Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])/[CH:10]=[C:11](\[O:13][CH3:18])/[CH3:12])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)CC(=O)Nc1cccc(OC(C)=O)c1
Agent: COC([O-])[O-]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CO/C(C)=C\C(=O)Nc1cccc(OC(C)=O)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 2038 %

Procedure:
A mixture of 50 g of m-acetoxy-acetylacetanilide, 1 g of p-toluene sulfonic acid and 50 ml of methyl orthoformate was stirred for 16 hours at 20°C. and after the addition of 2 ml of quinoline and 200 ml of toluene, the reaction mixture was heated at 140°C. for 4 hours while distilling off a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 29.5 g of m-acetoxy-3-methoxy-crotonanilide melting at 111°C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC
Temperature: 80 °C
Yield: 24 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (111 mg, 0.80 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (100 mg, 0.402 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-30% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[S:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10]I>[H-].[Na+]>[CH3:10][S:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1
Reactant: CI
Reactant: O=c1[nH]cc(Cl)c(=S)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CSc1nc(=O)[nH]cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
5-Chloro-4-thiouracil (0.0027 mol) was dissolved in 1 M sodium hydride (3 ml) and methyl iodide (0.007 mol) added. The solution was stirred at room temperature for 3 hr. and the solid precipitate collected and recrystallised from water; yield 21%, m.p. 254° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:4]2[CH2:3]1.[OH-].[Na+].O.Cl>C(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ncccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2cccnc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 1.61 g (5.6 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]-diazepine-3-carboxylate, 0.33 g (8.2 mmol) of sodium hydroxide, 9 ml of water and 27 ml of ethyl alcohol is heated to boiling under reflux for 25 minutes. The mixture is treated with 8.2 ml of 1 N hydrochloric acid, the ethanol is removed by distillation, the residue is diluted with water and left to stand in an ice-bath for 1 hour. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepine-3-carboxylic acid of melting point 292°-295°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43]Br>CN(C=O)C>[CH3:39][O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:9](=[O:12])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:25][CH:26]=1
Reactant: COC(=O)C(C)(C)CBr
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 95 °C
Yield: 8 %

Procedure:
(±)-Cis-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid methyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (400 mg, 0.92 mmol) was dissolved in DMF (25 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate—70/30 dichloromethane/ethyl acetate) to afford the pure ester (40 mg, 8%).
Reaction SMILES: [C:1]1([C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](OC)=[O:28])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[Cl-].[Li+]>O1CCCC1.C(O)C.C(OCC)(=O)C.Cl>[C:37]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([CH2:27][OH:28])[CH2:10]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reaction time: 1.83 h
Yield: 87.4 %

Procedure:
To a solution of (2S,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3:3.63 g) in tetrahydrofuran (36 ml) under ice cooling are added a solution of sodium borohydride (371 mg) in ethanol (15 ml) and a solution of lithium chloride (554 mg) in tetra-hydrofuran (15 ml), and the mixture is warmed to room temperature and stirred for 110 minutes. The reaction mixture is diluted with ethyl acetate under ice cooling, neutralized with 1N-hydrochloric acid (10 ml) to decompose remaining reagent. The organic layer is taken, washed with water and saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (4:3.02 g) as colorless foam. Yield: 88%.
Reaction SMILES: [C:1]1([CH:16]=[CH:17][C:18]([O:20]CC)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][C:13]([O-:15])=[O:14])=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C>[C:1]1([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=Cc1ccc(C=CC(=O)[O-])c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C=CC(=O)O)c2ccccc12
Yield: 96.1 %

Procedure:
In 2 mL of ethanol, were dissolved 115 mg (0.35 mmol) of ethyl 3,3'-(1,4-naphthalenediyl)diacrylate and 196 mg (3.49 mmol) of potassium hydroxide. The solution was refluxed for 2 hours. Thereto, 1N hydrochloric acid was added to bring the solution to pH=1. The deposited crystal was washed successively with water, and ethanol, and dried to obtain 90.2 mg (95%) of 3,3'-(1,4-naphthalenediyl)-diacrylic acid in a yellow crystal state.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][CH:9]([CH2:22]Br)[S:8]1)=[O:5])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C1SC(CBr)CN1c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)OCC)S1
Yield: 44.5 %

