Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: NCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.7 %

Procedure:
Triethylamine (18.9 g, 136 mmol) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) in N,N-dimethylformamide (100 mL). 4-Aminobutan-1-ol (11.1 g, 124. mmol) was added with a syringe and the reaction mixture was allowed to stir under a nitrogen atmosphere at ambient temperature for 17 hours. A portion (85 mL) of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (2×50 mL) then with brine (75 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a solid. This material was recrystallized from ethyl acetate/hexanes to provide 15.07 g of 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol as yellow powder. An additional 5.70 g was isolated from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:23]3[CH2:30][CH2:29][C:26]4([CH2:28][CH2:27]4)[C@H:25]([OH:31])[CH2:24]3)=[O:22])[C:14](=[O:32])[C@@H:13]2[CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCO>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:23]3[CH2:30][CH2:29][C:26]4([CH2:27][CH2:28]4)[C@H:25]([OH:31])[CH2:24]3)=[O:22])[C:14](=[O:32])[C@H:13]2[CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Yield: 27 %

Procedure:
The title compounds were prepared by chiral separation of (S)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (63% ds) on a Reprosil Chiral NR, (40% EtOH in n-heptane) to give 27% of (R)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 61) as off-white foam, MS: 488.19 (MH+, Cl) and 42% of (S)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 60) as off-white foam, MS: 488.19 (MH+, Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:17])N(OC)C)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][Mg]Cl>C1COCC1>[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:17])[CH3:18]
Reactant: C[Mg]Cl
Reactant: COC(=O)c1cc(Br)cc(C(=O)N(C)OC)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
The compound methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3 g, 7.6 mmol) was dissolved in dry THF (50 mL), solution was cooled to 0° C. and methylmagnesium chloride (3M in THF, 2.5 mL, 7.6 mmol)) was added dropwise. The reaction mixture was slowly allowed to come to room temperature and stirred further for 6 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution. The product was extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% EtOAc in petroleum ether) to get methyl 3-acetyl-5-bromobenzoate (0.95 g, yield 49%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (t, J=1.3 Hz, 1H), 8.37 (t, J=1.7 Hz, 1H), 8.28 (t, J=1.6 Hz, 1H), 3.97 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([NH2:21])=O)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]#[N:21])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C(N)=O)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C#N)c2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
3-(5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzamide (0.20 g, 0.48 mmol) was suspended in acetonitrile (4 mL). POCl3 (0.11 mL, 1.2 mmol) was added and the reaction stirred in a sealed tube at 70° C. for 4 hours. The solution was cooled and neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and concentrated. The crude material was triturated with ether/EtOAc and filtered. The solid was dried to give the title compound (0.065 g, 34%). 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 6.44 (bs, 1H), 7.58-7.68 (m, 3H), 7.83 (d, 1H), 7.92 (s, 1H), 8.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16](=O)[NH:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:28])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16]([Br:28])=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c2ccc(OCc3ccccc3)nc2n1-c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccccc1-n1c(Br)nc2ccc(OCc3ccccc3)nc21
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A solution of 5-(benzyloxy)-3-(2-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (244 mg, 0.728 mmol) and POBr3 (2.086 g, 7.28 mmol) in toluene (30 mL) was heated to 100° C. for 72 h in a 40 mL sealed scintillation vial. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO3 (200 mL) and the mixture was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (148 mg). LCMS m/z=398.0 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)=[O:9])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:25]=[CH:24][CH:23]=1)[CH:1]=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cccc(OCC(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-(2-(3-formylphenoxy)acetyl)piperazine-1-carboxylate (49)/(5.55 mmol) was taken in DCM and cooled to 0° C. when TFA (5 ml) was added drop wise and then stirred at rt for 16 h when TLC confirmed completion of reaction. The reaction mixture was concentrated and neutralized with satd NaHCO3 solution followed by extraction with DCM. The combined organic extracts was dried, concentrated and used directly for the next step (86%). LCMS: 98.12% (M++1).
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10]1.Cl>CO>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)nn(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 50-mL egg plant-type flask, aqueous 5 N sodium hydroxide solution (1.3 mL, 6.5 mmol) was added to a THF (5 mL)-methanol (5 mL) mixed solution of methyl 1-methyl-3-phenyl-1H-indazole-6-carboxylate (604 mg, 22 mmol), and stirred overnight at 60° C. With cooling with ice, aqueous 5 N hydrochloric acid solution (1.3 mL, 6.5 mmol) was added to the reaction solution, and concentrated to obtain a mixture of the title compound with salt, as a colorless solid.
Reaction SMILES: [Cl-].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[CH:10]2)C=CC=CC=1.[CH:29]1([CH2:35][CH2:36][O-:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na+]>>[NH:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][O:37][CH2:36][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:11]=[CH:10]1
Reactant: [O-]CCC1CCCCC1
Reactant: CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(CCCOCCC2CCCCC2)c[nH]1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propane chloride (see Example 63) and 15 mmol of sodium 2-cyclo-hexylethanolate are treated as described in Example 5.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][OH:24])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: OCc1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3CO)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-(hydroxymethyl)phenylboronic acid to give 478. MS (ESI+) 402.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41 (td, J=7.4, 1.1 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.02-5.83 (m, 1H), 5.16 (t, J=5.3 Hz, 1H), 4.56 (q, J=6.1 Hz, 4H), 4.45 (d, J=5.3 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Cl:56]CCl>CO.Cl>[ClH:56].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 0.5 h

