34][C@H:10]([NH:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:31]=[CH:30][C:29]=1[F:36]
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(CBr)cc1Br
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4-(bromomethyl)-1-fluorobenzene using a method analogous to that described in Examples 509 and 510.
Reaction SMILES: C[O-].[Na+].CC1C=CC(S(O[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:17]#[N:18])(=O)=O)=CC=1.Cl.[NH2:24][CH:25](C(OCC)=O)[C:26]([O:28][CH2:29]C)=[O:27]>CO>[NH2:18][C:17]1[CH:16]=[C:15]([C:19]([CH3:20])([CH3:21])[CH3:22])[NH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)C(C)(C)C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred sodium methoxide solution (15% by weight, 80 mL total) was added drop-wise a solution of 1-cyano-3,3-dimethylbut-1-en-2-yl 4-methylbenzenesulfonate (10.0 g, 36 mmol) and diethyl aminomalonate hydrochloride salt (9.0 g, 43 mmol) in methanol (50 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours, the solvent was removed under vacuum and the crude product was dissolved in water and extracted with ethyl acetate. The combined organic layers was washed with brine, dried and the solvent removed under vacuum. The crude product was purified by column chromatography (silicagel, dichloromethane:methanol 95:5) to afford 2.4 g of the desired methyl 3-amino-5-tert-butyl-1H-pyrrole-2-carboxylate used as such in the next step.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Cl

Procedure:
-- To a suspension of 21.4 g (0.1 mole) of 2-acetoxy-5-chlorobenzoic acid in 100 ml of refluxing benzene is added in portions over 1 hour 20.8 g (0.1 mole) of phosphorous pentachloride. The clear solution is refluxed for 1 hour, then concentrated to dryness. The residue is distilled, bp 112°C at 0.1 mm to give a clear oil which solidified on standing, mp 35°-8°C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH:28]([S:30]([CH:33]=C)(=[O:32])=[O:31])=[CH2:29]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][CH2:28][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: C=CS(=O)(=O)C=C
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(C)(=O)=O)C3)cc1OCC2

Procedure:
Following the procedure for 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with vinyl sulfone to give 191 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, s), 7.60 (1H, s), 7.05 (1H, dd, J=8.32, 1.83 Hz), 6.94 (1H, d, J=1.78 Hz), 5.99-5.89 (1H, m), 4.48-4.39 (4H, m), 3.78-3.70 (2H, m), 3.71-3.62 (1H, m), 3.25-3.18 (2H, m), 3.04 (3H, s), 3.02-2.95 (4H, m), 1.56 (6H, d, J=6.64 Hz). LCMS: RT=5.58 min, M+H+=457
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CN(C=O)C.Cl[CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:10][CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cc(S)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-chloro-5-methoxybenzenethiol (2.1 g) and DMF (dry) (30 mL) were added methyl 4-chloroacetoacetate (1.407 mL) and K2CO3 (1.994 g) at 0° C., and the mixture was stirred at room temperature for 5 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.440 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12](=O)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].Cl.[NH2:26][OH:27]>C(O)C>[CH2:1]([N:3]([CH2:22][CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12](=[N:26][OH:27])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCO)c1ccc(C2=CC(=O)C(=O)c3ccccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCN(CCO)c1ccc(C2=CC(=NO)C(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)naphthalene-1,2-dione (8.5 g, 26.48 mmol) in absolute ethanol (150 ml) was treated in one portion with hydroxylamine hydrochloride (3.68 g, 52.96 mmol) recrystallised from 75:25 EtOH:H2O and stirred at RT for 2 hrs. The mixture was then evaporated in vacuo and the residue suspended in H2O (500 ml). The aqueous phase was then basified to pH 10 with ammonium hydroxide solution and extracted into EtOAc (×4). The combined organics were then dried (Na2SO4) and evaporated in vacuo to afford the product, 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)-2-(hydroxyimino)naphthalen-1(2H)-one, as a dark red solid (9.1 g, 100%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)#[N:41]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:5]1[N:6]=[CH:7][N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)[CH2:46][C:45]1[CH:48]=[CH:49][C:42]([C:40]#[N:41])=[CH:43][CH:44]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(C#N)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (977 mg, 2.55 mmol) in THF (25 ml) was cooled to −78° C. Lithium hexamethyldisilazide (2.68 ml, 2.68 mmol) was added dropwise and the reaction stirred 30 min at −78° C. 4-Cyanobenzyl bromide (500.7 mg, 2.68 mmol) was added and the reaction stirred a further 4 hrs at −78° C. and then at −20° C. for 12 hr. The reaction was quenched with water (10 ml) and saturated NaHCO3 solutuon (10 ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 3% MeOH in CH2Cl2) afforded the product.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH:7]([F:9])[F:8]>N1C=CC=CC=1.ClCCCl>[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([Cl:3])=[O:15])[CH:7]([F:9])[F:8]
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(Cl)c1cccc(OC(F)(F)C(F)F)c1
Reaction time: 4 h
Yield: 95 %