Procedure:
A.solution of 2-ethoxycarbonylimino-3-(3-tri-fluoromethylphenyl)-5-bromomethylthiazolidine (0.7 g) and potassium t-butoxide (0.25 g) in t-butanol (30 ml) was refluxed for 5 hours, and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.25 g of 2-ethoxycarbonylimino-3-(3-trifluoromethyl-phenyl)-5-methylenethiazolidine (Compound (i)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH2:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:26](OCC)(=[O:28])[CH3:27]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH:20][C:26](=[O:28])[CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(-c2ccncc2)c(-c2cccc(F)c2)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ncc(-c2ccncc2)c(-c2cccc(F)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (200 mg, 0.751 mmol) acetic anhydride (6 mL) and conc. sulfuric acid (4 drops) was stirred at 90° C. for 16 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate, water and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (×2) and brine, and then dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diethyl ether, and then the resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (126 mg, 54%)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:11](=[O:25])[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[C:11](=[O:25])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A stirring suspension of 4-(benzyloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (3.0 g, 8.44 mmol) and palladium on activated carbon (1.63 g, 10 wt. %, wet, Aldrich) in THF (150 mL) and methanol (250 mL) was placed under hydrogen (balloon) for 1 h. The resulting mixture was purged with nitrogen and then diluted with THF (150 mL) and methanol (50 mL). After stirring under nitrogen for 30 min, the mixture was filtered through a pad of CELITE® 545 filter aid and the filtrate was evaporated under reduced pressure to give 2.28 g crude product as a dark greenish solid. MS (ESI) 266 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][OH:13])=[N:7][CH:8]=1.[H-].[Na+].[Br:16][C:17]1[C:18](Cl)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:16][C:17]1[C:18]([O:13][CH2:12][C@H:10]2[CH2:11][C@@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=2)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1
Reactant: Cc1ncc(Br)c(Cl)n1
Reactant: COc1ccc([C@H]2C[C@@H]2CO)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methanol (S,S-DD3, ent2) (1.1 g, 6.1 mmol) in THF (25 mL) was added sodium hydride (300 mg, 7.4 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. Next, a solution of 5-bromo-4-chloro-2-methylpyrimidine (MM2) (1.5 g, 7.4 mmol) in THF (5 mL) was added and the reaction mixture was stirred at ambient temperature for two hours. Aqueous sodium bicarbonate (20 mL) was carefully added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated to afford the title compound as a yellow oil, which was sufficiently pure to use in the subsequent step without further purification. 1H NMR (500 MHz, DMSO): δ 8.60 (s, 1 H), 8.12 (d, J=3.0 Hz, 1 H), 7.30-7.22 (m, 2 H), 4.42 (d, J=7.1 Hz, 2 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.19 (dt, J=8.6, 4.6 Hz, 1 H), 1.75 (s, 1 H), 1.14 (dt, J=8.8, 4.7 Hz, 1 H), 1.04 (dt, J=8.9, 4.7 Hz, 1 H); LRMS m/z (M+H) 350.3 found, 350.2 required.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[ClH:12].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[ClH:12].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8][CH2:7]2)[CH2:25][CH2:26]1
Reactant: O=C1CSCN1CCCCBr
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1cccc(N2CCN(CCCCN3CSCC3=O)CC2)c1C

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (4.0 g) and 1-(2,3-dimethylphenyl)piperazine hydrochloride (3.8 g) in 100 ml of anhydrous CH3CN were added K2CO3 (9.3 g) and NaI (200 mg). The mixture was heated to 80° with stirring under N2.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][CH3:16])(C)(C)C>O1CCOCC1.CO>[CH3:16][O:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH2:8].[ClH:1]
Reactant: CO[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl(cis-2-methoxycyclohexyl)carbamate (0.17 g, 0.74 mmol) in methanol (0.5 mL). The reaction mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure to afford the desired product as HCl salt. Analytic LCMS (M+H)+: m/z=130.1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Agent: Cl
Product: O=C(Cc1cccnc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(pyridin-3-yl)acetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.83-8.84 (bs, 1H), 8.75 (d, J=5.5 Hz, 1H), 8.36-8.50 (m, 2H), 7.96-8.02 (m, 2H), 7.92 (dd, J=8.0, 5.5 Hz, 1H), 7.73-7.75 (m, 1H), 7.59-7.70 (m, 4H), 4.00 (s, 2H); MS (APCI+) M/Z 391 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:47])[C@H:3]([NH:16][C:17]([C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]([O:30][C:31]3[CH:32]=[N:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=3)[CH:27]=[C:26]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:25]=2)=[CH:22][CH:23]=1)=O)[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:45][O:44][CH2:43][C@H:42]([CH3:46])[O:41][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([C:21]2[NH:20][C:19]([C:17]3[O:1][C@@H:2]([CH3:47])[C@@H:3]([CH2:4][O:5][Si:6]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:8])[CH3:9])[CH:13]([CH3:14])[CH3:15])[N:16]=3)=[CH:23][CH:22]=2)[CH:25]=1)[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[N:33][CH:32]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 90 %

