Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][N:21]3[C:20](=[O:22])[C:19]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]4[C:17]3=[O:27])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)OCC(CN1C(=O)c3ccccc3C1=O)O2
Reaction time: 6 h
Yield: 101.4 %

Procedure:
A mixture of 8-t-butyl-2-chloromethyl-1,4-dioxaspiro(4,5)decane (10 g, 40 mmol) (prepared as described in EP 281842; see also the references cited in this document for-related compounds), potassium phthalimide (8.9 g, 48 mmol) and a catalytic amount of tetra-n-butyl ammonium iodide in DMF (80 ml) were heated to 120° C. for 3 hours. Additional potassium phthalimide (2.8 g, 16 mmol) was then added and heating was continued for 6 hours. The solvent was then evaporated in vacuo and toluene (150 ml) was added. After filtration from insoluble material the organic phase was washed two times with brine (100 ml), dried (MgSO4) and evaporated in vacuo. The resulting residue (22 g) was purified by flash chromatography on silica (toluene/ethylacetate 3:1) yielding the title compound as light yellow crystals (14.5 g, Fp. 97°-115° C.).
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCCC>[N:11]1([CH2:1][CH:2]2[C:7](=[O:8])[CH:6]3[CH2:9][CH2:10][N:3]2[CH2:4][CH2:5]3)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: C=C1C(=O)C2CCN1CC2
Solvent: CCCCCC
Product: O=C1C2CCN(CC2)C1CN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A reaction flask containing 2-methylenequinuclidin-3-one (6.86 g, 50 mmoles) and a magnetic stir bar was charged with piperidine (12 ml, 120 mmoles). The mixture was stirred at room temperature for 18 hours, and the mixture was added to hexane (300 ml). The solution was filtered through Celite® and the filtrate was concentrated in vacuo (maximum temperature 60° C.) to provide 11.03 g (99%) of the product as a pale yellow solid, mp 34°-37° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[CH:7]2.Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]([CH3:13])=[CH:7]2
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1c(C)cc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 322 g. (0.81 mole) of a 60% mineral oil dispersion of sodium hydride in 250 ml. of dry DMF was added dropwise a solution of 100 g. (0.67 mole) of 5-fluoro-2-methylindole in 300 ml. of dry DMF. The mixture was stirred at ambient temperature for thirty minutes and then treated dropwise with o cooling with a solution of 121.5 g. (0.67 mole) of ethyl α-bromopropionate. Workup of the reaction mixture, after quenching with water and extraction of the product with ethyl acetate, afforded ethyl α-(5-fluoro-2-methyl-1-indolyl)-propionate.
Reaction SMILES: [CH2:1]([N:8]([CH:10]([C:15]([O:17]C)=O)[C:11]([O:13][CH3:14])=[O:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH2:20].CO>CO>[CH3:14][O:13][C:11](=[O:12])[CH:10]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])[C:15]([NH:20][CH3:19])=[O:17]
Reactant: CN
Reactant: COC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Solvent: CO
Product: CNC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 56 %

Procedure:
To a methanol (39 mL) solution of dimethyl [benzyl(methyl)amino]propanedioate (Intermediate 1-2, 13 g), a 9 mol/L-methylamine-methanol solution (14 mL) was added at room temperature, followed by stirring the mixture for 26 hours at room temperature. The reaction mixture was concentrated under reduced pressure, whereafter ethyl acetate and water were added to the resulting residue to isolate the organic layer. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (hexane/ethyl acetate=50/50→chloroform/acetone=95/5) to obtain ({[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)amino}methyl)benzene (pale yellow oil) (7.1 g, 56%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][O:22][C:19](=[O:21])[CH3:20])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 60 %

Procedure:
To 38.7 g (0.1 mol, 1.0 eq.) of 4-octyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 5 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 17.6 g of 4-octyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 60.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: Cc1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C
Yield: 60 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1.Cl.[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C>[CH3:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[CH:11][C:2]1[N:3]2[N:14]=[N:15][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2nc(Cl)cnc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2c1ncc1nnnn12
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution was made of 0.5 g. of 2-chloro-5-methylquinoxaline, 10 ml. of 0.1N HCl and 0.6 g. of sodium azide in 35 ml. of denatured ethanol. The reaction mixture was stirred for 6 hours at reflux temperature. When the mixture was allowed to cool, the product, 6-methyltetrazolo[1,5-a]quinoxaline, crystallized in 91 percent yield and was separated by filtration. The product had a melting point of 160°-62° C., and was identified by nuclear magnetic resonance analysis and elemental microanalysis, the results of which were as follows.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([OH:11])=O)=[O:6])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
To a solution of (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]cyclohexanepropanoic acid (93 g., 343 mmole) in dry tetrahydrofuran (1 1.) was added a 20% molar excess of 1,1'-carbonyldiimidazole over a period of less than 10 minutes with very efficient stirring to keep the internal temperature below 30° . After stirring for 30 minutes, N,O-dimethylhydroxylamine hydrochloride (36.8 g., 377 mmole) was added, followed by triethylamine (38.2 g., 377 mmole). After stirring at room temperature for 4 hours, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The amber colored residue (100 g.) was dissolved in ether (900 ml.) and poured into 1N HCl (1 l.). The acidic aqueous phase was separated, further extracted with ether and the combined ethereal solutions were washed with water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4) to give (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]-N-methoxy-N-methylcyclohexane-propanamide as a colorless oil. [α]D =-12.9° (c=1, methanol). TLC (silica gel; 1:1, ethyl acetate:hexanes) Rf =0.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:26]C(OCC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[BrH:45].C(OCC)C>C(O)(=O)C>[BrH:45].[BrH:45].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH2:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1nnc(CNC(=O)[C@@H](N)Cc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 79 %

