Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[S:19][C:20]2[C:21]([N:26]=1)=[N:22][CH:23]=[CH:24][CH:25]=2.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[S:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:26]=[C:18]1[O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1
Reactant: Clc1nc2ncccc2s1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: OCCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (1.16 g, 8.4 mmol, 1.2 equiv.) and K2CO3 (1.94 g, 14.06 mmol, 2 equiv.) in CH3CN (12 mL) was added 2-chloro[1,3]thiazolo[4,5-b]pyridine (1.2 g, 7.03 mmol, 1 equiv.). The reaction mixture was heated to 80° C. and stirred for 16 h. Satd. aq. Na2CO3 (25 mL) was added to the reaction mixture, which was then extracted with isopropyl acetate (2×30 mL). The combined organic layers were dried, filtered, and concentrated. The crude material was purified by column chromatography (50% EtOAc/hexanes-100% EtOAc), which afforded the title compound as a light orange oil (74%). MS (ESI): mass calcd. for C14H12N2O2S, 272.32; m/z found, 273.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.37-7.29 (m, 4H), 7.22 (dd, J=7.9, 4.8, 1H), 3.88 (dd, J=12.5, 6.5, 2H), 2.91 (t, J=6.6, 2H), 2.03 (t, J=5.9, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[CH2:17][CH2:16]2)[C:4]=1[CH3:21]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: COc1c(C)c(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 23.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(trifluoromethoxy)benzene (542 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 160 mg (yield 16%). Melting point was 162 to 164° C. (hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14](C(=O)C(F)(F)F)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CO>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 93.6 %

Procedure:
A mixture of 1-{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2yl}-2,2,2-trifluoroethanone (1.088 g, 2.1 mmol) and anhydrous K2CO3 (2.861 g, 20.7 mmol) in MeOH (150 ml) was refluxed under N2 for 18 hr, then evaporated in vacuo to a yellow residue. This was dissolved in H2O (25 ml) and extracted with EtOAc (3×50 ml). The combined extracts were dried over MgSO4, and concentrated in vacuo to give 0.881 g of crude yellow product. Purification by flash chromatography, eluting first with EtOAc:MeOH (8:2), then with EtOAc:MeOH (1:1) gave 0.842 g (95% yield) of yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[O:14][C:15]([CH3:19])=[CH:16][C:17]=1[SH:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:12][C:13]1[O:14][C:15]([CH3:19])=[CH:16][C:17]=1[S:18][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cc(S)c(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2cc(C)oc2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 113.6 %

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (2.00 g, 11.7 mmol), 2,5-Dimethyl-furan-3-thiol (1.50 g, 11.7 mmol), and K2CO3 (3.233 g, 23.4 mmol) heated in DMF at 100° C. for 4 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (3.5 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c[nH]cc1C
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of ethyl 4-methyl-3-pyrrolecarboxylate (1.57 g, 10 mmol) in anhyd THF (30 mL) cooled to −78° C. was added NBS (1.9 g, 10 mmol). After stirring 1 h at −30° C., the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc-Hex (0:100 to 30:70), to yield ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0, 86%) as a white solid. 1H-NMR (CDCl3): δ 8.54 (1H, brs), 7.38 (1H, d), 4.27 (2H, q), 2.24 (3H, s), 1.33 (3H, t). To a solution of ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0 g, 8.6 mmol) in anhyd DMF (30 mL) at 0° C. was added portionwise NaH (60% in mineral oil, 705 mg, 17.6 mmol) under nitrogen. After 1 h at ambient temperature, the reaction mixture was charged with iodomethane (1.5 mL, 24 mmol) and then stirred at ambient temperature overnight. The reaction mixture was quenched by cautious addition of water and then extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with EtOAc-Hex (0:100 to 20:80), to provide the title compound (1.64 g, 78%) as a white solid. 1H-NMR (CDCl3): δ 7.33 (1H, s), 4.25 (2H, q), 3.58 (3H, s), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: [Si:1]([N:8]1[C@H:11]([C:12]#[CH:13])[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[Si:1]([N:8]1[C@H:11]([C:12]2[CH:13]=[N:21][NH:20][N:19]=2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1c1cn[nH]n1
Temperature: 80 °C
Yield: 8.3 %

Procedure:
A mixture of 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (3.0 g) and trimethylsilylazide (15 ml) was heated at 80° C. for 20 hours. The reaction mixture was allowed to room temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane ethyl acetate=(1:1) to give 1-tert-butyldimethylsilyl-4(S)-(2H-1,2,3-triazol-4-yl)-2-azetidinone (0.3 g, 8.3%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:10]=1.[OH-].[Na+]>CO.O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:10]=1
Reactant: COC(=O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Yield: 46 %

