Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CCNCC
Solvent: CO
Product: C[C@@H](N[C@@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1R)-6-Bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 17.5 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=160 (c 0.20, MeOH); 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 9.85 (s, 1H), 9.30 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.43 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.78 (m, J=6.4 Hz, 1H), 4.60 (m, 1H), 2.77-2.65 (m, 2H), 2.20-2.05 (m, 1H), 2.05-1.95 (m, 2H), 1.88-1.80 (m, 1H), 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90; Cl, 8.69. Found: C, 59.34; H, 5.45; N, 6.87; Cl, 8.67.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1B(O)O)=[O:22].[F-].[K+].B(O)O>O1CCOCC1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[CH:21]=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccsc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: OBO
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3sccc3C=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methyl 2-bromo-3-cyclohexyl1H-indole-6-carboxylate (prepared as described in published International patent application WO 2004/087714), (3-formyl-2-thienyl)boronic acid (1.2 eq), spray-dried KF (5 eq) and Pd(tBu3P)2 (0.2 eq) were dissolved in dioxane (0.15 M); the reaction mixture was stirred under N2 at RT for 4 h, then more KF, boronic acid and catalyst were added and stirring was continued overnight. All volatiles were evaporated in vacuo and the title compound was isolated by flash chromatography (PE/EtOAc 8:2). Yield 99%; MS (ES+) m/z 368 (M+H)+.
Reaction SMILES: OC1C=C(C=C(OCC2C=CC=CC=2)C=1)C(NC1C=CN(C)N=1)=O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:35][C@@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:35][C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1

Procedure:
The preparation of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide was described earlier. (3S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate was prepared in an analogous fashion to (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate, as described in Example 25.
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CCO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])=[N:9]2)=[C:15]([C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[CH:16]=1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: [Pd]
Solvent: CCO
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(N)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)—N,N-dibutyl-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxamide (1.1 g, 2.0 mmol) in EtOH (10 mL) was added 10% Pd—C (0.04 g) followed by stirring under H2 balloon pressure at RT for 5 h. The reaction mixture was filtered through celite, the bed was washed with EtOH (20 mL) and the filtrate was concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as an ‘off white’ solid 0.8 g (77%). Rf=0.33 (40% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 7.30-6.82 (m, 5H), 6.80-6.15 (m, 3H), 5.72-5.50 (m, 2H, D2O exchangeable), 5.20-4.78 (m, 1H, D2O exchangeable), 4.90-4.00 (m, 2H), 4.00-2.22 (m, 9H), 2.20-2.00 (m, 3H), 1.60-0.60 (m, 14H); LC-MS: m/z 518.3 (M+H); HPLC: 98.64% (RT=5.997 min., method B).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>Cl.O.C(OCC)(=O)C>[N:20]([C:17]1[CH:16]=[CH:15][C:14]([N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)[CH3:13])=[CH:19][CH:18]=1)=[N+:27]=[N-:28]
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1nc(N(C)c2ccc(N=[N+]=[N-])cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (20 mg, 0.076 mmol) in 1.2 mL of 1N HCl was added 100 uL of methanol and it was cooled 0° C. One drop of concentrated HCl was added and the solution was stirred at 0° C. for 0.25 h. To the solution was added dropwise a solution of sodium nitrite (25 mg, 0.36 mmol) in 200 uL of water. The reaction mixture was stirred for 0.5 h, then was added a solution of sodium azide (25 mg, 0.38 mmol) in 300 uL of water followed by another batch of sodium azide (25 mg, 0.38 mmol). The reaction mixture was stirred at the 0° C. for 1 h. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (20-25% ethyl acetate/hexanes) on silica gel to give the title compound (19.8 mg, 0.068 mmol, 90%). 1H NMR (CDCl3): 7.76 (m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H), 7.13 (m, 2H), 6.98-7.13 (m, 4H), 3.61 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1.Cl.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][O:28][CH3:27])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1
Reactant: CON
Reactant: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Agent: Cl
Product: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)NOC)cc12

