Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3Cl)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4Cl)n3n2)cc1
Yield: 32.3 %

Procedure:
Applying the Cyclization Procedure 1, 2-chloro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 53) (127 mg, 0.33 mmol), 1,2-dichloroethane (6.6 mL) and phosphorus oxychloride (0.250+0.154 mL, 4.33 mmol), to afford 7-(2-chlorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (39 mg) as a yellow solid. MS m/z 366 (M+1).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.S([O-])(OCCC(C)C)=O.[I:21]CI>>[I:21][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: ICI
Agent: CC(C)CCOS(=O)[O-]
Product: Cc1cc(I)ncc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 2-amino-4-methyl-5-nitropyridine in 10 mL of diiodomethane was added 1.8 mL of isopentyl sulfite at room temperature, stirred at this temperature for 30 minutes, and after raising the temperature to 80° C., the solution was stirred for 2 hours. The diiodomethane was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to afford 897 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][O:28]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>O1CCCC1.CO.Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][OH:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CCOC3CCCCO3)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CCO)[nH]c2c1
Yield: 66.2 %

Procedure:
A solution of methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-carboxylate (2.21 g, 4.80 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and 6N hydrochloric acid (20 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H-indole-6-carboxylate (1.20 g, yield 66.7%).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: Fc1cccc(Br)c1Cl
Product: Cc1cc2c(s1)CN(C)CCC2Oc1cccc(Br)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:38])[C:15]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:12](F)[C:11]=2[F:40])[CH2:6]1)(=[O:3])[CH3:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:38])[C:15]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:12]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:11]=2[F:40])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2ccccc2OCOCCOC)c2cc(N3CCC(NC(C)=O)C3)c(F)c(F)c2c1=O
Product: CCOC(=O)c1cn(-c2ccccc2OCOCCOC)c2cc(N3CCC(NC(C)=O)C3)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
Ethyl 7-(3-acetamidopyrrolidin-1-yl)-5,6-difluoro-1-(2-methoxyethoxymethoxyphenyl)-4-oxo-4H-quinoline-3-carboxylate is reacted with benzylamine by a procedure similar to that of Example 22 step 3 to prepare the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C=O)C.O>[NH2:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:27]([N:26]([CH3:30])[CH3:25])=[O:28])[CH2:9]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)N1CCCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
(R)-tert-Butyl-azepan-3-ylcarbamate (250 mg, 1.17 mmol) was dissolved in DMF (0.5 mL), and DIEA (0.41 mL, 2.3 mmol). Dimethylcarbamoyl chloride (0.16 mL, 1.8 mmol) was then added and the reaction was stirred at RT for 1 hour. An additional aliquot of dimethylcarbamoyl chloride (0.16 mL, 1.8 mmol), DIEA (0.41 mL, 2.3 mmol), and DMF (0.5 mL) were added and the reaction was stirred for 6 hours. The solution was diluted with water (1 mL) and the solvents were removed under reduced pressure. The residue was dissolved in a mixture of EtOAc and H2O and the aqueous layer was extracted with EtOAc (×2). The organic extracts were combined, washed with brine, dried, and concentrated. The crude material (300 mg) was dissolved in HCl/dioxane (4 M, 2 mL) and stirred at RT for 1 hour. The solid that formed during the reaction was removed by filtration, suspended in EtOAc, and washed with 1 M NaOH (aq). The aqueous solution was then extracted with EtOAc (×3) and the combined organic extracts were washed with brine, dried, and concentrated to give (R)-3-amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:18]([C:27]#[N:28])=[C:19]([CH3:26])[NH:20][C:21]([CH3:25])=[C:22]3[C:23]#[N:24])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][OH:32])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO[Si](C)(C)C(C)(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-indazole-1-carboxylic acid tert-butyl ester (6.58 g), from Synthetic Example 21, was dissolved in THF (350 mL), under Argon, and a solution of TBAF in THF (1M, 28.5 mL) was added. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated ammonium chloride solution, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated to give crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10](O)[C:11](=O)[CH3:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(OC=C)(=O)C.[OH-].[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Cl-].[Na+].O.CO>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:11][NH:10]2
Reactant: COc1cc(Br)cc(N(O)C(C)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C=COC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(Br)c2cc[nH]c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
N-(3-Bromo-5-methoxy-phenyl)-N-hydroxy-acetamide (360 mg, 1.384 mmol) was dissolved in vinyl acetate (1.92 mL, 20.8 mmol), and Li2PdCl4 (18.2 mg, 69 μmol) was added. The reaction mixture was stirred for 3 hours at 60° C. The reaction mixture was diluted with EtOAc and brine; the organic layer was separated and concentrated under reduced pressure to give a solid, which was dissolved in 20 mL of MeOH. 1N aqueous NaOH (2.61 mL, 2.61 mmol) was added, and the reaction was stirred for two hours at room temperature. The reaction mixture was quenched by addition of 2 N aqueous HCl (1.3 mL, 2.6 mmol), followed by addition of 500 mg of Na2CO3. After addition of 50 mL of EtOAc, the organic layers were separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (20 g SiO2, EtOAc/heptane in a gradient from 0/100 to 1/4) to yield the title compound as a liquid (145 mg, 46% over 2 steps). 1H-NMR (600 MHz; DMSO-d6): 11.26 (brs, 1H), 7.31 (dd, 1H), 6.93 (d, 1H), 6.90 (d, 1H), 6.29 (dd, 1H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[N:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=[O:27])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(CC(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetate (1.85 g, 3.83 mmol) in 50 mL dichloromethane was added 30 ml of TFA. The mixture was stirred 2 h at ambient temperature, then concentrated and recrystallized from EtOAc to furnish 1.4 g (86%) of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid as a colorless solid. LCMS (ESI) m+H=427.1. 1H NMR (400 MHz, CD3OD) δ 9.95 (s, 1H), 9.08 (m, 1H), 8.69 (m, 1H), 8.63 (s, 1H), 8.34 (s, 1H), 7.47 (m, 2H), 7.21 (m, 2H), 5.03 (s, 2H), 3.86 (s, 3H).