Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>CN(C)C=O>[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:2])=[O:36]
Reactant: OCCCCCCCCOCc1ccc(F)c(F)c1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Reaction time: 16 h
Yield: 60.8 %

Procedure:
Pyridinium dichromate (1.23 g, 3.27 mmol) was added at 0° C. to a solution of 8-(3,4-difluoro-benzyloxy)-octan-1-ol (254 mg, 0.93 mmol) in N,N-dimethylform-amide (2 mL). The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-[ethyl acetate/formic acid 100:1] gradient) afforded 8-(3,4-difluoro-benzyloxy)-octanoic acid (162 mg, 61%). Colorless oil, m/e=285.1 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][OH:21]>>[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:21][CH2:20][CH3:19])=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][OH:21]
Reactant: CN=C=O
Agent: OCC#CC#CCO
Agent: OCCC#CC#CCCO
Product: CCOC(=O)NC

Procedure:
The limitation in this process is that the total number of diols and isocyanates or diols and organic sulfonic acid agents is at least three, thereby resulting in a co-crystallized composition directly recoverable from the reaction mixture. For example, methylisocyanate can be reacted with a mixture of 2,4-hexadiyn-1,6-diol and 3,5-octadiyne-1,8-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane) and (2) 3,5-octadiyn-1,8-diol bis(methylurethane). Similarly, methylisocyanate and ethylisocyanate can be reacted with 2,4-hexadiyn-1,6-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane), (2) 2,4-hexadiyn-1,6-diol bis(ethylurethane) and (3) 2,4-hexadiyn-1-ol-methylurethane-6-ol-ethylurethane.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[CH:57]=[CH:56][C:55]5[C:51](=[CH:52][N:53]([CH3:58])[N:54]=5)[C:50]=4[O:59][C:60]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[CH:57]=[CH:56][C:55]5[C:51](=[CH:52][N:53]([CH3:58])[N:54]=5)[C:50]=4[O:59][C:60]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[CH:43][CH:42]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cn1cc2c(ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc32)n1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1cc2c(ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc32)n1
Yield: 89 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-methyl-4-oxo-2-phenyl-4,8-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (15 mg, 89%). 1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.82 (d, J=9.4 Hz, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.49-7.40 (m, 5H), 7.39-7.33 (m, 2H), 7.25-7.21 (m, 2H), 4.23 (s, 3H), 2.51-2.42 (m, 2H), 2.37-2.28 (m, 2H), 2.13-2.03 (m, 1H), 1.77-1.64 (m, 1H). LCMS (Method E): RT=3.13 min, [M+H]+=422.
Reaction SMILES: C(S)C.[Na].[O:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C>CN(C=O)C>[O:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]
Reactant: COc1ccccc1-n1ccccc1=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=c1ccccn1-c1ccccc1O
Temperature: 100 °C

Procedure:
Sodium ethanethiol (0.108 g, 1.29 mmol) was added to a solution of 2-(2-oxo-2H-pyridin-1-yl)-anisole (0.100 g, 0.497 mmol) in DMF (2 mL), and the reaction mixture was heated at 100° C. for 3 hr. The reaction mixture was partitioned between CHCl3 and saturated aqueous ammonium chloride and treated with 8N HCl (pH=1). The organic layer was separated, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and taken up in EtOAc, then extracted with 2% NaOH solution. The aqueous basic layer was acidified with 10% HCl solution, then extracted with EtOAc, the organic layer washed with brine, dried (Na2SO4), filtered, and concentrated to give the desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:33])=[CH:12][C:11]=1[F:34])=O)(C)(C)C.[ClH:35].O1CCOCC1>C(#N)C>[ClH:35].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:28][CH2:29]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:33])=[CH:12][C:11]=1[F:34]
Reactant: Cc1c(-c2ccc(CNC(=O)OC(C)(C)C)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1c(-c2ccc(CN)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 4 h

Procedure:
8-(4-((tert-Butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (24 mg, 0.051 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed affording after filtration the title compound EXAMPLE 49 as a yellow solid (17.7 mg, 86%). ESI-MS m/z: 453 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCN1CCCC1COc1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCN1CCCC1COc1ccc(NS(=O)(=O)CC)cc1