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ; 8.75 (s, 1H), 8.37 (s, 1H), 7.61 (s, 1H), 7.21–7.28 (m, 1H), 6.88–7.00 (m, 2H), 5.54 (s, 2H), 4.70 (s, 2H), 3.82 (s, 3H), 3.59 (q, 2H, J=7.0 Hz), 1.20 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 376.1. HRMS calcd for C19H20F2N3O3 (M+H) 376.1473. found 376.1485. HPLC: 99.24% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2OC(C)(C)[C@H](O)[C@@H:23]([N:30](CC(OCC)=O)C3C=CC=CC=3)[C:22]=2C=1)#[N:17].NCCC1C=CC=CN=1>>[N:17]1[CH:16]=[CH:18][CH:19]=[CH:20][C:21]=1[CH2:22][CH2:23][NH:30][C@H:6]1[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:15])([CH3:1])[C@@H:7]1[OH:8]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Agent: NCCc1ccccn1
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](NCCc2ccccn2)[C@H]1O
Temperature: 25 °C

Procedure:
A solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile ((1.0 g, 5.0 mmol, the title A compound of Example 3) and 2-aminoethylpyridine (1.1 g, 9.0 mmol) was heated in a sealed tube at 75° C. for 18 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography to afford an oil, which solidified upon standing (1.4 g, 87%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])=[O:6].[OH-].[Na+].Cl>CO>[O:6]=[C:5]1[C:7]2[C:8](=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[N:4]1[CH2:3][C:2]([F:25])([F:24])[F:1]
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.2 g of ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate (5.9 mmol) were dissolved in 10 ml of methanol and 1.5 ml of a 5 M aqueous NaOH solution (7.5 mmol) were added. The mixture was stirred at RT for 18 h and then set to pH=7 using aqueous HCl solution. The solvents were removed under reduced pressure and the residue was suspended in 10 ml of water. This suspension was set to pH=2 using a 2N aqueous HCl solution and extracted 3 times with 10 ml each time of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. The residue was crystallized with diethyl ether/DIP, mp: 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[C:59]([F:67])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:64])[F:65])[CH:60]=[C:59]([F:67])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:68][CH:69]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
To a solution of 103 mg (0.53 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 169 mg of TBTU (0.53 mmol) in 6 ml DMF, were added 0.45 ml (2.63 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.57 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 211 mg white solid (70%). MS (EI) 530.2 (M)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[NH:28][CH:25]2[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.8 %

Procedure:
4-Trifluoromethoxyphenyl isocyanate (1.03 g, 5 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. A solution of N—BOC-4-aminopiperidine (781 mg, 5 mmol) in dry THF (10 mL) was slowly added. The reaction was allowed to warm to RT and stir for 12 hours. The solvent was removed and the residue chromatographed from ethyl acetate to give intermediate 41 (1.71 g, 95%) as a white solid: Mp 160-162° C. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.22 (d, J=7.6 Hz, 1H), 3.81 (d, J=13.0 Hz, 2H), 3.67-3.59 (m, 1H), 2.90 (s, 2H), 1.79 (dd, J=12.6, 2.5 Hz, 2H), 1.40 (s, 9H), 1.25 (dq, J=12.1, 3.9 Hz, 2H). HRMS calculated for C18H24F3N3O4−H+402.1641. found (ESI(−), [M−H]) 402.1612.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[Br:18]N1C(=O)CCC1=O.O>C(#N)C.CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Br:18])[CH:12]=3)[NH:7][C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c(nc1N)[nH]c1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 35 mg, 0.15 mmol) in acetonitrile (1 mL) and N,N-dimethylformamide (1 mL), was added N-bromosuccinimide (37 mg, 0.209 mmol) in one portion at −10° C. The mixture was warmed to room temperature and stirred for one hour. Water was added and the mixture was extracted with methylene chloride (3×20 mL). Extracts were combined, dried over sodium sulfate, filtered and concetnrated to afford the crude product which was subsequently purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-6-bromo-9H-pyrido[2,3-b]indole-3-carboxamide (34, 20 mg, 40%) as yellow solid. NH4OAc standard conditions. DAD Retention Time=6.12 min. M+H=307. 1H NMR (300 MHz, MeOD): δ 8.65 (d, J=6.9 Hz, 1H), 8.03 (d, J=4.9 Hz, 1H), 7.43-7.37 (m, 1H), 7.33-7.27 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([Cl:22])[C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[Cl:22][C:11]1[C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=12
Reactant: Clc1c2c(nc3ccccc13)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Clc1c2c(nc3ccccc13)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2-Benzyl-10-chloro-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (1.54 g, 5 mmol) was dissolved in methylene chloride, followed by adding thereto 1-chloroethyl chloroformate (0.81 ml, 7.5 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and methanol (20 ml) was added to the residue, and the resulting mixture was heated under reflux at 80° C. for 1 hour. The reaction mixture was concentrated and a 1N-aqueous potassium hydroxide solution was added thereto, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by suspension in diethyl ether/hexane to obtain the desired compound (656.4 mg, 60%) as a light-yellowish-white substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[C:17]([Cl:18])[C:12]2=[N:11]1)[C:5]#[N:6].[Br:22][Si](C)(C)C>C(#N)CC>[Br:22][C:14]1[C:13]2=[CH:20][N:10]([C:9]3[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[Cl:21])[N:11]=[C:12]2[C:17]([Cl:18])=[CH:16][N:15]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Cl)ncc(Cl)c3n2)c(Cl)c1
Solvent: CCC#N
Product: N#Cc1cc(Cl)c(-n2cc3c(Br)ncc(Cl)c3n2)c(Cl)c1
Yield: 96.9 %

