Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1.Br[C:38]1[C:43]([Cl:44])=[CH:42][C:41]([Cl:45])=[CH:40][N:39]=1.COCCOC.O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[C:17]([C:38]4[C:43]([Cl:44])=[CH:42][C:41]([Cl:45])=[CH:40][N:39]=4)=[CH:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
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
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a suspension of 1 g (1.96 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 0.58 g (2.55 mmol) of 2-bromo-3,5-dichloropyridine in 10 mL of a 2/1 DME/water mixture, argon is sparged through for 10 minutes, followed by successive addition of 0.81 g (5.88 mmol) of K2CO3 and 0.159 g (0.14 mmol) of Pd(PPh3)4. The reaction mixture is heated for 4 hours at 80° C. and then cooled and diluted in 50 mL of EtOAc. The organic phase is washed with 2×20 mL of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue is then purified on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 40% EtOAc, to give 0.4 g of methyl 2′-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:7][C@H:6]1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:3].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[CH2:35][CH2:36][I:37]>CCOC(C)=O>[I-:37].[C:2]([O:4][C@H:5]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N+:19]([CH2:36][CH2:35][C:34]2[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=[C:32]([O:31][CH3:30])[CH:33]=2)([CH3:21])[CH3:20])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:7][C@H:6]1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(CCI)cc(OC)c1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CC[N+](C)(C)CCc3cc(OC)cc(OC)c3)C(=O)[C@@H]2OC(C)=O)cc1
Product: [I-]
Temperature: 50 °C
Reaction time: 97 h
Yield: 63.7 %

Procedure:
To a flask under nitrogen was added 5.0 g (0.0121 mole) of diltiazem, 3.52 g (0.0121 mole) of 3,5-dimethoxyphenethyl iodide, and 20 ml of EtOAc. The reaction mixture was heated at 50° C. for 24 hr then at 75° C. for 97 hr. The reaction was cooled to RT, the solvent decanted, and the oily residue washed three times with EtOAc. The oily residue was dissolved in methylene chloride, washed with water and dried over MgSO4. The solvent was evaporated to give 5.45 g of a mixture of the title product and diltiazem hydroiodide as a tan foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1Cl)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-4-fluorophenol (0.65 g) and sodium hydride (210 mg) in dry 1,2-dimethoxyethane (15 ml) was stirred at room temperature for 30 minutes. A solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (1 g, prepared in a similar manner to that described in Example 6) in 1,2-dimethoxyethane (35 ml) was added dropwise to the stirred mixture. The mixture was stirred at room temperature for 21 hours, then was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in dichloromethane, washed with a 5% aqueous solution of sodium hydroxide followed by water, dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The solid residue was purified by flash chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 1:1), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.99 g, (m.p. 89°-91° C.).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:26]([C:23]1[N:24]=[CH:25][C:20]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of tert-butyl 2-(4-hydroxybenzoyl)hydrazinecarboxylate (0.688 g, 2.73 mmol) and 5-bromo-2-nitropyridine (0.554 mg, 2.73 mmol) and caesium carbonate (1.33 g, 4.08 mmol) in N,N-dimethylformamide (7 mL) was stirred overnight at 80° C. The solution was concentrated and the residue was taken with dichloromethane and water. The organic phase was dried on MgSO4 and concentrated. The crude product was purified by column chromatography (silica gel, 5% MeOH in CH2Cl2), to give 736 mg of the mixture nitropyridine and bromopyridine.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[O:5][C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)=[O:10]>O.C1COCC1>[CH3:3][C:4]1[O:5][C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[O:10]
Reactant: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2cc(-c3ccccc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)cc1C(=O)NCCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 71 %