Procedure:
A solution of methyl 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (1.37 g; 4 mmol) in methanol (20 ml) was treated at reflux for 4 hours with a solution of sodium hydroxide (0.32 g; 8 mmol) in water (24 ml). After evaporation to dryness the residue was acidified at pH 6 with 12N HCl. The resulting solid was triturated with water and subsequently with ether to give 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid. Yield: 46%
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O1CCOCC1>O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[C:43]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[CH:12]=[N:13][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)[C:15]=3[CH3:16])=[O:10])=[CH:4][CH:3]=2)[CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Br)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 94.9 %

Procedure:
To N-(6-bromopyridin-3-yl)-5-methyl-1-[5-(tri fluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.0 g), cesium carbonate (6.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (287 mg), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2.28 g) were added 1,4-dioxane (26 ml) and water (7 ml), and stirred at 110° C. for 6.5 hours. To the reaction solution was added water, and the obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.53 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:19].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)cc(OC)c2ccc(F)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(=O)n(CC=O)c2cc(F)ccc12
Reaction time: 5 h
Yield: 93.2 %

Procedure:
A solution of 7-fluoro-4-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinolinone (0.386 g, 1.66 mmol), sodium periodate (0.83 g, 3.7 mmol) and osmium tetroxide (1.7 ml, 4% in water) in 1,4-dioxane (15 ml) containing water (3 ml) was stirred for 5 h. The mixture was separated between dichloromethane and water. The organics were isolated, dried and concentrated to provide the title compound (0.364 g, 93%).
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].Cl>O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][OH:4])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12

Procedure:
In 100 ml of water is suspended 10 g of 7-aminocephalosporanic acid (briefly, 7-ACA), and with ice-cooling and stirring, 2N-aqueous sodium hydroxide solution is added gradually to maintain the pH at 12.5 to 13.4. After about 2 hours of stirring, the reaction mixture is assayed by TLC and after confirming the disappearance of the starting material (7-ACA), the reaction mixture is adjusted to pH 3.4 with 4N-hydrochloric acid. The crystals that separate out are collected by filtration, washed with water and acetone, and dried in vacuo over phosphorus pentoxide to give 5.4 g light yellow crystals of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2nc(C3CCCC3)ccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc2c(c1)CCC(C1CCCC1)N2
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 2-cyclopentylquinoline (7.95 g, 40.3 mmol) and nickel (II) chloride hexahydrate (1.63 g, 6.85 mmol) in methanol (120 ml) cooled in an ice/methanol bath was added sodium borohydride (6.1 g, 161.2 mmol) portionwise over 1.5 h. The cooling bath was removed and the reaction stirred for a further 30 minutes. The methanol was then removed in vacuo. To the resulting black precipitate was added 2 M hydrochloric acid (100 ml) and then basified with 10 M potassium hydroxide. The mixture was poured into a separating funnel and extracted with ether (4×200 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give 2-cyclopentyl-1,2,3,4-tetrahydroquinoline (7.45 g, 37.1 mmol) as a light brown oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>O>[CH2:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: Nc1cccc(F)n1
Reactant: CCC1CCCN1
Solvent: O
Product: CCC1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 66.8 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2-ethylpyrrolidine (0.664 g, 6.7 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:30) to afford 6-(2-ethylpyrrolidin-1-yl)pyridin-2-amine (0.57 g, 67%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.100 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[CH2:23]=[O:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(#N)C>[OH:10][C:5]1[C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]=[O:24]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: C=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cccc(OC(F)(F)F)c1O
Reaction time: 120 h
Yield: 41.3 %