Procedure:
React 4-[(1-butyl-2-pyrrolidinyl)methoxy]benzeneamine with ethanesulfonyl chloride in pyridine in a manner similar to Example 16 to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[S:16][C:15]=2[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([S:19]([N:8]3[CH2:7][CH2:6][NH:5][CH:4]([CH2:2][CH3:3])[CH2:9]3)(=[O:21])=[O:20])[S:16][C:15]=2[CH:23]=1
Reactant: CCC1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a methylene chloride solution (30 ml) of 2-ethylpiperazine hydrochloride (307 mg) was added (6-chlorobenzo[b]thien-2-yl)sulfonyl chloride (438 mg) and triethylamine (498 mg). The resulting mixture was stirred at room temperature for 26 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:20), whereby the title compound (255 mg) was obtained as a pale yellow oil. MS (FAB) m/z: 345 [(M+H)+, Cl35], 347 [(M+H)+, Cl37]. 1H-NMR (CDCl3) δ: 0.95(3H,t,J=7.8 Hz), 1.24-1.46(2H,m), 2.16(1H,t,J=10.7 Hz), 2.54(1H,dt,J=2.9,11.2 Hz), 2.65-2.75(1H,m), 2.95(1H,dt,J=2.9,11.2 Hz), 3.04-3.10(1H,m), 3.65-3.72(2H,m), 7.43(1H,dd,J=8.8,2.0 Hz), 7.75(1H,s), 7.81(1H,d,J=8.8 Hz), 7.86(1H,s).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[CH:23])=[N:20][CH:21]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=3)=[N:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Nc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 4-iodoaniline (732 mg, 3.28 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (700 mg, 3.28 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[N:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=1>CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:19](/[CH:22]=[C:28]2/[CH:29]=[N:24][CH2:25][CH2:26][CH2:27]/2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: C1=NCCCC1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(/C=C2/C=NCCC2)ccc1Cl

Procedure:
2-Chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.152 g, Example 31a) and 2,3,4,5-tetrahydropyridine trimer (Org. Synth., 1977, Vol.56, 118-122, 0.038 g) were dissolved in methanol (3 ml) and heated at reflux for 4 h. The mixture was evaporated under reduced pressure then purified by HPLC eluting a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a white foam (0.046 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[O:44][N:43]=[C:42]([C:45]([CH3:51])([CH3:50])[C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[O:38])=[C:32]([F:52])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]3[O:44][N:43]=[C:42]([C:45]([CH3:50])([CH3:51])[C:46]([F:49])([F:48])[F:47])[CH:41]=3)=[O:38])=[C:32]([F:52])[CH:31]=2)[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)on1)C(F)(F)F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)no3)c(F)c2)cnc1OCc1ccc(OC)cc1
Yield: 23.3 %