Procedure:
A mixture of 3,5-dichloro-4-(4,7-dichloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile (250 mg, 0.70 mmol) and bromotrimethylsilane (0.462 mL, 3.50 mmol) in propionitrile (4.0 mL) was heated under reflux for 4 hours. The resultant mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a beige solid (273 mg, 97% yield). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.16 (s, 1H), 7.85 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65]OC(NC(C1C=C(C)C=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[C:51]([CH3:65])[CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1cccc(C)c1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1cccc(C)c1
Yield: 34 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-m-tolyl-acetic acid (0.046 g, 0.206 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-m-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.039 g, 34%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.91 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenylacetyl chloride (0.35 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2CH2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-phenylacetamide (0.41 g, 55%) as a white solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.80-7.61 (m, 3H), 7.29 (s, 5H), 5.19-5.12 (dd, J=5.1 and 12.41 Hz, 1H), 4.71 (d, J=5.5 Hz, 2H), 3.53 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.03 (m, 1H); 13HNMR (DMSO-d6) δ 172.77, 170.65, 169.82, 167.45, 166.93, 139.19, 136.15, 134.68, 133.18, 131.53, 129.05, 128.25, 127.13, 126.43, 121.90, 48.85, 42.24, 37.85, 30.93, 21.98; Anal. Calcd. For C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 65.16; H, 4.75; N, 10.11.
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH3:6].C(O)C.Cl>O1CCCC1>[OH:3][C@H:4]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](NCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.43 mL) was added to a solution of ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}biphenyl-4-carboxylate (0.15 g), ethanol (20 mL) and tetra hydrofuran (5 mL). The mixture was stirred at 60° C. for 16 hrs, and heated under reflux at 100° C. for 7.5 hrs. A 2 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added, and heated under reflux for 16 hrs. After being cooled to room temperature, 2 mol/L hydrochloric acid (0.60 mL) was added, and the precipitate was collected by filtration to afford the title compound as a pale yellow amorphous (0.13 g). The structure and physical data were shown in table 3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](NC2C3C(=CC=CC=3)N=C(C)C=2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.C[O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32].CCN(C(C)C)C(C)C>CO>[CH3:34][CH:33]([CH3:35])[C@H:31]([NH:32][C:13]([NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)=[O:14])[C:30]([OH:29])=[O:36]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc3ccccc23)c2ccccc2n1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)N[C@H](C(=O)O)C(C)C)c2ccccc2n1
Temperature: 80 °C

Procedure:
A suspension of 1,3-bis-(2-methyl-quinolin-4-yl)-urea (342.4 mg, 1 mmol), valin methyl ester hydrochloride (167.6 mg, 1 mmol) and DIPEA (0.34 mL, 2 mmol) in MeOH (10 mL) is heated at 80° C. for 15 h. The solvent is evaporated and the residue is dissolved in 6N aqueous HCl (6 mL). The reaction mixture is heated at 90° C. for 12 h. Evaporation and purification by preparative HPLC provides the title compound.