Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[C:6]([C:15]([N:17]([CH:26]([C:30]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)[C:27]([NH2:29])=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:16])=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[C:6]([C:15]([N:17]([CH:26]([C:30]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)[C:27]([NH2:29])=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:16])=[N:7][C:8]([NH:3][CH2:1][CH3:2])=[N:9][CH:10]=1
Reactant: Cc1ccc(CN(C(=O)c2nc(S(C)(=O)=O)ncc2Cl)C(C(N)=O)c2ccc3c(c2)OCCO3)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Ethylamine was passed through an ice-cold solution of the sulfone from example 243 (0.15 g, 0.28 mmol) in THF (3 ml) for 20 minutes. After 2 hours at room temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate (10 ml) and the solution was washed with water (10 m[), saturated NaHCO3 solution (2×10 ml), brine (10 ml), dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (10 g) eluting with a gradient of pentane-ethyl acetate from 90110 to 30/70 in 10% increments of ethyl acetate to give the title compound as a foam 107 mg, (76%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[F:34][C:2]([F:1])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20][CH2:21]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 58.8 %

Procedure:
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylate (89 mg, 0.18 mmol, PCT WO2006090224 EXAMPLE 1, Step 5) in tetrahydrofuran (1 mL), methanol (1 mL) and 2 N aq. sodium hydroxide (1 mL) is stirred at 70° C. for 17 h. The mixture is neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate is filtered. The precipitate is triturated with diethylether to give 50 mg (58%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>>[Cl:41][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1CN(CCCCCCCCCCCO)CC(C)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCCCCCCCCCCl)CC(C)O1

Procedure:
This intermediate (5.1 g.) was prepared using the procedure described in Example 4c except using 9.35 g. (0.033 mole) of 2,6-dimethyl-4-(11-hydroxyundecyl)morpholine, 9.43 g. (0.036 mole) of triphenylphosphine, and 70 ml. of carbon tetrachloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13](OCC)=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[NH3:23]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([NH2:23])=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(N)=O)C1

Procedure:
Ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (0.1 g, 0.315 mmol) was taken in 4 ml aqueous ammonia and microwaved at 120° C. for 5 minutes. The solid product precipitated out after the reaction was filtered through Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash to obtain 1.25 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.85 (bs, 1H), 7.5-7.6 (m, 2H), 7.4 (s, 1H), 7.2 (d, 1H), 6.85 (s, 1H), 4.6-4.7 (m, 2H), 4.4 (t, 2H), 3.7-3.8 (m, 2H), 3.1-3.2 (m, 4H), 3.0 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:27])[C:7]2[C:12]([CH:13]=1)=[C:11]([Cl:14])[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=1)=[C:9]([Cl:26])[CH:8]=2)=[O:4]>CO.[OH-].[K+]>[Cl:14][C:11]1[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:9]([Cl:26])[CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[N:6]2[CH3:27]
Reactant: COC(=O)c1cc2c(Cl)c(Oc3ccc(O)c(C(C)C)c3)c(Cl)cc2n1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(Oc2c(Cl)cc3c(cc(C(=O)O)n3C)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 74.8 %

Procedure:
To a solution of 4,6-dichloro-5-(4-hydroxy-3-isopropyl-phenoxy)-1-methyl-1H-indole-2-carboxylic acid methyl ester (32 mg, 0.078 mmol) in 50% aqueous MeOH (4 mL) was added potassium hydroxide (3N, 154 μL). The resulting solution was stirred for 19 hours at room temperature, diluted with potassium hydroxide (0.1N, 16 mL) and the solution was washed with EtOAc (3 times 10 mL). The aqueous solution was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (3 times 15 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to afford the title compound (23 mg). 1H NMR (400 MHz, CD3OD) δ7.64 (s, 1H), 7.24 (s, 1H), 6.63 (d, 1H), 6.57 (d, 1H), 6.29-6.26 (dd, 1H), 4.03 (s, 3H), 3.22-3.15 (m, 1H), 1.11 (d, 6H). MS (APCI−) Calc: 393.0, Found: 392.2 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O>O1CCCC1>[Br:23][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)nc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(Br)n2C(=O)OC(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 67.7 %

Procedure:
Methyl 6-[1-(t-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate (835 mg, 2.76 mmol) synthesized in Example (11a) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (492 mg, 2.76 mmol) was added, and stirring was carried out at room temperature for 19 hours under nitrogen atmosphere. Water (30 mL) was added, and extraction was carried out with diethyl ether (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (712 mg, yield 68%) as a pale yellow oil.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O>>[CH:8]1[C:2]2[C:1](=[O:9])[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:4][C:3]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K]
Product: O=C1Nc2ccccc2Oc2ccccc21