Procedure:
5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxamide (A) (500 mg) was dissolved in a mixture of methanol (5 ml), dichloromethane (3 ml) and concentrated hydrochloric acid (0.7 ml) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was dissolved in a minimum of methanol. Ether was added to precipitate a solid which was collected by filtration. The solid was recrystallised from acetonitrile/methanol to give 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxamide hydrochloride (220 mg), m.p. 264° C. (dec); NMR (d6 -DMSO+d4 -acetic acid): 1.29(t, 3H), 1.39(t, 3H), 3.02(q, 2H), 3.42(q, 2H), 5.66(s, 2H), 7.1(d, 2H), 7.25(d, 2H), 7.45-7.75(complex m, 5H), 9.03(s, 1H); mass spectrum (+ve FAB, methanol/DMSO/NBA): 480 (M+H)+ ; microanalysis, found: C, 61.7; H, 4.9 ; N, 18.7%; C27H25N7O2HCl.0.5H2O requires: C, 61.7; H, 4.9; N, 18.6%.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cccnc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.19 min.; [M+H]+: 417.16 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][N:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:4][C:3]1=[O:22].C(N(CC)CC)C.[CH:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])=O>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:30]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([OH:37])=[O:36])[N:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[N:9]=[C:5]2[NH:4][C:3]1=[O:22]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (2.12 g) and triethylamine (0.8 ml) was added to a suspension of Resin bound 3-formylbenzoic acid in dimethylformamide (15 ml), and the mixture was shaken at 90° C. for 16 hours. The resin was filtered and washed (3 times) DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum to give the subtitle compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1ccc(F)cc1

Procedure:
172 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (105 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=O)[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1.B.C1COCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[CH2:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1Cc2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C1
Temperature: 25 °C

