Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.7 %

Procedure:
In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 3-bromopropanol (26.1 g), and the mixture was stirred at 100° C. for 20 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3-(4-bromophenoxy)-1-propanol (20.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C@H:27](Cl)[CH3:28]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:27]([C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[Cl:20])[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1ccncc1Cl
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2ccncc2Cl)nc2nc(N)sc12
Yield: 8 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (860 mg, 2.87 mmol) and 3-chloro-4-[(1R)-1-chloroethyl]pyridine from the previous step. Purification by flash chromatography yielded the title compound (105 mg, 8% yield) as a diastereomeric mixture.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:15][C:16](=[O:21])C(Cl)(Cl)Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26](CC2C=CC=CC=2)[CH2:25][CH2:24]1>>[NH:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[NH:15][C:16]2=[O:21])[CH2:24][CH2:25]1
Reactant: O=C(c1ccccc1)c1cccnc1NC(=O)C(Cl)(Cl)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C1Nc2ncccc2C(c2ccccc2)N1C1CCNCC1

Procedure:
In similar way as in Preparation Example 89, the title compound was synthesized from 3-benzoyl-2-trichloroacetylaminopyridine and 4-amino-1-benzylpiperidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.[CH3:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([C:46]([F:49])([F:48])[F:47])[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][C:41]=12)=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:43]1[CH2:44][CH2:45][N:40]2[C:39]([C:46]([F:49])([F:47])[F:48])=[N:38][C:37]([C:35]([NH:34][CH3:33])=[O:36])=[C:41]2[CH2:42]1)=[O:5]
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (598 mg, 2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (135 mg, 1 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (573 mg, 3 mmol) and N, N-diisopropylethylamine (774 mg, 6 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 13 (650 mg, yield 61.0%) as a white solid.
Reaction SMILES: FC(F)(F)[C:3]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4]1.O=S(Cl)Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C@:23]([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1>ClCCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:31][C:7]([CH:3]2[CH2:4][CH2:5][CH2:6]2)=[O:9])([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-trifluoromethylcyclobutyl carboxylic acid (22.7 mg, 0.135 mmol) in DCE (1 mL) was added SOCl2 (16 mg, 0.135 mmol) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool down to room temperature and TEA was added (31 μL, 0.23 mmol), followed by the addition of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (20 mg, 0.045 mmol). The reaction was stirred at room temperature for 18 h, concentrated and the residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide (5.2 mg, 22% yield). LCMS: RT=2.14 min [M+H] 525.2 (LCMS Method 2.); NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1H, s; 8.13 ppm, 1H, s; 7.68 ppm, 1H, m; 7.11 ppm, 6H, m; 6.87 ppm, 1H, m; 6.57 ppm, 2H, m; 5.87 ppm, 1H, t, J=53 Hz; 4.45 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.51 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.09 ppm, 1H, m; 2.20 ppm, 4H, m; 1.94 ppm, 2H, m.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](N)=[O:5].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: NC(=O)c1cc(F)c(F)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 9 h

Procedure:
A mixture of 2,3-dichloro-4,5-difluorobenzamide (0.5 g) and 18N-sulfuric acid (2.5 ml) was stirred at 125° to 135° C. for 9 hours, and then poured into ice water. After standing overnight, the resulting precipitate was collected by filtration and recrystallized from hexane-benzene to give the title compound (0.3 g) as colorless prisms.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:25])[CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=CC=1)([O-])=O.[NH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30]>>[C:15]([NH:14][CH2:13][CH2:12][C:11]([NH:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30])=[O:25])([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(CCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(CCNC(=O)OCc1ccccc1)NCCS(=O)(=O)O
Yield: 81.7 %

Procedure:
1.9 g (5.5 mmoles) of N-carbobenzoxy-β-alanine-p-nitrophenyl ester (Biochemistry 4, 1884 1965) are reacted with 0.63 g (5 mmoles) of taurine as described in Example 1 to obtain 1.35 g (82%) of N-carbobenzoxy-β-alanyl-taurine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CN(C)CCCCN
Product: CN(C)CCCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 26, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67) and 4-dimethylaminobutylamine.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:22])=[O:23])[CH:19]=[CH:20][C:12]1=2)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of 4-(2-(cyanomethoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 0.364 mmol) in DCM (30 mL) was added TFA (0.5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by prep HPLC purification to obtain 4-(2-(cyanomethoxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a white solid (39 mg, 25%). MS (ESI, positive ion) m/z; 429.0 (M+1). 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 1H), 7.23-7.15 (m, 2H), 7.12 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.1 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.19 (d, J=8.5 Hz, 1H), 5.18 (s, 2H), 4.32 (t, J=4.2 Hz, 2H), 3.64 (t, J=4.2 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:13](=[S:14])[CH2:12][CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:19][CH2:20][CH2:21][S:14][C:13]1[C:8]([CH3:7])=[C:9]([CH:10]=[CH:11][CH:12]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(SCCBr)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
30.3 g (0.22 mol) of potassium carbonate were added to 40.0 g (0.22 mol) of methyl 3-thio-2-methylbenzoate in 500 ml of acetone, and 82.6 g (0.22 mol) of 1,2-dibromoethane were added dropwise. After 10 hours of stirring at room temperature, the solvent was distilled off, the residue was taken up in water/ethyl acetate and the organic phase was dried and concentrated. The oil that remained was chromatographed over silica gel using ethyl acetate/cyclohexane=1/10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1.Cl>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Agent: Cl
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 146 was prepared from bis(4-fluorophenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 2H), 7.30–7.19 (m, 4H), 7.11–7.07 (m, 1H), 7.01–6.96 (m, 5H), 6.88 (d, 1H, J=7.7 Hz), 6.69 (s, 1H), 4.97 (septet, 1H, J=6.3 Hz), 4.79 (s, 1H), 4.11 (q, 1H, J=6.8 Hz), 3.39 (q, 2H, J=5.6 Hz), 2.98–2.92 (m, 2H), 2.52–2.40 (m, 3H), 1.98 (t, 2H, J=11.5 Hz), 1.85–1.78 (m, 2H), 1.72–1.54 (m, 3H), 1.27 (d, 6H, J=6.3 Hz); ESMS m/e: 550.3 (M+H)+; Anal. Calc. for C32H37F2N3O3.0.87 HCl: C, 66.84; H, 6.61; N, 7.31.Found: C, 66.83; H, 6.48; N, 7.31.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl>ClC1C=CC=CC=1>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:6]1[CH:14]=[CH:13][C:12]([Cl:2])=[CH:11][CH:7]=1)=[O:9]
Reactant: Cc1cccc(C(=O)Cl)c1O
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Temperature: 100 °C

Procedure:
Chlorobenzene (78.79 g, 71.6 ml; 0.7 mole) and AlCl3 (14 g, 0.105 mole) were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture was stirred and heated at 100° C. overnight. The cooled mixture was added to conc. HCl (10 ml) and ice, extracted with ether, and ether washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and the filtrate distilled, to give (after removal of the ether), a main fraction 2-hydroxy-3-methyl-4'-chlorobenzophenone, b.p. 148°-152° C./0.5 mm (8.18 g), which solidified to yellow microplates, m.p. 55°-58° C.