Procedure:
The starting material 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2-chloronitrobenzene, followed by oxidation to the carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired starting material.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCI
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[(benzyl oxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (Intemediate 1, step 2, 2 g) in anhydrous dimethylfomamide (15 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.22 g of a 55-60% dispersion in mineral oil), at 0° C. After 45 min at 0° C., 1-iodopropane (0.55 ml) was added in one portion and the solution allowed to reach ambient temperature and stirred overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (25 ml) and dichloromethane (25 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (3×25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.74 g) as a solid. mp 160°-163° C.; 1H NMR (360 MHz, CDCl3)δ0.82 (3H, t, J=10.5 Hz), 0.94-1.48 (5H, m), 1.50-1.76 (5H, m), 1.79-1.90 (1H, m), 1.96-2,08 (1H, m), 2.70-2,84 (1H, m), 3.46-3.59 (1H, m), 4.22-4.35 (1H, m), 5.06-5.16 (3H, m), 5.07 (1H, d, J=12.0 Hz), 7.21-7.40 (7H, m), 7.44-7.59 (2H, m).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7](=[S:10])SC)([OH:3])=[O:2].[OH-].[Na+].O.[N-:14]=[N+:15]=[N-:16].[Na+]>CCOCC>[C:1]([CH2:4][CH2:5][N:6]1[C:7]([SH:10])=[N:16][N:15]=[N:14]1)([OH:3])=[O:2]
Reactant: CSC(=S)NCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCn1nnnc1S

Procedure:
To a mixture of 25.37 g. (0.143 mol.) of methyl 2-carboxyethyldithiocarbamate and 5.6 g. (0.143 mol.) of sodium hydroxide in 210 ml. of water was added 9.25 g. (0.143 mol.) of sodium azide. The reaction mixture was refluxed for one hour then cooled, diluted with 100 ml. of ether and acidified to pH 1.7. The layers were separated, the aqueous phase was extracted with ether and the combined extracts were dried (MgSO4) and evaporated to dryness to give a residue which was recrystallized from acetone-chloroform to give 1-(2-carboxyethyl)tetrazole-5-thiol, m.p. 158°-160° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.[H-].[Na+].Cl[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=1>CN(C=O)C>[N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:48]=[CH:49][C:40]=1[O:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(C4CCOCC4)c4nc(CO)cn34)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(C4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
Into a 10 mL round-bottom flask was placed a solution of compound 90j (150 mg, 0.300 mmol) in DMF (2 mL), followed by the addition of sodium hydride (30.0 mg, 1.25 mmol) at 0° C. The mixture was stirred for 15 min at 0° C., and 2-chloroquinoline (74.2 mg, 0.460 mmol) was added. The reaction mixture was stirred overnight at 70° C. Upon cooling, the reaction was quenched with water. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:3 v/v)) to obtain compound 91a as a light yellow solid (130 mg, 69% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H39N7O4: 622.3 (M+H). found: 622.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].Br[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CC1C=CC=CC=1>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]3[N:6]=[C:2]4[N:3]([CH:8]=3)[CH:4]=[CH:5][S:1]4)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Nc1nccs1
Reactant: O=C(CBr)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cn5ccsc5n4)CC3)nc3ccccc32)cc1
Yield: 5.3 %