Procedure:
N-[(1R,2R)-2-Hydroxy-1-{[(triisopropylsilyl)oxy]methyl}propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.03 g, 1.49 mmol) synthesized in Example (91b) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.54 g, 2.99 mmol) and triethylamine (0.83 mL, 5.97 mmol) were added, followed by stirring at 50° C. for 4.5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 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=20%-50%) to afford the desired compound (901 mg, yield 90%) as a white solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(O)(=O)C>[OH-].[K+]>[NH2:1][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:4]1[C:2](=[O:3])[NH:16][C:14](=[S:15])[NH:13][N:12]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccccc1-c1n[nH]c(=S)[nH]c1=O
Temperature: 115 °C
Yield: 86.2 %

Procedure:
This was prepared by a modified literature procedure (Doleschall, G.; Lempert, K. Tetrahedron 1973, 29, 639-649). Isatin (10 g, 67.96 mmol) was dissolved in ca. 10% aqueous KOH (9.9 g in 100 mL of water) and then treated with thiosemicarbazide (6.28 g; 68.90 mmol). After 1 hour of heating at 115° C. (bath temperature), the reaction mixture was poured over ice and treated with glacial acetic acid drop-wise, till the pH was ca. 5. The yellow fluffy precipitate was filtered, washed copiously with water (8×50 mL) and dried first in air and then under high vacuum to afford 12.9 g of yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]([OH:16])=[O:15]>C(O)(=O)C.Br>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2c(C(=O)O)cccc2c1Br
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(Br)c(O)ccc12
Yield: 73 %

Procedure:
A mixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g, 0.11 moles, described in example 1b) in glacial acetic acid (460 ml) and 47% aqueous HBr(417 ml) was heated at reflux for 9 hr. The resulting precipitate was collected, washed with water and dried over P2O5 under reduced pressure. The precipitate was recrystallized from ethanol-water to give 21.45 g of 5-bromo-6-hydroxy-1-naphthalenecarboxylic acid; mp>225° C.; NMR (DMSO-d6) δ 8.0 (m, 5H), 11.0 (broad, 1H), 12.6 (broad, 1H).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([OH:7])[C:5]#[CH:6].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH3:12]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:8]([O:7][CH2:4][C:5]#[CH:6])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CCO
Reactant: CCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: C#CCOCCCCC
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a 500 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and thermometer was charged 140 grams (g) of 50% sodium hydroxide in water (1.75 mol), 1.88 g of tetrabutyl ammonium bromide (5.83 mmol), and 120 mL of dry hexane. The reaction mixture was stirred rapidly at ambient temperature followed by the dropwise addition of 13 g (0.232 moles) of propargyl alcohol and 43.16 ml (0.35 moles) of n-pentyl bromide. The reaction was refluxed for 3 hours, after which two phases formed when agitation was stopped. The upper (organic) phase was collected via a separatory funnel, and this material was distilled at atmospheric pressure. The purest fractions were combined to afford 28.2 g of a clear pale yellow liquid which was consistent with the target molecule upon analysis by 1H NMR. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 0.95 (m, 3H); 1.33 (m, 4H); 1.55 (m, 2H); 2.40 (s, 1H); 3.50 (m, 2H); 4.15 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29](I)=[CH:28][C:27]=2[F:35])=[CH:22][C:21]=1[CH3:36].COC1CCCC1>CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:29]2[C:30]([O:32][CH3:33])=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([CH3:36])[CH:22]=3)=[C:27]([F:35])[CH:28]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Solvent: COC1CCCC1
Product: COC(=O)c1cc(Br)ccc1Nc1cc(F)c(-c2ccc(Cl)c(C)c2)cc1OC
Temperature: 100 °C
Yield: 94.6 %

Procedure:
A sealable vial was charged vial with methyl 2-amino-5-bromobenzoate (3.63 g, 15.80 mmol), cesium carbonate (8.75 g, 26.9 mmol), Pd2(dba)3 (0.362 g, 0.395 mmol), xantphos (0.457 g, 0.790 mmol), and 4′-chloro-2-fluoro-4-iodo-5-methoxy-3′-methyl-1,1′-biphenyl (7.14 g, 18.96 mmol). The vial was sealed with septum cap and CPME (31.6 ml) was added. The mixture was heated at 100° C. for 2 h. The mixture was cooled and partitioned between water (30 mL) and EtOAc (50 mL). There was an insoluble solid that was suspended between the layers. The organic layer and the solid were collected together and the mixture was concentrated. The resulting yellow solid was taken up in DCM (100 mL) and filtered through a plug of celite. The mother liquor was concentrated to give a yellow solid that was slurried in IPA (100 mL) and collected by vacuum filtration to provide methyl 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzoate (7.15 g, 14.94 mmol, 95% yield) as a yellow solid. (ESI) 476.1 (M−H)−.