Procedure:
To a mixture of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 0.519 mmol) and 2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (212 mg, 0.519 mmol) in water (1 mL) and 1,4-dioxane (3 mL) was added Cs2CO3 (338 mg, 1.038 mmol) and PdCl2(dppf) (38.0 mg, 0.052 mmol) under N2. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 20 min. The mixture was then concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield a off white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (100 mg, 0.121 mmol, 23% yield): 1H NMR (400 MHz, CD3OD) δ 7.42-7.28 (m, 5H), 7.27-7.21 (m, 2H), 6.92-6.84 (m, 2H), 6.36 (s, 1H), 4.50 (s, 2H), 4.11 (d, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.79-3.75 (m, 3H), 1.52 (s, 6H), 1.45 (t, J=7.2 Hz, 3H); ES-LCMS m/z 468 (M−119).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:14]([CH3:13])[CH3:25])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCCNCCCN(C)C
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCCN(C)C)CCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(3-(dimethylamino)propyl)-N′,N′-dimethylpropane-1,3-diamine as starting materials to give the aimed compound.
Reaction SMILES: Cl.CC1(C)[O:7][C@H:6]([CH2:8][N:9]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[C:16]3[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]3=[O:25])=[CH:10]2)[CH2:5][O:4]1.O>C(#N)C>[OH:7][C@@H:6]([CH2:5][OH:4])[CH2:8][N:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]2=[O:25])=[CH:10]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H]3COC(C)(C)O3)cc2n(C)c1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (2 M in diethyl ether) (92 ml, 185 mmol) was added dropwise to a solution of (R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (7.15 g, 18.46 mmol) and water (6.65 g, 369 mmol) in acetonitrile (35.1 mL). The mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction mixture under vacuum afforded the title compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl.[Cl-].[NH4+]>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][C:8]=3[OH:11])[O:1][CH2:2][CH2:3][CH2:4]4)[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)OCCC2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of chroman-7-ol (Cube, R. V., et al., Bioorg. Med. Chem. Lett. (2005), 15(9):2389-93) (0.55 g, 3.66 mmol) in tetrahydrofuran (11 mL) under nitrogen was added isopropylmagnesium chloride (2.4 mL, 2 M in tetrahydrofuran, 4.8 mmol). The resulting solution was stirred at 0° C. for 30 min. A suspension of 1-(diphenylmethyl)indoline-2,3-dione (1.16 g, 3.70 mmol) in dichloromethane (4 mL) was added. The reaction was stirred at 0° C. for 10 min, then warmed to ambient temperature and stirred for 15.5 h. The reaction was diluted with saturated ammonium chloride solution (10 mL) and the organic solvents were removed under reduced pressure. The residual mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (7:3) to afford 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one (1.37 g, 81%) as a light yellow solid: mp 204-206° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.90 (s, 1H), 7.49 (dd, J=5.6, 3.2 Hz, 1H), 7.38-7.23 (m, 10H), 7.12-7.06 (m, 2H), 6.95 (s, 1H), 6.52-6.47 (m, 3H), 4.23 (s, 1H), 4.121 (dd, J=5.7, 4.5 Hz, 2H), 2.53 (t, J=6.3 Hz, 2H), 1.95-1.87 (m, 2H); MS (ES+) m/z 486.1 (M+23).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1)=[O:9])=O.[BH4-].[Na+]>CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:17]1)=[O:9]
Reactant: COC(=O)c1cccc(C(=O)NCC2CCN(C(=O)OCc3ccc(C)cc3)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(COC(=O)N2CCC(CNC(=O)c3cccc(CO)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methylbenzyl 4-({[3-(methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate (EXAMPLE 540) (100 mg, 0.24 mmol) in MeOH (2 mL) was added sodium borohydride (0.18 mg, 4.7 mmol). The solution was stirred at rt for 2 h, quenched with saturated NH4Cl (aq) and extracted with EtOAc. The organic layer was dried over NaSO4, filtered and concentrated. The residue was chromatographed on silica gel (gradient elution, 2:1 hexane:EtOAc to EtOAc) to give 4-methylbenzyl 4-({[3-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([C@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy (2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (225.3 mg) in dichloromethane (20 ml), 3-chloroperbenzoic acid (70%, 113 mg) was added at 0° C., and the mixture was stirred at room temperature for 20 hours. To the reaction solution, sodium thiosulfate solution was added, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give, as pale yellow crystals 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 77) (125.5 mg).
Reaction SMILES: [CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Reactant: COC(=O)CCN
Agent: Cl
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps B-C of Example 82, using (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate in Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6×250 mm, 5 μm. Modifier 0.05% DEA. Mobile Phase: 60/40 CO/ethanol. Flow: 2.35 mL/min. Retention time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH:34]([CH3:36])[CH3:35])[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:15]([C:29](OCC)=[O:30])[CH2:14]1)#[N:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O.C(OCC)C>[C:7]([C:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH:34]([CH3:35])[CH3:36])[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:15]([CH2:29][OH:30])[CH2:14]1)#[N:8]
Reactant: CCOC(=O)C1CN(CCCC(C#N)(c2ccccc2)C(C)C)CCN1CCOc1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(F)cc2)C(CO)C1)c1ccccc1
Yield: 99.5 %

Procedure:
Into a diethyl ether solution (5.0 ml) of lithium aluminum hydride (20 mg) was added dropwise a diethyl ether solution (3.0 ml) of 213 mg of ethyl 4-(4-cyano-5-methyl-4-phenylhexyl)-1-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate under ice-cooling. After stirring under ice-cooling for one hour, water (0.1 ml), a 1N aqueous sodium hydroxide (0.1 ml) and water (0.2 ml) were successively added to the reaction solution. Anhydrous magnesium sulfate was added to the reaction solution, and the unnecessary product was filtered. The solvent was evaporated, to give the title compound (194 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Na].[CH3:16][CH:17]([C:20](=O)[CH3:21])[CH:18]=O>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:20]([CH3:21])[C:17]([CH3:18])=[CH:16][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C(C)C=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Agent: [Na]
Solvent: CC(=O)O
Product: Cc1cn2nc(SCc3ccccc3)nc2nc1C
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 5.0 g (24 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 5.0 g (41 mmol) of the sodium salt of 2-methyl-3-oxobutanal in 200 ml of glacial acetic acid was heated at reflux overnight. The solution was cooled to room temperature and the reaction mixture was concentrated by evaporation at reduced pressure. The residue was combined with ice and H2O to separate a tan solid. The solid was collected by filtration, dried and carefully recrystallized from ethyl acetate to yield 3.53 g (54%) of the desired product as a crystalline solid, m.p. 147°-149° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: S=C=Nc1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=S)Nc4ccccc4)cc3c2C1
Yield: 45.2 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.8 mg (0.0874 mMol) phenyl isothiocyanate, 7.2 mg (39%) of the title compound were recovered.