Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.O[CH:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1>>[F:11][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(F)CC2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Deoxo-Fluor® was added to a solution of 1,1-dimethylethyl 4-hydroxy-1,4′-bipiperidine-1′-carboxylate (0.500 g, 1.76 mmol) dropwise at −78° C. The mixture was maintained at −78° C. for 30 min before it was warmed to room temperature and stirred for 2 h. The mixture was washed with saturated aqueous sodium bicarbonate. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via column chromatography (1:200 methanol/methylene chloride) to afford 1,1-dimethylethyl 4-fluoro-1,4′-bipiperidine-1′-carboxylate (0.300 g, 60% yield) as a colorless oil.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[NH2:7].[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20].O>C1(C)C=CC=CC=1>[CH3:14][NH:7][C@H:6]([C:5]([O-:4])=[O:13])[CH2:8][CH2:9][C:10]([O-:12])=[O:11].[CH3:3][NH:20][C@H:19]([C:21]([O-:23])=[O:22])[CH2:18][CH2:17][C:16]([O-:15])=[O:24].[Zn+2:2].[Zn+2:2]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: COC(=O)[C@@H](N)CCC(=O)[O-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: CN[C@@H](CCC(=O)[O-])C(=O)[O-]

Procedure:
Zinc bis(methyl-glutamate) was prepared by reacting 12.2 grams of zinc oxide and 48.3 grams of monomethyl-glutamate also known in the art as glutamic acid 5-methyl ester as named in C.A.S. Reg. No. 1499-55-4, pg. 458 Aldrich Catalog Handbook 1979-80 in 500 ml of toluene in a one-liter, one-neck round-bottom flask equipped with a magnetic stirrer, reflux condenser and Dean-Stark Trap. The mixture was refluxed to obtain a theoretical amount of water in the Dean-Stark Trap. A white powdery product was recovered by filtration.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][NH:22][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:26][CH2:25]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: NCC1CC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC2CC2)s1
Yield: 52 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using aminomethylcyclopropane instead of rac-2-amino-1-butanol, to the title compound (93 mg, 52%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=360.2 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH:13]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:4]
Reactant: CC(=O)OCCc1ncccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Cc2ncccc2N1
Yield: 32.6 %

Procedure:
A mixture of 2-(3-nitro-2-pyridyl)ethyl acetate (10.1, 48 mmol), tin(II)chloride dihydrate (54.3 g, 240 mmol) and ethyl acetate was stirred and heated at reflux for 5 hours. The reaction mixture was allowed to cool overnight, filtered through diatomaceous earth and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography using increasingly polar solvent mixtures starting with methylene chloride and ending with methylene chloride/methanol (10/1). Removal of the solvent by evaporation gave 4-azaoxindole (2.1 g, 33%).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5].ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+].O>C1COCC1>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:9]([O:15][C:10](=[O:25])[NH:11][C:12]2=[CH:13][CH:14]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
8.13 g of compound 15 (37.5 mmole) was dissolved in 145 ml THF. This solution was added dropwise to a solution of 12.9 g m-chloro-perbenzoic acid (74.8 mmole) in 55 ml THF and stirred overnight. To the reaction mixture 150 ml saturated sodiumbicarbonate and 500 ml water were added. The resulting suspension was extracted three times with 250 ml ethyl acetate. After evaporation compound 16 was obtained as a white solid (7.4 g, 84% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[F:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccc(C)cc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(F)cc(-c3cc(C)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.77 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 197-199° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Br[CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(=O)OCCBr
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CC(=O)OCCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in example 15 using 2-bromoethylacetate. The final product was obtained in 21% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH2:18][O:19][CH2:20][C:21]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:17]=2)[N:14]([CH:40]2[CH2:42][CH2:41]2)[N:13]=[CH:12]3)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:40]1([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:17][C:16]=3[CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:12]=[N:13]2)[CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cnn(C4CC4)c23)(c2ccccc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cnn(C4CC4)c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-1-cyclopropyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (12.8 mg, 0.2 mmol) and formalin (152 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 23 mg (95%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.71-7.73 (m, 2H), 7.65-7.67 (m, 2H), 7.40 (m, 1H), 7.24-7.30 (m, 4H), 7.16-7.19 (m, 1H), 4.93 (s, 2H), 3.49-3.52 (m, 1H), 3.46 (s, 2H), 2.51-253 (m, 2H), 2.16 (s, 3H), 2.12-2.22 (m, 4H), 1.91-1.96 (m, 2H), 1.21-1.24 (m, 2H), 0.88-0.92 (m, 2H), 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 145.8 139.1, 133.0, 132.7, 131.9, 128.3, 127.8, 127.3, 127.1, 126.5, 126.1, 122.3, 119.6, 119.1, 110.6, 70.9, 52.0, 50.8, 46.3, 40.8, 32.7, 32.1, 8.2. Mass spec.: 477.41 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH3:19])[C:12](=[O:20])[N:11]([CH2:21][CH3:22])[C:10]=2[N:9]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:28])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH3:19])[C:12](=[O:20])[N:11]([CH2:21][CH3:22])[C:10]=2[N:9]=1
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CC)c1=O
Yield: 67.4 %