Procedure:
Lithium hydroxide (3.3 mg, 0.136 mmol) in water (1 ml) was added into methyl 2-[(4-{2-[(2-methyl-5-phenyl-3-furoyl)amino]ethyl}phenoxy)methyl]benzoate (32 mg, 0.068 mmol) dissolved in THF(2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99 and 2:98) as eluant gave 22 mg the desired product, yield 71%.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:18])([CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred solution of 10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 9.67 g, 32.8 mmol) in DMA (710 mL) under nitrogen was added methyl iodide (2.25 mL, 36.08 mmol). The mixture was cooled in ice/water to 2.5° C. Sodium hydride (60% dispersion in mineral oil, 1.45 g, 36.08 mmol) was added in one portion. A small exotherm to 4° C. was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, and then stirred at room temperature overnight. Solvent was removed in vacuo and the light-brown liquid residue was treated with water. This afforded a solid, which was filtered off and washed with water. The solid material was dissolved in DCM (200 mL) and the solution dried using MgSO4, filtered and evaporated to give an off white solid which was purified on a 330 g Si column (Companion). loading as a solution in DCM (60 mL) The column having been equilibrated with 30% Ethyl Acetate in isohexane, and eluted with 30% Ethyl Acetate in isohexane for the first 5 minutes and then with a linear gradient slowly rising to 100% Ethyl Acetate. Product containing fractions were combined and evaporated to dryness to give the title compound as a white solid (9.29 g, 92%)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.Cl.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([NH:23][C@@H:19]([CH2:18][CH:15]3[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]3)[C:20]([NH:36][CH2:35][CH2:34][NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:22])=[N:6][C:5]=2[CH:7]=1
Reactant: NCCNc1ccc(F)cc1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared from 2,5-dichlorobenzooxazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine-2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) a 8.35 (d, 1H, J=8 Hz), 8.18 (t, 1H, J=5.8 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=2.0 Hz), 6.90 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 6.84(m, 2H), 6.51(m, 2H), 4.19(m, 1H), 3.15(m, 2H), 2.98(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28ClFN4O2(M+H+) 459.19. found 459.4.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([F:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[Cl-:1].[Cl-:1].[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([F:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][NH+:25]=3)=[CH:20][CH:19]=2)[NH2+:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(F)Cc1ccc(-c2ccccn2)cc1
Reactant: Cl
Solvent: CO
Product: CC(C)(C)CC1=C[NH2+]C(C(F)Cc2ccc(-c3cccc[nH+]3)cc2)=N1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to a solution of 4-(2,2-dimethylpropyl)-2-[1-fluoro-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed to afford the title compound. (M+H) found: 338.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: O
Product: O=C1c2c(-c3ccccc3)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) and 4-(pyrrolidine-1-yl)piperidine (30.0 mg) was stirred at 150° C. for 3 hours. To the remaining product, water was added and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium hydrogen carbonate and was dried on anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:methanol=3:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (25.0 mg, 51%).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>O1CCOCC1.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[C:18][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1
Reactant: C#CCN(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.4 %

Procedure:
Tri-t-butylphosphine (0.25 M in dioxane, 11.9 ml, 3.0 mmol, 0.2 eq.), 3-dimethylamino-1-propyne (2.2 ml, 20.8 mmol, 1.4 eq.), and diisopropylamine (2.7 ml, 19.3 mmol, 1.3 eq.) are added sequentially to a mixture of 4-bromonitrobenzene (3 g, 14.9 mmol), copper (I) iodide (198 mg, 1.0 mmol, 0.07 eq.), and Pd(PhCN)2Cl2 (570 mg, 1.5 mmol, 0.1 eq.) in dioxane (20 ml), under an argon atmosphere. The resulting mixture is stirred for 22 h at RT and concentrated. The residue is dissolved in EE and water and filtered through a pad of celite. The aqueous layer is separated and extracted with EE. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords 2.72 g of the title compound as a brown oil: ESI-MS: 205.0 [MH]+; tR=2.51 min (purity: 100%, gradient J); TLC: Rf=0.41 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: O=C1C2C=CC=CC=2SC2C=CC(C(C)C(O)=O)=CC=2C1.N[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])=[CH:25][C:24]=1[CH2:34][C:35]([OH:37])=[O:36].[C:38]([OH:47])(=[O:46])[C:39]1[C:40](=[CH:42][CH:43]=[CH:44][CH:45]=1)[SH:41]>>[C:35]([CH2:34][C:24]1[CH:25]=[C:26]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:27]=[CH:28][C:23]=1[S:41][C:40]1[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=1[C:38]([OH:47])=[O:46])([OH:37])=[O:36]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Agent: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Product: CC(C(=O)O)c1ccc(Sc2ccccc2C(=O)O)c(CC(=O)O)c1

