Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Br:11]Br>OS(O)(=O)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][NH:7]2)=[CH:3][C:2]=1[F:1]
Reactant: Fc1ccc2c(c1)CCN2
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Fc1cc2c(cc1Br)NCC2
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 5-fluoroindoline (4.65 g, 34 mmole) in conc. H2SO4 acid (60 ml) under argon was treated with silver sulfate (5.5 g, 18 mmole) and stirred for 0.5 h, then cooled to −5° C. and treated dropwise over 15 min with bromine (5.6 g, 35 mmole). The mixture was maintained at −5° C. for 0.5 h, then allowed to warm to room temperature over 1 h, before adding cautiously to well stirred ice/water (600 ml). The mixture was filtered through Kieselguhr, then basified by addition of 40% NaOH solution and extracted with Et2O (2×300 ml). The combined extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a beige solid (6.5 g, 89%). MH+ 216/218.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:1])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of methyltriphenylphosphonium bromide (16.1 g, 45.2 mmol, 3.0 eq.) in THF (50 mL) was cooled to −78° C. 1M Sodium bis(trimethylsilyl)amide in THF (38.0 mL, 41.4 mmol, 2.75 eq.) was added and the mixture was stirred for 30 minutes. A solution of (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (3.0 g, 15.0 mmol, 1.0 eq.) in THF (10 mL) was slowly added and the mixture was stirred at −78° C. for 2 hours. The mixture was warmed to room temperature over 3 hours and the reaction was quenched with half saturated NH4Cl (50 mL). The organic layer was washed with saturated aqueous NaCl (50 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting oil was slurried in hexanes (50 mL) and the precipitate was filtered off. The filtrate was concentrated, diluted with hexanes (25 mL), and chilled at −20° C. overnight. The precipitate was filtered off and the filtrate was purified by column chromatography (0-100% EtOAc in hexanes) to yield (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (2.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[NH:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([C:18]1[NH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=1)=[O:7]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(C(=O)c2cc(OC)cc(OC)c2)c1

Procedure:
By the procedure of Example 64, but a 5 hour reaction time, 3,5-dimethoxybenzoyl chloride (4.0 g., 20 mmoles) was reacted with methyl pyrrole-3-carboxylate to yield, without recrystallization, methyl 5-(3,5-dimethoxybenzoyl)pyrrole-3-carboxylate (3.7 g., m.p. 115°-120° C., m/e 289).
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to ethanol (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). 1H NMR (CDCl3): 1.06-1.12, 1.31-1.36, 1.80-0.193, 2.25-2.49, 2.62-2.92, 3.74-4.08, 4.81 and 5.27, 6.20 and 6.54, 7.24-7.57.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9].CO.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Solvent: CO
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a stirred solution of N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (9-01) (1.7 g, 5.46 mmol) in methanol (30 mL) aqueous NaOH (218.4 mg, 5.46 mmol, 2M) was added. After heating to reflux, benzyl bromide (0.654 mL, 5.46 mmol) was added and heating was continued for 24 h. After completion of the reaction, the mixture was concentrated to remove methanol, then diluted with water and extracted with dichloromethane. The combined organic layer was washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (10-01) (1.02 gm, 46.48%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=C(N=C=S)C=CC=1>>[CH3:48][O:52][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 262 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-methoxy phenyl isothiocyanate. The compound of example 262 was used directly without isolation for the preparation of compound of example 263.
Reaction SMILES: ClC1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)[C:15](=[O:30])[C:16]1C=C(C(F)(F)F)[CH:19]=[C:18](C(F)(F)F)[CH:17]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][C:45]=2[NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[C:40]([O:58][CH3:59])[CH:39]=1.C(Cl)C1OCCC1>>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][C:45]=2[N:50]([CH2:19][CH:18]2[CH2:17][CH2:16][CH2:15][O:30]2)[C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[C:40]([O:58][CH3:59])[CH:39]=1
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reactant: COc1cc(F)ccc1-c1ccncc1NC(=O)OC(C)(C)C
Agent: ClCC1CCCO1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCCO1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from tert-butyl 4-(4-fluoro-2-methoxyphenyl)pyridin-3-ylcarbamate and tetrahydrofurfurylchloride after a reaction time of 72 hours at 70° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (38%). MS (ESI): m/z=403.205 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Br:13]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][C:10]=1[Br:13])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)c(C(=O)O)c1Cl
Solvent: CC#N
Product: Nc1c(Br)cc(Cl)c(C(=O)O)c1Cl
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
A mixture of 3-amino-2,6-dichloro-benzoic acid (5 g, 24 mmol, Step b) in acetonitrile (50 mL) was treated with N-bromosuccinimide (5.1 g, 29 mmol) and the reaction mixture was stirred at 90° C. for 45 minutes. Acetonitrile was removed under vacuum and the residue was partitioned between water (200 mL) and ethyl acetate (200 mL). Organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to yield 3-amino-4-bromo-2,6-dichloro-benzoic acid (5 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3-methyl-pyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=2[CH3:18])[C:23]([OH:25])=[O:24])[CH:11]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (0.3305 g, 1.135 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.3782 g, 1.443 mmol), potassium carbonate (0.3196 g, 2.312 mmol), and bis(di-tert-butyl(4-dimethylaminophenyephosphine)dichloropalladium(II) (81.9 mg, 0.116 mmol) in 1,4-dioxane (5.0 mL, 64 mmol) and water (0.5 mL, 30 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, acidified with 10% aqueous citric acid, and extracted twice with ethyl acetate. The combined organic extracts were reduced in volume under evaporation and the product collected via filtration as a white precipitate and dried under vacuum to yield 365.5 mg (91%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid. LCMS (ESI): M+H=347.2; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 2.34 (s, 3H), 2.14-2.02 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)=[C:4]([OH:17])[CH:3]=1.[C:18]([CH2:23][CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:19].[Cl-].[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:23]([CH3:24])[C:18](=[O:19])[O:17]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)c2ccc(Cl)cc2oc1=O
Temperature: 200 °C
Reaction time: 15 h
Yield: 51.7 %

Procedure:
A mixture of (4-chloro-2-hydroxyphenyl)(4-fluorophenyl)methanone (200 mg) and (carboethoxyethylidene)triphenylphosphorane (435 mg) was heated with stirring at 200° C. for 15 hours. After cooling, the reaction mixture was diluted with ethyl acetate and the solution was poured into an aqueous saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and filtered through a column of porous diatomite (Chem Elut). The filtrate was concentrated and the resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=97/3 to 90/10) to give the titled compound (119 mg) as a yellow powder.