Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH3:30][C:31](=[CH2:34])[CH2:32][NH2:33].[CH3:35]N1CCCC1=O>O>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][C:31]([CH3:30])=[CH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:35])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: CN1CCCC1=O
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: C=C(C)CN
Solvent: O
Product: C=C(C)CNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 160 °C
Reaction time: 36 h

Procedure:
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (372.0 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and 2-methylprop-2-en-1-amine (213.0 mg, 3.0 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated with stirring at 160° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 407.0 mg of the product as a light yellow solid. MS obsd. (ESI+) [(M+H)+] 408.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.Cl>C(O)C.O>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]3[NH:10][C:9](=[O:11])[NH:8][C:6]3=[N:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Temperature: 25 °C
Yield: 128.2 %

Procedure:
To a suspension of 10.11 g 1,3-dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one (Example 5) in 200 ml absolute ethanol and 80 ml water was added 25.34 g stannous chloride dihydrate (SnCl2.2H2O) and 120 ml concentrated hydrochloric acid. The reaction mixture was heated at reflux for 6 hours, then cooled to room temperature and allowed to stand until crystals formed. The latter was collected by decantation and additional product obtained by concentration of the mother liquors to 60% of the original volume. The total solid product was washed with ethanol and ether and dried (high vacuum at 120° C.) to give 11.52 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one in the form of its hydrochloride salt and containing ethanol of crystallization, m.p. 277-283° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[CH:19]=2)=[C:13]([Cl:28])[CH:12]=1>CN(C=O)C.S(=O)(O)[O-].[Na+].O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[C:19]=2[Cl:1])=[C:13]([Cl:28])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-Chlorosuccinimide was (13.0 g, 99.0 mmol) added to a suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (24) (32.54 g, 89.9 mmol) in DMF (500 mL). The suspension was allowed to stir at room temperature overnight. The reaction mixture was diluted with saturated sodium bisulfite (200 mL) and water (1 L) resulting in formation of a thick white precipitate which was isolated by filtration and washed with water. The solids were dissolved into THF. Two volumes of diethyl ether were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to provide an orange solid. The solid was triturated with diethyl ether to provide the desired product as an off-white solid (25) (13.34 g, 37%). MS (APCI−) m/z 393, 395, 397 (M−; Cl, Br pattern) detected.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].CC(C)([O-])C.[K+].[O:22]1[CH2:25][C:24](=O)[CH2:23]1>C1COCC1>[O:22]1[CH2:25][C:24](=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:23]1
Reactant: O=C1COC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a solution of triethyl 2-phosphonopropionate (800 mg, 3.4 mmol) in anhydrous THF (3 mL) was added potassium tert-butoxide (340 mg, 3.1 mmol). The reaction was stirred for 1 h at RT then oxetan-3-one (CAS-RN 6704-31-0, available from commercial suppliers, 220 mg, 3.1 mmol) was added in a single portion. The reaction was heated at reflux for 20 h then cooled to RT and adsorbed onto silica gel. Purification by automated column chromatography (Biotage SP4) on silica gel (12 g Grace cartridges) eluting with EtOAc: n-heptane (gradient elution, 0% (equil., 5 CV), 0% (5 CV) 0-100% (25 CV), 100% (10 CV)) afforded (i) (151 mg, 31%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=4)[C:28]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>O1CCCC1.CO.O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=4)[C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}acetate (136.8 mg, 0.263 mmol) in tetrahydrofuran (4 ml) was added a solution of lithium hydroxide-water (22.1 mg, 0.526 mmol) in MeOH-water (1:1) (2.8 ml) at 5° C. and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N-hydrochloric acid (0.8 ml) at 5° C. and extracted with EtOAc. The organic layer was washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo to give (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}acetic acid (129.0 mg, 100%).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].OS(C(F)(F)F)(=O)=O>>[OH:2][C:1]1[C:9]2[C:4]([CH2:6][CH3:7])=[CH:3][C:1](=[O:2])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCc1cc(=O)oc2cc(O)cc(O)c12
Reaction time: 16 h
Yield: 127.8 %

Procedure:
A suspension of phloroglucinol (1.04 g, 8.35 mmol) in ethyl propionyl acetate (1.24 mL, 8.71 mmol) was added over 0.5 h to triflic acid (2 mL). The reaction was mechanically stirred in an ice bath for 16 h. The reaction was quenched by carefully pouring in to an ice bath. The solid was filtered and dried yielding a white solid (1.1 g, 83.2%): mp. 248-252° C.; 1H NMR (DMSO-d6) δ 1.15 (t, 3H), 2.91 (q, 2H), 5.83 (s, 1H), 6.17 (d, 1H), 6.26 (d, 1H) 10.3 (s, 1H) 10.6 (s, 1H).
Reaction SMILES: [C:1]([S:4][C:5]([CH3:38])([CH3:37])[CH:6]([NH2:36])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=1[Cl:20])=[O:8])(=[O:3])[CH3:2].[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>N1C=CC=CC=1>[C:1]([S:4][C:5]([CH3:38])([CH3:37])[CH:6]([NH:36][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:13]([Cl:20])=[CH:14][N+:15]([O-:19])=[CH:16][C:17]=1[Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)SC(C)(C)C(NS(=O)(=O)c1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
4-((2S)-2-(3-(acetylthio)-2-amino-3-methylbutanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (101 mg, 0.170 mmol) was dissolved in pyridine (1 ml), then benzenesulfonyl chloride (60 mg, 0.340 mmol) was added at 0° C., and the mixture was stirred at RT for 2 hours. The reaction was quenched with HCl 1N, and the product was extracted with EtOAc. The organic phase was washed with HCl 1N (2×) and brine, then dried over Na2SO4. The solvent was removed and the crude product was purified by preparative reverse-phase HPLC to give 10 mg of the desired compound (Yield 8%).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].[CH3:26][I:27]>CC(C)=O>[I-:27].[CH3:26][N+:20]1([CH2:19][C:16]2[CH:17]=[CH:18][C:6]3[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:7]=3[CH:15]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1oc2ccc(CN3CCOCC3)cc2c1-c1ccccc1
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(Cc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)CCOCC1
Product: [I-]
Reaction time: 24 h