Procedure:
Compound 64 (1.20 g, 3.24 mmol) obtained in Example 7 was dissolved in 25 ml of dimethylformamide. To the solution were added 1.12 g (8.10 mmol) of potassium carbonate and subsequently 0.40 ml (6.49 mmol) of methyl iodide, and the resultant mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from isopropanol to give 840 mg (yield 68%) of Compound 65 as pale yellow needles.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([CH:21]=O)[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:17]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(OCC)=O)C>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19](/[CH:21]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:17]2)=[CH:30][CH:31]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Sodium hydride (60%, oily, 1.10 g) was added to a solution of 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (9.66 g) and ethyl diethylphosphonoacetate (5.46 ml) in N,N-dimethylformamide (150 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. Ice water was poured into the reaction mixture, and the resulting crystals were collected by filtration. After drying, recrystallization from ethyl acetate-hexane gave ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]propenoate (10.60 g, yield: 93%). Melting point: 113–114° C.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22]O)[CH:17]=[CH:18][CH:19]=2)[N:7]=1.B(Br)(Br)[Br:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(=O)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][Br:31])[CH:15]=2)[N:7]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(Br)c(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)c(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 3-[3-({4-[(2-bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}amino)phenyl]propan-1-ol (3.0 g, 6.3 mmol) in methylene chloride (40 mL) was added slowly a solution of boron tribromide in methylene chloride (31 mL, 31 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred over the weekend. The resultant mixture was cooled in dry ice when Na2CO3 (saturated aqueous solution) was added. The mixture was filtered and the solid collected was triturated with EtOAc, followed by washing with cold water to give the desired product (3.0 grams, 91%) as an off-white powder. LCMS for C20H19Br2ClN4O (M+H)+: m/z=524.8, 526.8, 528.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH:13]=O)[CH2:6]2.[CH3:15][O:16][C:17]1[C:33]([O:34][CH3:35])=[CH:32][C:20]2[CH2:21][C:22](=[O:31])[N:23]([CH2:26][CH2:27][CH2:28][NH:29][CH3:30])[CH:24]=[CH:25][C:19]=2[CH:18]=1>>[CH3:30][N:29]([CH2:13][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6]1)[CH2:28][CH2:27][CH2:26][N:23]1[C:22](=[O:31])[CH2:21][C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:33]([O:34][CH3:35])[CH:32]=2)[CH2:25][CH2:24]1
Reactant: COc1cc2c(cc1OC)[C@@H](C=O)C2
Reactant: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 7, starting from (75)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde and 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3-dihydro-2H-3-benzazepin-2-one, a compound is obtained which is hydrogenated by following the procedure described in patent specification EP 0 534 859 (Example 1, Step D) to yield ivabradine base, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OCc1cccnc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)ccc1OCc1cccnc1
Reaction time: 12 h