Procedure:
A solution of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 3A-1 (7 mg, 0.018 mmol) and BH3THF (166 ml, 166 mmol) was stirred at room temperature for 1 hour and at 50° C. for 17 hours. After the reaction mixture was cooled to room temperature, MeOH (5 ml) was added. The reaction mixture was heated under reflux for 2 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with 4 M HCl/dioxanes (1 ml) and concentrated under vacuum. The residue was dissolved in CH2Cl2 and hexanes were added to precipitate 8A-1 as a colorless solid (2 mg, 27%): +APCl MS (M+H) 372.5; 1H NMR (CD3OD): δ 7.59-7.43 (m, 4H), 7.38 (d, 2H), 7.20 (d, 2H), 4.80-4.65 (m, 2H), 3.91-3.82 (m, 1H), 3.68-3.55 (m, 2H), 1.52 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30]Br)=[O:26])([CH3:23])([CH3:22])[CH3:21].[I-].[K+]>CN(C)C=O.O>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-methoxysalicylate (11.48 g, 63 mmol) in dimethylformamide (30 mL) was added solid K2CO3 (13.06 g, 94.5 mmol), 1-tert-butoxycarbonylamino-3-bromopropane (22.5 g, 94.5 mmol), and freshly ground potassium iodide (1.5 g). The resulting slurry was placed under a nitrogen atmosphere and stirred for 2.5 days. The slurry was diluted with water (250 mL), washed with 1 N NaOH (2×250 mL), water (250 mL), and brine (250 mL), then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified on a preparative (Waters Prep LC™) 500 A chromatography apparatus using two silica columns and a hexanes through 1:1 hexanes:EtOAc gradient to provide methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (19.93 g, 93.3%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]#[C:19]/[CH:18]=[CH:17]/[CH2:16][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccc2ccccc12
Reactant: CC(C)(C)C#C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C#C/C=C/COCc1cccc2ccccc12
Reaction time: 1 h

Procedure:
5 g of 1-(Hydroxymethyl)naphthalin are in THF are treated at room temperature with 900 mg of 80% NaH (dissolved in mineral oil) and stirred until the evolution of gas ceases (ca. 1 hr.). A solution of 6.36 g of (E)-1-bromo-6,6-di-methyl-2-hepten-4-ine in DMF are added dropwise and the reaction mixture stirred overnight at room temperature.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(Nc2ccc(O)cc2)c(C(C)=O)c1
Yield: 80.3 %

Procedure:
1-[2-(4-Benzyloxyphenylamino)-5-methoxyphenyl]ethanone (9 g, 0.0258 mole) in 810 ml of ethanol and 90 ml of acetic acid was hydrogenated in a Parr apparatus in the presence of 900 mg of 10% palladium-on-carbon catalyst. After the required amount of hydrogen had been consumed, the reaction mixture was filtered and the solvents removed in vacuo. The residue was partitioned between ether and 10% aqueous sodium bicarbonate. The ether extracts were dried (MgSO4), the solvent removed, and the residue chromatographed on silica gel using chloroform as the eluant. There was obtained 5.33 g of 1-[2-(4-hydroxyphenylamino)-5-methoxyphenyl]ethanone, orange solid, m.p. 118°-119° C.
Reaction SMILES: [CH2:1]([CH:4]([S:8]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:17](NC(=O)CCC(N)=O)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[CH2:20]([O:19][C:17]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])(=[O:9])=[O:10])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)CCC(=O)NC(=O)OCc1ccccc1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 109.5 %

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 7.8 g (27 mmole) 3-[(1-propylbutyl)sulfonyl]alanine and 7.4 g (30 mmole) N-Cbz succinamide in 100 ml methylene chloride. The reaction was cooled to 0° C., and 6.9 g NMK was added dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours at which point HPLC analysis indicated complete reaction. The reaction was concentrated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 11.4 g of N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine that was used without further purification. M+H=386.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:1]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:17][CH2:16]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A solution of propargyl bromide (0.766 g, 6.44 mmol) in acetonitrile (25 mL) was added with 1-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) and potassium carbonate (1.11 g, 8.03 mmol), and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (1.01 g, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](O)[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:25])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc(O)c2ccccc2c1-c1ccccc1
Product: CCOC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 1-hydroxy-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester (1.17 g, 4 mmol; can be obtained according to A. Marsili et al., Ann. Chim. (Rome), 1962, 52, 112-120), and concentrated POCl3 (10 ml) was refluxed with stirring for 1 h. Then the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 ml), concentrated aqueous NaHCO3 solution (40 ml) was added and the mixture was stirred vigorously for 1 h. Subsequently, the organic phase was separated, dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (1.20 g); MS-(+)-ion: M+1=312.0.