Procedure:
203 parts by weight of thionyl chloride and 1 drop of pyridine are added to a mixture of 352 part by weight of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoic acid in 900 parts by volume of 1,2-dichloroethane. After stirring the mixture for 4 hours under reflux and concentrating it under reduced pressure, 359 parts by weight (yield: 95% of theory) of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoyl chloride, of nD 25 =1.4660, are obtained. The IR spectrum shows C=O bands at 1770 and 1748 cm-1, and fluoroalkoxy bands at 1225, 1190 and 1125 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[S:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>C(OCC)(=O)C>[OH:1][C:2]1[C:19]([OH:20])=[C:18]([N+:21]([O-:23])=[O:22])[C:5]2[S:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)cc12
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCOCC2)sc2c([N+](=O)[O-])c(O)c(O)cc12

Procedure:
(5,6-Dihydroxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (0.10 g) was dissolved to ethyl acetate (60 ml). Nitric acid (2 eq, 2 M solution in dichloromethane) was added in small portions at 55° C. 15 minutes after last addition the mixture was cooled, washed with water, dried with Na2SO4 and concentrated to small volume. The precipitated product was filtered.
Reaction SMILES: [NH3:1].C([O:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8])(C)(C)C>CO>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH2:19][NH2:1])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([OH:6])=[O:8]
Reactant: N
Reactant: CC(C)(C)OC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Solvent: CO
Product: NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonia gas was passed through a cooled solution of 4-(3-tert-butoxycarbonylphenyl) benzyl bromide (65 g, 0.18 mol) in methanol (2 L) for 6 h. Then the reaction mixture was stirred at RT overnight. Methanol was removed under vacuum. To the residue 6N aqueous solution of HCl (200 mL) was added and stirred overnight. Concentrated completely to get 4-(3-carboxyphenyl)benzylamine as a hydrochloride salt (20 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncc(F)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
0.14 g of 5-(4-chlorophenyl)-4-(3,5-difluoro-2-pyridyl)-6-methyl-2H-py ridazin-3-one and 5 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.14 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.08 g of 3-chloro-5-(4-chlorophenyl)-4-(3,5-difluoro-2-pyridyl)-6-met hylpyridazine (hereinafter, described as compound (15) of the present invention.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)C2CC2)c1

Procedure:
N-(3-Acetylphenyl)cyclopropanecarboxamide was prepared by the reaction of m-aminoacetophenone, diisopropylethylamine and cyclopropanecarboxylic acid chloride in dichloromethane.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.Cl>C1COCC1>[F:1][CH:2]([F:8])[C:3](=[O:4])[CH2:25][C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)=[CH:23][CH:22]=1)=[O:26]
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15.8 h
Yield: 91.6 %

Procedure:
Ethyl difluoroacetate (2.30 g, 18.5 mmol) was placed in a 100 mL round bottom flask and dissolved in THF (25 mL). To the stirred solution was added 25 weight % sodium methoxide (4.90 g, 22.6 mmol) followed by 4'-morpholinoacetophenone (3.45 g, 16.8 mmol). The reaction was stirred at room temperature overnight (15.8 hours), then treated with 3N HCl (13 mL). The reaction was extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a green solid (4.36 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (3.27 g, mp 102°-3° C., 69%). 1H NMR (CDCl3) 300 MHz 15.80 (br s, 1H), 7.86 (d, J=9.1 Hz, 2H), 6.90 (d, J=9.1 Hz, 2H), 6.46 (s, 1H), 5.99 (t, J=54.4 Hz, 1H), 3.84 (m, 4 H), 3.36 (m, 4H); 19F NMR (CDCl3) 300 MHz: -126.75 (d); M+283.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[CH3:19][C:18]([Si:15]([CH3:17])([CH3:16])[O:9][CH2:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(CCO)o1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Reaction time: 2 h

Procedure:
To a solution of compound 21A (2.00 g, 15.9 mmol) in DMF (50 mL) was added imidazole (1.62 g, 23.9 mmol), followed by tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol). After 2 h at 25° C., the reaction was poured into diethyl ether (300 mL) and washed with water (1×100 mL), 1 N HCl (1×100 mL), water (1×100 mL), brine (1×50 mL) and dried over anhydrous MgSO4. Crude compound 204A was analyzed by LCMS and NMR and determined to be pure enough to be carried on directly to the next step. HPLC: 100% at 4.347 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.