Procedure:
A mixture of 2 parts of 2-thiazolamine, 12.7 parts of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone, 6.4 parts of sodium carbonate and 135 parts of methylbenzene was stirred and refluxed for 3 hours using a water separator. The whole was filtered and the filtrate was evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 0.5 parts (5.3%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(imidazo[2,1-b]thiazol-6-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 222.7° C. (compound 149).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22]C)=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (50 mg, 0.159 mmol) in MeOH (2 mL) was added aqueous 1M NaOH (159 μL, 0.159 mmol). The reaction was stirred at room temperature for 4 hours, treated with additional aqueous 1N NaOH (159 μL, 0.159 mmol), and stirred at room temperature overnight. Aqueous 1N HCl (318 μL, 0.318 mmol) was added to the solution, and the solvents were removed in vacuo to afford the title product. 1H NMR (400 MHz, CD3OD) δ 7.39-7.36 (m, 2H), 7.32-7.28 (m, 3H), 5.24 (s, 3H), 4.38-4.34 (t, 2H), 2.90-2.86 (t, 2H), 2.13-2.06 (dt, 2H); ES MS (M+1)=302.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH3:23])[C:14]=1[OH:24]>C([O-])([O-])=O.[K+].[K+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH3:23])[C:14]=1[OH:24]
Reactant: Cc1cc2ccccc2c(Br)c1O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1O
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A mixture of 2,4-dichlorophenylboronic acid (1.0 g), tetrakis(triphenylphosphine)palladium(0) (300 mg), 1-bromo-3-methyl-naphthalen-2-ol (5B, 625 mg) in K2CO3 (2 M, 5.3 mL) and DME (26 mL) was degassed with argon and sealed in a Schlenk tube. The reaction was heated to 80° C. for 75 minutes, then cooled to room temperature. The reaction was diluted with EtOAc and filtered through a pad of silica gel. The silica was washed with EtOAc and the combined organics were concentrated. The crude residue was purified by flash column chromatography (0-18% EtOAc in hexanes) to yield 784 mg of desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccncc2)cc1
Yield: 111.4 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 9, 4-bromo pyridine (2 g, 8.44 mmol) was coupled with (4-bromophenyl) boronic acid (1 g, 9.2 mmol) in sodium carbonate (3.57 g, 33.7 mmol), Pd(PPh3)4 (487 mg, 0.422 mmol) and toluene/ethanol/water (50/50/20 ml) to afford 2.2 g of the crude product which was taken as such for next reaction. LCMS: 235.9 m/z=(M+2).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)/[C:25]1=[O:42])=O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:31]=[C:32]2[NH:24][C:25](=[O:42])[C:26]3([CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)[C:27]2=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(I)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(I)c2)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 192a (1.2 g, 3.5 mmol) in toluene (40 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (10 mL) was added. After the reaction mixture was stirred at room temperature for 0.5 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3 then 1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.56 g, 77%).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11](O)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:42][C@H:43]([C:54]([CH2:56][Cl:57])=[O:55])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:53])[NH:49][N+:50]([O-:52])=[O:51].Cl>CN(C)C=O.C1COCC1.O.[Cl-].[Na+].O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH:42][C@H:43]([C:54]([CH2:56][Cl:57])=[O:55])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:53])[NH:49][N+:50]([O-:52])=[O:51])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N=C(NCCC[C@H](N)C(=O)CCl)N[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The preformed protected dipeptide, Cbz-L-Leu-L-ProOH, (2.0 mmol) was allowed to react with isobutyl chloroformate (0.29 ml, 2.1 mmol), in the presence of N-methylmorpholine (0.24 ml, 2.1 mmol) at 0° C. for 20 min. A solution of H-L-Arg(NO2)CH2Cl.HCl (0.60 g, 2.0 mmol) in dimethylformamide (4 ml) was added dropwise. After stirring for 20 min at 0° C., N-methylmorpholine (0.22 ml, 2.0 mmol) in THF was added. The resulting solution was stirred at 0° C. for an additional 40 min, then at RT for 1 hr. The reaction mixture was diluted with H2O and brine (25 ml each), extracted twice with ethyl acetate (25 ml each). The combined organic layers were washed with 10% citric acid, saturated NaHCO3 and brine (15 ml each), dried over MgSO4, and the solvent was removed in vacuo to give Cbz-L-Leu-L-Pro-L-Arg(NO2)CH2Cl. The product was treated with HF (7 ml) and anisole (0.5 ml) at 0° C. for 20 min. After the HF was removed, the residue was diluted with cold H2O and washed with diethyl ether two times (5 ml each). The organic volatiles were removed under reduced pressure before lyophilizing the crude H-L-Leu-L-Pro-L-Arg-CMK.2HF to a powder. A crude purification of the material was accomplished on a Sephadex SP-C25 (H+form) column using 0-1.0N HCl stepwise gradient which yielded H-L-Leu-L-pro-L-Arg-CMK.2HCl. The product was further purified on a Supelco LCNH2 column eluted with a 10-50% (v/v) hexane/isopropanol (10% methanol) gradient, and dried in vacuo. The product was characterized by 360 MHz 1H NMR. The product was dissolved in water, methanol, or suitable aqueous solutions for analysis or other uses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:7]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 18.1 using 3-bromo-4-chlorobenzoic acid and 4-(trifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 1) tR=3.38 min, m/z=393.9-395.8 [M+H]+, m/z=391.9-393.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.3 Hz, 2H) 7.82 (d, J=8.3 Hz, 1H) 7.87 (d, J=9.0 Hz, 2H) 7.97 (dd, J=8.4, 2.1 Hz, 1H) 8.34 (d, J=2.2 Hz, 1H) 10.55 (s, 1H).