Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]=2[S:7][C:6]=1[C:21]([OH:23])=O)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1.O>CN(C=O)C>[NH:38]1[C:37]([NH:36][C:21]([C:6]2[S:7][C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=3[C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[N:41][N:40]=[N:39]1
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(C(=O)O)sc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a stirred solution of 1.43 g (4.2 mmol) of 3-isopropoxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid in 15 mL of DMF were added 1.07 g (6.6 mmol) of 1,1'-carbonyldiimidazole. The reaction mixture was heated at 85° C. for 2 hours. 5-Aminotetrazole (0.655 g, 7.7 mmol) was added to the reaction mixture in one portion, and the mixture was stirred at 85° C. for 8 hours. The solution was cooled to 24° C. and stirred at that temperature for 18 hours. The reaction mixture was diluted by addition of 100 mL of water and was extracted three times with 50 mL portions of chloroform. The extracts were washed with 50 mL of 2N HCl, water, brine, dried over Na2SO4, and concentrated to dryness by evaporation of the solvent under reduced pressure. The residue was crystallized from 500 mL of diethyl ether to give 1.02 g of 3-isopropoxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 189°-191° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:15]
Reactant: O=C(Cl)CCCCCl
Reactant: COc1ccccc1
Product: COc1ccc(C(=O)CCCCCl)cc1

Procedure:
Using anisole (15.0 g) and 5-chlorovaleryl chloride (18.0 ml) according to the same method as that of Reference. Example 1, the title compound was obtained as colorless crystals (27.3 g) having a melting point of 67 to 68° C.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12](Cl)=[O:13].[CH3:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:16]([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13]
Reactant: CC(CC(C)(C)C)c1ccccc1N
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)c1ccccc1NC(=O)c1c(C(F)(F)F)nn(C)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
At from 0° C. to −10° C., a solution comprising 8.1 g (42.4 mmol) of 5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl chloride in 80 ml of tetrahydrofuran is added dropwise to a solution comprising 6.5 g (28.3 mmol) of 2-(1,3,3-trimethylbutyl)phenylamine and 5.7 g (56.6 mmol) of triethylamine in 200 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 h. For work-up, the mixture is filtered through silica gel and concentrated. Purification on silica gel (petroleum ether/ethyl acetate 3:1) gives 10.1 g (94% of theory) of [5-fluoro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[2-(1,3,3-trimethylbutyl)phenyl]carbox-amide of log P (pH 2.3)=4.14.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Reactant: NCc1ccccc1Cl
Product: Clc1ccccc1CNc1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (200 mg, 0.50 mmol) and 2-chlorobenzylamine (281 mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol 50:1 to 20:1) to afford the crude product (110 mg). Then the crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 58 mg, 25.1%). 1H NMR (300 MHz, CD3OD): δ 8.72 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.59 (d, 1H, J=6.9 Hz), 7.46-7.28 (m, 5H), 4.75 (brs, 2H), 4.17 (brs, 2H), 3.93 (brs, 4H), 3.59-3.28 (m, 5H). LC-MS: [M+H]+ 466.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.CC(C)=O>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC(C)=O
Solvent: CCO
Product: N#Cc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Yield: 79.3 %

Procedure:
4-phenylpiperazine (41.4 g, 0.26 mol) was added to a solution of 4-(bromomethyl)benzonitrile (25 g, 0.13 mol) in 60 ml ethanol and the mixture was refluxed for one hour. After filtration of the precipitated N-phenylpiperazinium bromide, the filtrate was evaporated and the residue was recrystallized in a chloroform: acetone mixture to afford 28.6 g (79% yield) of 4-(4-phenylpiperazinylmethyl)benzonitrile.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Cyclopentyl chloroformate was added to a stirred solution of the amino ester (A) (0.15 g.) and N-methylmorpholine (0.27 g.) in dichloromethane (3 ml.) at 0°-5° C., under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at 0°-5 ° C., the cooling bath removed, and stirring continued for 1 hour. The mixture was then poured into 1M hydrochloric acid (15 ml.), and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.18 g., 89%) as a colorless oil; NMR: 1.66(m, 6H), 1.82(m,2H), 3.83(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s,2H, CH2.Ar), 5.04(m,1H, --CHO--), 7.09(m, 3H), 7.22(d,1H), 7.42(dd, 1H), 7.48(d,1H), 7.57(br,1H), 9.18(br,1H, CONH), 10.57(s,1H, H1 -indole).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][CH:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:41][CH2:40][CH2:39][CH:38]([CH3:43])[CH3:37])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of 2-ethyl-1-hexanol (yield: 120 mg, 52%). mp 98–99° C. 1H NMR (300 MHz, DMSO-d6) δ 0.73 (d, J=7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:12]1([C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([OH:18])[N:1]([C:3]3[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=3)[C:9]([OH:11])=[O:10])[N:2]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: NNc1cc(C(=O)O)ccn1
Product: O=C(O)c1ccnc(-n2nc(C3CC3)cc2O)c1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-hydrazinylpyridine-4-carboxylic acid and ethyl 3-cyclopropyl-3-oxopropanoate according to the procedure for the preparation of Example 1. 1H NMR (400 MHz, CD3OD): δ 0.83-0.88 (2H, m), 1.05-1.09 (2H, m), 1.88-1.91 (1H, m), 4.86 (1H, s), 7.70 (1H, dd, J=5.2, 1.2 Hz), 8.54 (1H, d, J=5.2 Hz), 8.75 (1H, s). [M+H] Calc'd for C12H11N3O3, 246; Found, 246.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)C>[NH2:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCC1CCCN(Cc2ccc(Cl)cc2)C1
Yield: 57.7 %

Procedure:
To a solution of 10.52 g of the crude 1-(p-chlorobenzyl)-3-phthalimidomethylpiperidine in ethanol (100 ml) was added hydrazine monohydrate (1.8 ml, 58 mmol) and the mixture was heated under reflux for 2 hours. After cooling, 10% aqueous sodium hydroxide (200 ml) was added to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (150 ml×3) and then the combined organic layer was then extracted with 10% aqueous hydrochloric acid (150 ml×3). The combined aqueous hydrochloric acid layer was washed with chloroform (100 ml), 10% aqueous sodium hydroxide was added until it became strongly basic and then extracted with chloroform (100 ml×3). The combined organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude 3-aminomethyl-1-(p-chlorobenzyl)piperidine (3.93 g). A total yield of two steps=92%. This compound was used for the subsequent reaction without purification.