Procedure:
0.50 g of 5-chloro-2-[[(N-benzyloxycarbonyl-L-phenylalanyl)aminomethyl]-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone was treated with a 35% solution of hydrogen bromide in glacial acetic acid for 1 hour. Dry diethyl ether was then added and the separated solid was filtered off, washed with ether and dried in vacuo. The crude product was purified by precipitation from methanol/ethyl acetate. There was obtained 0.36 g (79%) of 5-chloro-2-[3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone dihydrobromide of melting point 164°-171° C (slow decomposition).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH:27]([NH2:30])([CH3:29])[CH3:28].CCOC(C)=O>C(Cl)Cl>[CH:27]([NH:30][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH3:29])[CH3:28]
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)c1ccc(Cc2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A stirred solution of 4-(2-oxo4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)-benzenesulfonyl chloride (Preparation 1, 17 mg, 42 μmol) in anhydrous CH2Cl2 (0.5 mL) was treated dropwise with an excess of i-PrNH2 (145 μL, 1680 μmol). After stirring at 20° C. for 10 min, the reaction mixture was submitted to column chromatography (EtOAc) to furnish the title compound (8 mg, 45%): δH (CD3OD)=1.00 (d, 6H), 3.35 (sept, 1H), 4.20 (s, 2H), 7.00 (s, 1H), 7.15–7.20 (m, 3H), 7.50 (dd, 1H), 7.60 (d, 1H), 7.80 (d, 2H); m/z (ES+)=466.1 [M+H+MeCN]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]([C:29]3[CH:31]=[CH:32][C:26]([S:23]([C:22]([F:34])([F:21])[F:33])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(-n2c(-c3ccc(Br)cc3)ccc2-c2ccc(Br)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a slurry of the product from Example 26E (0.60 g, 1.52 mmol) and 4-(trifluoromethylsulfonyl)aniline (0.51 g, 2.27 mmol) in toluene (12 mL) was added a 1N solution of titanium(IV) chloride (1.6 mL, 1.6 mmol) in toluene. The mixture was stirred overnight at room temperature and then heated to reflux for 3 hours. The cooled mixture was filtered and the solid residue was suspended in a mixture of water and diethyl ether. The solid was diluted with water and ether and stirred vigorously for 15 minutes. The mixture was filtered and then washed thoroughly with diethyl ether to give the title compound as a crude mixture that was used in subsequent reactions without further purification (0.60 g, 68% yield crude).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2].Cl.O1CCOCC1>CCO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1F
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(C#N)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Combined tert-butyl 2-(4-cyano-2-fluorophenyl)acetate (227.3 mg, 0.966 mmol) with EtOH (5 mL) and added a 4M hydrogen chloride solution in dioxane (0.121 mL, 0.483 mmol) and stirred in a heating block at 60° C. for 16 h. Then the reaction mixture was concentrated via rotary evaporation and re-constituted in EtOH (5 mL). An additional portion of a 4M hydrogen chloride solution in dioxane (17.61 mg, 0.483 mmol) was added to the vial and the mixture was stirred at 60° C. for an additional 1 h. The reaction mixture was then concentrated via rotary evaporation and dried in vacuo to give the title compound (198 mg, 99% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.27 (t, J=7.07 Hz, 3H) 3.72 (d, J=1.26 Hz, 2H) 4.19 (q, J=7.24 Hz, 2H) 7.36-7.40 (m, 1H) 7.40-7.43 (m, 1H) 7.43-7.46 (m, 1H). MS m/z [M+H]+ 208.0.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: COCCN
Product: COCCNc1cccc([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)c1