Procedure:
To a 1.9 g. (0.0056 mole) sample of N-(2-nitro-3-phenyl-5-benzofuranylmethyl)morpholine (the product of Example 6) in 100 ml. of acetone is added 1.0 g. of methyliodide. After setting for one week, an additional 1.0 g. of methyliodide is added. After 1 day of stirring, the precipitated solid is separated by filtration and extracted with 300 ml. of refluxing ethanol to provide yellow crystals of N-methyl-N-(2-nitro-3-phenyl-5-benzofuranylmethyl)morpholinium iodide, m.p. 226°-230° C., having the structure ##STR15##
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].C(#[N:29])C>>[NH2:29][CH:21]1[CH2:24][CH2:23][N:22]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:20]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC#N
Reactant: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)c(F)c21
Temperature: 5 °C

Procedure:
A suspension of 0.81 g (3.0 mmole) of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 1.28 g (10 mmole) of 3-acetylamminopyrrolidine [U.S. Pat. No. 4,341,784] and 1.5 g (15 mmole) of triethylamine in 50 ml of acetonitrile was refluxed for four hours. The solvent was removed in vacuo and the residue was dissolved in 50 ml of 6.0M hydrochloric acid/ethanol (1:1). The mixture was refluxed for four hours and the ethanol was removed in vacuo. The residue was diluted to 100 ml with water and adjusted to pH 7.3 with 1.0N sodium hydroxide. After cooling to 5° C., the precipitate was removed by filtration, washed successively with water, ethanol, ether, and dried in vacuo to give 0.6 g of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 240°-242° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[B:10](OC)([O:13]C)[O:11]C.Cl>C1COCC1.[Cl-].[Na+].O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([B:10]([OH:13])[OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Bromobenzyl alcohol (2.0 g, 10.7 mmol) was dissolved in dry THF (50 ml) in a dry 100 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/acetone bath. n-Butyl lithium (11 ml of a 2.13M solution in hexane, 23.5 mmol) was added. The reaction was warmed to room temperature for 1 hour, then cooled in an ice water bath. Trimethyl borate (1.3 ml, 11.2 mmol) was added and the mixture was stirred at room temperature overnight, then treated with 2N aqueous HCl to pH 2, and stirred for 3 hours. Brine (15 ml) was added, and the mixture was extracted with ethyl acetate (3×15 ml). The organic materials were combined, dried (MgSO4) then concentrated under reduced pressure which gave of 3-hydroxymethylbenzeneboronic acid (98%) as a clear oil.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)(C)C.Cl.FC1C=C(C=CC=1OCCN1CCCCC1)C(O)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:74]=[CH:75][C:76]=1[O:77][CH2:78][CH2:79][N:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[CH2:49][N:50]([CH:71]([CH3:73])[CH3:72])[C:51]1[CH:56]=[C:55]([O:57]C)[CH:54]=[CH:53][C:52]=1[CH:59]1[CH2:68][CH2:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([O:69]C)[CH:65]=2)[CH2:60]1>>[F:45][C:46]1[CH:47]=[C:48]([CH:74]=[CH:75][C:76]=1[O:77][CH2:78][CH2:79][N:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[CH2:49][N:50]([CH:71]([CH3:73])[CH3:72])[C:51]1[CH:56]=[C:55]([OH:57])[CH:54]=[CH:53][C:52]=1[CH:59]1[CH2:68][CH2:67][C:66]2[CH:65]=[C:64]([OH:69])[CH:63]=[CH:62][C:61]=2[CH2:60]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(Cc1ccc(OCCN3CCCCC3)c(F)c1)C(C)C)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)C)C2
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Product: CC(C)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 68.6 %

Procedure:
Synthesized from isopropyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]isopropyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (402 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (262 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(CNc2ccccn2)cc1
Yield: 56.2 %

Procedure:
4-Hydroxybenzaldehyde (3.9 g, 32 mmol) and 2-aminopyridine (3.0 g, 32 mmol) were stirred in toluene (100 ml) at room temperature for 5 min. After concentrating in vacuo the residue was dissolved in ethanol (50 ml) and hydrogenated over Pd/C (100 mg) under a hydrogen atmosphere, for 18 h. The reaction mixture was filtered, concentrated and the crude product was chromatographed (dichloromethane-silica) to yield the title compound as white crystals (3.6 g, 56%). 1H NMR (CDCl3) δ 8.10 (1H, m), 7.49 (1H, m), 7.14 (2H, d, J 7.8 Hz), 6.79 (2H, d, J 7.8 Hz), 6.64 (1H, m), 6.47 (1 H, d, J 7.8 Hz), 4.79 (1H, br s) and 4.32 (2H, d, J 5.2 Hz).