Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(CN2CCN(CCO)CC2)cc1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCN(CCO)CC3)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.4 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzoic acid (122 mg, 0.46 mmol), o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzamide as white solid (30 mg, 16.4%). LRMS (M+H+) m/z: calcd 398.23. found 398. HPLC purity (214 nm): 89%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:32])([F:31])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1.FC1C=C(F)C=CC=1[C@]1([C@H](OC2N(C3C=CC(OCC(F)(F)F)=CC=3)N=NN=2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:32])[F:31])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](Oc1nnnn1-c1ccc(OCC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 41.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.35 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.31 g of 1-[4-(2,2,2-trifluoroethoxy)phenyl]-5(1H,4H)-tetrazolone, a mixture (3:2, 0.22 g) of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,2-trifluoroethoxy)phenyl]-5(1H,4H)-tetrazolone and (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-[4-(2,2,2-trifluoroethoxy)phenyl]-1H-tetrazol-5-yloxy]ethyl]oxirane was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[CH:21][C:20]([C:23](=O)/[CH:24]=[CH:25]/[N:26](C)C)=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O.[NH2:31]N>CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]5[NH:31][N:26]=[CH:25][CH:24]=5)=[CH:21][N:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Solvent: O
Solvent: CO
Product: c1cc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)[nH]n1

Procedure:
A mixture of (2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-one (D53) (195 mg, 0.5 mmol) and hydrazine hydrate (0.4 ml) in methanol (3 ml) was heated at reflux for 24 hours. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E215). MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:20]([CH3:21])[CH3:19])=[O:6]
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)N(C)C
Reaction time: 1 h

Procedure:
2-Methoxy-4-(2',2'-dimethylpropionamido)-benzoyl chloride (1.12 g) in dry THF (10 ml) was added dropwise over 30 minutes to a stirred solution of dimethylamine (1.17 g of a 40% aqueous solution) in THF (15 ml) at 0°-5° C. After completion of the addition the solution was stirred for 1 hour at 5°-10° C., stood at room temperature overnight, poured into water, and extracted with ethyl acetate. The extract was dried and evaporated to give the product as a yellow solid (0.889 g), m.p. 143°-144° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)=[CH:3][CH:2]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>CC#N.FC(F)(F)C(O)=O>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:11]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)[nH]n1
Reactant: C1=COCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccc(C)cc2)n(C2CCCCO2)n1
Yield: 117.3 %

Procedure:
A mixture of methyl 5-p-tolyl-1H-pyrazole-3-carboxylate (224 mg, 1.03 mmol), 3,4-dihydro-2H-pyran (190 μL, 2.07 mmol) and trifluoroacetic acid (2 μL, 0.02 mmol) in anhydrous MeCN (3 mL) was refluxed for 2 hrs. The solvent was evaporated. The residue was resuspended in CH2Cl2 (50 mL) and was washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 6:4) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylate (363 mg, 68%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH2:12]1COCC1.[N+](=C)=[N-]>C(OCC)C>[Cl:11][C:6]1[C:7]([CH2:8][C:9](=[O:10])[CH3:12])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: C1CCOC1
Reactant: O=CCc1c(Cl)ncnc1Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)Cc1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 500 mL two necked round bottom flask was charged with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.2 g), dry diethyl ether (80 mL) and dry THF (80 mL). The reaction mixture was cooled to 0° C. and diazomethane solution in diethyl ether (30 mL) was slowly added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 24 hours under nitrogen atmosphere before being quenched by acetic acid (20 mL), followed by water (100 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude 1-(4,6-dichloropyrimidin-5-yl)propan-2-one (0.94 g) which was used as was. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 4.19 (s, 2H), 8.85 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH2:6])=[C:7]([Cl:11])[C:8]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Br)c(Cl)cc1N
Product: Cc1cc(Br)c(Cl)c(Cl)c1N

Procedure:
This material was prepared from 4-bromo-5-chloro-2-methylaniline by chlorination with N-chlorosuccinimide. The product was isolated as a solid, m.p. 66°-68° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[F:31][C:29]([F:30])([F:32])[C:26]1[N:24]2[N:25]=[C:20]([N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:11][CH2:10][C:9]4=[O:18])[CH2:4][CH2:3]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C1CCc2ccccc2N1C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-piperidin-4-yl-3,4-dihydroquinolin-2-one hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-3,4-dihydroquinolin-2-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[C:26]([C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38])(=[O:28])[CH3:27]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C(C)=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.67 mmol) of 2'-hydroxy-5'-methylacetophenone was alkylated with 1.68 g (7.34 mmol) of methyl 2-bromophenylacetate to afford 1.25 g (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35]([NH2:37])=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[CH2:38](N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[Cl:1][C:2]1[C:3]([C:35]([NH2:37])=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N:20]([CH3:38])[C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:16][CH:17]=3)[C:6]=2[CH:34]=1
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.8 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamine (293 mg, 2.90 mmol) and methanesulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13](C)[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([S:64]([CH3:63])(=[O:66])=[O:65])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CCC(c2cn(S(C)(=O)=O)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and methanesulfonylchloride (commercially available). MS (m/e): 489.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>Cl>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 80 °C

Procedure:
3-Bromo-4-methoxyphenylacetic acid (4.1 g, 16.7 mmol) in EtOH (100 mL) was treated with concentrated HCl (2 drops) and heated to 80° C. for 3 days. After cooling to room temperature, the mixture was concentrated to give the title compound.