Procedure:
The title compound, MS: m/e=551.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and 2-methoxy ethylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[Br:14]Br>C(Cl)Cl>[Br:14][C:10]1[CH:11]=[CH:12][C:5]2[O:4][CH2:3][C:2]([CH3:13])([CH3:1])[CH2:8][O:7][C:6]=2[CH:9]=1
Reactant: CC1(C)COc2ccccc2OC1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)COc2ccc(Br)cc2OC1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
8.55 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine (see Example 10) were dissolved in 70 ml of methylene chloride (CH2Cl2) and treated at 0° C. under an Argon atmosphere with a solution of 8.0 g of Br2 in 30 ml of CH2Cl2. The mixture was warmed to room temperature and left to react for 1 hour. It was then poured on to ice and extracted with ether. Washing with NaHCO3 solution and water, drying and evaporation yielded 13.35 g of 7-bromo-3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine as a colorless oil which was 94.5% pure and which contained 4.7% of starting material; it was processed in the crude state.
Reaction SMILES: C(N(C)C(=O)[C@@H](N[C:18]([C:20]1[N:21]([CH3:43])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37]CCCC)=[CH:24][CH:23]=2)=[O:19])C1C=CC=CC=1)C1C=CC=CC=1.C[OH:47].O.[OH-].[Li+]>C1COCC1>[OH:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:30]([NH:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:43])[C:20]([C:18]([OH:47])=[O:19])=[CH:28]2)=[O:42]
Reactant: CO
Reactant: CCCCOc1ccccc1C(=O)Nc1ccc2c(c1)cc(C(=O)N[C@H](C(=O)N(C)Cc1ccccc1)c1ccccc1)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of step (a) (2.0 g, 5.26 mM) was dissolved in THF (30 mL), methanol (10 mL), and water (10 mL). The mixture was treated with lithium hydroxide (882 mg, 21.04 mM) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to 15 mL and the pH was adjusted to about 3.0 with 1 N HCl. The mixture was extracted 3 times with ethyl acetate (25 mL). The ethyl acetate fractions were combined, dried over MgSO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=2)[CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.C(N(C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH2:2]1
Reactant: COc1ccc(-c2cnc(OCC(=O)NCC3CCNC3)nc2)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2cnc(OCC(=O)NCC3CCN(Cc4ccc(Cl)c(Cl)c4)C3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution containing N-(pyrrolidin-3-(RS)-ylmethyl)-2-(5-(4-methoxyphenyl)pyrimidin-2-yloxy)acetamide (0.44 mmol) in dichloroethane (10 mL) was added to a solution of 3,4-dichlorobenzaldehyde (85 mg, 0.48 mmol, 1.1 equiv.) and diisopropylethylamine (0.35 mL, 2.0 mmol, 4.5 equiv.) in dichloroethane (5 mL). Excess Na(OAc)3BH (140 mg, 0.66 mmol, 1.5 equiv.) was added and the reaction mixture was stirred rapidly at room temperature overnight. The reaction mixture was quenched with methanol, concentrated and diluted with 1:1 methanol/dimethyl sulfoxide. The solution was then purified directly using preparative reverse phase chromatography to give, after treatment with 4 M hydrochloric acid in dioxane (1 mL) and concentration, N-[1-(3,4-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-2-[5-(4-methoxyphenyl)pyrimidin-2-yloxy]-acetamide HCl salt (96 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1>C1COCC1>[O:21]=[C:17]1[CH2:16][C:15]2[C:19](=[CH:20][C:12]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:23][CH:22]=3)=[O:11])=[CH:13][CH:14]=2)[NH:18]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A dry 100 mL flask was charged with acetyl chloride (0.408 g, 5.20 mmol) and THF (40 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The brown solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the N-[4-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide as a tan solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1.[OH-].[K+]>CN(C=O)C.O.[Pd]>[CH3:21][C:20]1[N:16]([C:11]2[CH:10]=[C:9]([C:3]3[C:4](=[O:8])[NH:5][N:6]=[CH:7][CH:2]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])[C:17]([CH3:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2c(Cl)cn[nH]c2=O)cc1-n1c(C)ccc1C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccn[nH]c2=O)cc1-n1c(C)ccc1C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a solution of 5-chloro-4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one (0.90 g, 2.87 mmol) and KOH (0.40 g, 7.17 mmol) in DMF (1.2 ml) and water (11 ml) was added 10% Pd/C (0.05 g). The mixture was hydrogenated in a Parr vessel at 4.14 BAR for 18 hours. Aqueous 10% KOH (15 ml) was added and the mixture was filtered. The filtrate was take to pH 1 with conc. HCl and extracted with DCM. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/1:1) gave 0.429 g (54%) of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2
Reactant: Cc1ccc2c(Br)c(Cl)ccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc2c(Br)c(Cl)cc([N+](=O)[O-])c2n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
5-Bromo-6-chloroquinaldine (40 g) was dissolved in 220 ml of concentrated sulfuric acid. After cooling to 0° C., a solution of 20.5 g of potassium nitrate in 60 ml of concentrated sulfuric acid was added dropwise to the resulting solution in 30 minutes followed by stirring at room temperature for 2.5 hours. The reaction mixture was poured into 1.5 l of ice water and crystals which formed were collected by filtration. The filtrate was rendered alkaline to give a small amount of solids which together with the former solids were recrystallized from isopropanol to give 42.3 g of 5-bromo-6-chloro-8-nitroquinaldine. m.p. 141°-142° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (486 mg, 87%).