Procedure:
To a stirred, cooled (about 0° C.) solution of 1,4-Difluoro-2-nitro-benzene (3.0 mmol) and 3-pyridylcarbinol (3.1 mmol) in tetrahydrofuran (8 mL) was added lithium bis(trimethylsilyl)amide (3.2 mmol; 3.2 mL of a 1.0 M solution in tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4) and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:25]2[C:26]([N:45]([CH3:50])[S:46]([CH3:49])(=[O:48])=[O:47])=[CH:27][C:28]3[O:32][C:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[C:30]([C:40]([NH:42][CH3:43])=[O:41])[C:29]=3[CH:44]=2)=[N:13][C:14]=1[C:15]1[NH:24][C:18]2=[CH:19][N:20]=[CH:21][C:22]([F:23])=[C:17]2[CH:16]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[F:23][C:22]1[CH:21]=[N:20][CH:19]=[C:18]2[NH:24][C:15]([C:14]3[N:13]=[C:12]([C:25]4[C:26]([N:45]([CH3:50])[S:46]([CH3:49])(=[O:47])=[O:48])=[CH:27][C:28]5[O:32][C:31]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)=[C:30]([C:40]([NH:42][CH3:43])=[O:41])[C:29]=5[CH:44]=4)[CH:11]=[CH:10][C:9]=3[OH:8])=[CH:16][C:17]=12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Yield: 90.4 %

Procedure:
To a degassed solution of 5-(5-(benzyloxy)-6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.22 mmol) was dissolved in THF (5 mL) and charged with 10% palladium on carbon (0.1 g). The mixture was hydrogenated at room temperature under hydrogen pressure for 4 hours. The reaction mixture was filtered and the filtrate was extract with EtOAc and washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC to provide 5-(6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (120 mg, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 12.00 (s, 1H), 11.17 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.01 (t, J=6.0 Hz, 3H), 7.91 (s, 1H), 7.52 (s, 2H), 7.41˜7.35 (m, 3H), 3.19 (s, 3H), 2.95 (s, 3H), 2.80 (d, J=4.0 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.S(=O)(=O)(O)O>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18](=[O:20])[CH:19]=[CH:24][NH:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-ethanone (24.95 g) was dissolved in tetrahydrofuran (450 ml), and sodium methoxide (24.87 g) was added to the solution. The mixture was stirred at room temperature for one hr. Ethyl formate (37.07 ml) was then added thereto, and the mixture was stirred at room temperature for 2 hr. Water (150 ml) was then added thereto, and the mixture was stirred overnight. The reaction solution was adjusted to pH 4 by the addition of concentrated sulfuric acid at 0° C. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (10/1) to give 17.16 g (yield 66%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]=[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[NH2:9]
Reactant: Cc1cccc(C#N)n1
Reactant: CNN
Solvent: CCO
Product: CNN=C(N)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
6-Methylpyridine-2-carbonitrile (45.3 g, 0.384 mol) and methylhydrazine (94 mL, 5.30 mol) were mixed with ethanol (200 mL). The mixture was stirred at room temperature overnight, and then an additional portion (18 mL, 1.00 mol) of methylhydrazine was added, and the mixture was stirred for a further 16 h. The mixture was then evaporated to give 58.0 g of crude N′,6-dimethylpyridine-2-carbohydrazonamide (˜92% yield), which was used for the next stage of the synthesis without additional purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[O:42]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:37][NH:43][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NCc1ccco1)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 96.9 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCC(CC3CCN(C(C)C)CC3)CC2)cn1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.50 g), methyl 5-chloro-2-pyrazinecarboxylate (0.575 g) and potassium carbonate (0.615 g) were dissolved in acetonitrile (5 ml) and heated at 120° C. for 5 min in the microwave reactor. The crude mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). The basic fractions were evaporated to give the title compound (E2) as a yellow crystalline solid (0.825 g). MS electrospray (+ion) 361 (MH+)