Procedure:
A solution of 2-trifluoromethoxyphenol (5.13 g, 28.8 mmol) in anhydrous acetonitrile (150 mL) in oven-dried glassware was treated with triethylamine (15.0 mL, 108 mmol) and MgCl2 (4.11 g, 43.2 mmol) which had been dried under vacuum with heating. Paraformaldehyde (5.18 g, 172 mmol), which had been dried under vacuum with P2O5, was then added and the solution was heated to reflux. After 5 days, the reaction was quenched with 1 N HCl (200 mL). The mixture was extracted using Et2O (2×100 mL). The combined organics were washed with brine (2×150 mL), dried (Na2SO4) and concentrated to a yellow solid. Purification by column chromatography (silica gel, 98:2 to 95:5 hexanes/EtOAc) gave the title compound (2.45 g, 41%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.75-7.65 (m, 2H), 7.08 (t, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][CH3:12])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](OC)=[O:25])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]2[C:5]([CH:6]=[C:23]([C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[C:24](=[O:25])[N:11]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNc1c(C=O)cnc(Cl)c1C
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)c(C)c3n(C)c2=O)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 6-chloro-5-methyl-4-(methylamino)nicotinaldehyde (3.11 g, 16.8 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.25 g, 20.2 mmol) and potassium carbonate (2.8 g, 20.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at 105° C. overnight. LCMS monitored the reaction was completed. The reaction mixture was cooled to RT and quenched by water. The precipitate was filtered and dried to get the title compound (5.5 g, crude) as a yellow solid. MS (ES+) C18H17ClN2O3 requires: 344, 346. Found: 345, 347 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:32])[CH:19]=[CH:20][C:21]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH:15]=[CH:16][CH:17]=1)=O)(C)(C)C.[ClH:33].C(OCC)C>O1CCOCC1>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:32])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)[CH:15]=[CH:16][CH:17]=1.[ClH:33]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)C=Cc2ccc(OCC(=O)O)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCOc1cccc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3.3 h

Procedure:
A mixture of N-BOC amine 1d (0.20 g, 0.45 mmol) and 4 M hydrogen chloride in 1,4-dioxane (1.0 mL) was stirred at room temperature under a CaSO4 drying tube for 3.3 h. Dilution with diethyl ether produced a precipitate, which was collected by filtration and dried to give a yellow powder (0.17 g). 1H-NMR(300 MHz, d6 -DMSO): 13.1 (br, 1H), 8.09 (br, 3H), 7.87-7.82 (m, 3H), 7.78 and 7.74 (AB quartet, 2H, J=15 Hz), 7.63 (s, 1H), 7.53 (t, 1H, J=8 Hz), 7.28 (dd, 1H, J=8,2 Hz), 7.01 (d, 2H, J=9Hz), 4.78 (s, 2H), 4.30-4.26 (m, 2H), 3.36 (br, 2H). HR-MS: Calc. 342.1341, Found 342.1349. IR(KBr) cm-1 3398, 1744, 1656.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][OH:33])[C:6]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]=2[CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCOS(C)(=O)=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in pyridine (5 ml) is added with stirring methanesulfonyl chloride (0.11 ml) under ice-cooling, and the mixture is stirred at room temperature for two hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as colorless amorphous.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]2[CH:13]1[CH2:12][N:11]([CH3:26])[CH2:10]2)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2CNCC21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CC2C(C1)N(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Added to a solution of 29 mg of the thus obtained 2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]-nonane in acetonitrile (0.7 ml) were 0.038 ml (0.51 mmol) of a 37% aqueous solution of formaldehyde and 9.4 mg (0.15 mmol) of sodium cyanoborohydride. After the mixture was stirred for 1 hour and 20 minutes at room temperature, acetic acid was added until the reaction mixture reached pH 4, and the resultant mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2.[NH2:17][CH2:18][CH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2
Reactant: NCCO
Reactant: FC(F)(F)c1ccc2c(Cl)c(Br)cnc2c1
Solvent: O
Solvent: CC(C)O
Product: OCCNc1c(Br)cnc2cc(C(F)(F)F)ccc12

Procedure:
A solution of 12.4 g of 3-bromo-4-chloro-7-trifluoromethylquinoline and 6.1 g of 2-aminoethanol in 30 ml of isopropanol was heated at reflux for 4 hours. The mixture was cooled and diluted with 150 ml of water and the solid was collected and recrystallized from isopropanol. The yield was 8.2 g, mp 140°-141° C.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C@H:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[CH3:27][CH:26]([CH3:28])[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@@H:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:8][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:17][CH2:16]2)[CH:19]=1)=[O:29]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CCCS(=O)(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 1-propanesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:38])[CH2:23][NH:24][S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26]>>[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[S:25]([NH:24][CH2:23][C:22]([NH:21][CH2:20][CH2:19][NH:18][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])=[O:38])(=[O:27])=[O:26]
Reactant: NCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCCNC(=O)C1CCN(c2ccncc2)CC1
Yield: 49 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride hydrochloride salt was reacted with N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamide hydrochloride salt to give 2-(2-naphthalenesulphonamido)-N-{2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 49% yield, m.p. 107-109° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1ccc(F)c(F)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3,4-difluorophenol: 1H-NMR (CDCl3) δ 7.92 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.7, 2.8 Hz), 7.11 (1H, q, J=9.1 Hz), 6.95 (1H, d, J=8.7 Hz), 6.85–6.72 (1H, m), 6.71–6.59 (1H, m), 3.83 (3H, s).