Procedure:
A process for preparing 2-(10,11-dihydro-10-oxodibenzo [b,f] thiepin-2-yl)propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazotization and subsequent reaction with thiosalicylic acid to produce 2-[3-carboxymethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or its salt, esterifying the product to give a 2-[3-(lower)alkoxycarbonylmethyl-4-(2-(lower)alkoxycarbonylphenylthio)phenyl]-propionic acid (lower)alkyl ester, cyclizing the resulting ester to produce a 2-(10,11-dihydro-11-(lower)alkoxycarbonyl-10-oxodibenzo [b,f] thiepin-2-yl)propionic acid (lower)alkyl ester, and subjecting the resulting ester to hydrolysis and decarboxylation.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[Cl-].[CH3:22][O:23]C1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH:48]([CH2:52][CH2:53][CH2:54][CH3:55])C(O)=O)=[CH:40]1>CO>[CH3:19][N:18]([CH3:20])[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:22](=[O:23])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:48][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:39][CH:40]=2)=[O:4])[CH2:7][CH2:8]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)CN)CC1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: CCCCC(C(=O)O)c1c[nH]c2ccccc12
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)CNC(=O)CCCCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more nonpolar diastereomer of 2-amino-N-(4-dimethylamino-4-phenylcyclohexyl)-acetamide (276 mg, 1.0 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmole) were added to a solution of indol-3-yl-hexanoic acid (231 mg, 1.0 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The batch was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate, The organic phase was dried with Na2SO4 and evaporated. The more nonpolar amide was obtained as a colorless oil in a yield of 525 mg (100%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36](O)=[O:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36]([N:1]3[CH2:2][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:4]3)=[O:37])=[CH:32][CH:33]=2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirring solution of tert-butyl azetidine-3-carboxylate (64.55 mg, 0.41 mmol) in DMF (1 mL) were added DIEA (169.6 mg, 1.31 mmol), and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (100.0 mg, 0.21 mmol). The solution was cooled to 0° C. at ice bath and then HATU (74.11 mg, 1.31 mmol) in 1 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×10 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. to afford 117.6 mg (85%) of tert-butyl (S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate INT-38 as a solid powder without further purification for next step. LCMS-ESI (m/z) calculated for C30H35BrN4O4S: 626.2. found 627.2 [M+H]+, tR=3.884 min. (Method 16).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[C:34]([Mg]Cl)#[CH:35]>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:34]#[CH:35])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: C#C[Mg]Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Product: C#CC(O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 97.1 %

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (11B, 250 mg, 0.551 mmol) was added to a oven dried 20 mL microwave vial, charged with THF (10 ml), degassed under nitrogen and cooled to −78° C. To the mixture was added ethynylmagnesium chloride (1.322 ml, 0.661 mmol) dropwise and the reaction was slowly warmed to rt over 30 minutes. The reaction was quenched with saturated ammonium chloride, extracted 3×20 mL EtOAc, washed with brine, dried over sodium sulfate filtered and concentrated in vacuo to provide crude 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-ol (257 mg, 0.535 mmol, 97% yield) which was used without further purification. MS: [M+H]+ m/z 480.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].Br[CH2:19][CH:20]=[C:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]1=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[CH:32]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:21](=[CH:20][CH2:19][O:17][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=3)[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: BrCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3CCc3ccccc32)cc1)OCC
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (2.38 g, 0.01 mol), 5-(2-bromo-1-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.75 g, 0.01 mol) and potassium carbonate (5.14 g, 0.03 mol) in dimethylformamide (30 ml) was heated at 100° C. for 20 h. The reaction mixture was diluted with benzene (80 ml), washed with 5% aqueous citric acid (3×25 ml) and with saturated NaHCO3 (25 ml), dried (MgSO4) and evaporated. The residue (4.88 g) was purified by column chromatography on silica gel (benzene eluent) to yield the title compound; 2.3 g (53.7%).