Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[O:19]=[C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:23][CH2:22][N:21]1[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([O-])=[O:36]>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][N:40]=[C:32]([N:21]2[CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]2=[O:19])[CH:33]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: O=C([O-])c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Yield: 61 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with 2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 61% yield: mp 143-145° C.; 1H NMR (300 MHz, CDCl3) δ 8.64-8.53 (m, 2H), 8.36-8.35 (m, 1H), 7.68-7.63 (m, 1H), 7.40-7.38 (m, 1H), 7.29-7.02 (m, 6H), 4.57-4.52 (m, 4H), 4.06 (t, J=8.1 Hz, 2H), 3.53 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 157.2, 156.3, 153.0, 149.5, 148.4, 142.5, 137.1, 134.9, 123.9, 122.7, 122.1, 117.6, 117.3, 117.0, 116.8, 116.0, 108.9, 49.5, 43.0, 41.8, 41.5; MS (ES+) m/z 423.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:22][Mg]Br.C1COCC1>C(Cl)Cl>[CH3:4][C:2]([S@:5]([NH:7][CH:8]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:11][N:10]=1)[CH3:22])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg]Br
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-6) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at −78° C. After stirring at −78° C. for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mL×2). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][N:12]=C(C)C)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:9][C:8]1[C:7]2[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][N:12]=1
Reactant: COc1ccc(ON=C(C)C)c(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2onc(N)c2c1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
In 125 ml of dry methanol was dissolved 5-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile (10 g), followed by 125 ml of ethereal hydrochloric acid. The reaction was stirred under nitrogen overnight. The reaction was neutralized with saturated sodium carbonate solution and extracted with EtOAc. The organic layer was dried and concentrated in vacuo. Recrystallization of the residue from dichloromethane/petroleum ether afforded the expected product (6.8 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[OH:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C(F)(F)F)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C(F)(F)F)nn12
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (7.69 g) in tetrahydrofuran (25 mL) was added 6N hydrochloric acid (25 mL), and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was cooled to room temperature, neutralized with 2 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethanol (20 mL)-tetrahydrofuran (10 mL) was added sodium borohydride (631 mg) under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/30→50/50 (volume ratio)] to give the title compound as a colorless amorphous compound (4.27 g, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:28])[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33]>C(OCC)(=O)C>[Cl:37][C:36]([Cl:39])([Cl:38])[CH2:35][O:34][C:32](=[O:33])[NH:28][C:7]1[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:18]([CH3:20])[CH3:19])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reaction time: 0.08 h
Yield: 103 %

Procedure:
To a solution of Intermediate 54b (0.73 g, assumed 1.70 mmol) in ethyl acetate (8 mL) was added 1N sodium hydroxide solution (4.5 mL, 4.50 mmol). Stirred for 5 min then 2,2,2-trichloroethyl chloroformate (275 μL, 2.00 mmol) was added and the mixture stirred vigorously at RT for 3.5 h. Diluted with EtOAc, washed with water and brine, dried, and concentrated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in cyclohexane, to give the still impure title compound (1.01 g). 1H NMR (300 MHz, CDCl3): inter alia 1.02-1.15 (18H, m), 1.18-1.38 (12H, m), 2.34 (3H, s), 4.82 (2H, s), 6.43 (1H, s), 6.69-6.77 (2H, m), 6.84-6.96 (2H, m).
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]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[N:26][NH:25][C:24]1=[O:28]>>[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:25]1[C:24](=[O:28])[N:23]([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:27]=[N:26]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(F)cc1F
Product: C[C@@H](n1ncn(-c2ccc(F)cc2F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 58.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.07 g of 4-(2,4-difluorophenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(2,4-difluorophenyl)-3(2H, 4H)-1,2,4-triazolone (1.20 g) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: NCCCl
Product: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1.Cl.C([NH:22][C:23]([NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])=N)CCC>>[ClH:36].[OH:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]([NH:25][C:26]([C:28]2[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=2)=[O:27])=[NH:22])=[CH:7][CH:6]=1
Reactant: CC(O)COc1ccc(CCCCN)cc1
Reactant: CCCCNC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Product: CC(O)COc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1

Procedure:
Using general procedure Z, 4-[4-(2-hydroxypropyloxy)phenyl]butyl amine was converted into 4-[4-(2-hydroxypropyloxy)phenyl)]butylamidino-3,5-diamino-6-chloropyrazinecarboxamide hydrochloride, m.p. 212–214° C., APCI MS, M/Z=436 [C19H26ClN7O3+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](O)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:13])([F:12])[F:14])[CH:7]=[C:8]2[N:9]=1
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Reactant: O=C(O)c1sccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Temperature: 90 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
A mixture of 0.50 g of N2-methyl-5-trifluoromethylthiopyridine-2,3-diamine, 0.44 g of 3-chloro-thiophene-2-carboxylic acid, 0.51 g of EDCI hydrochloride, 30 mg of HOBt and 5 ml of pyridine was stirred at 90° C. for 10 hours. Water was poured into the cooled reaction mixture, and the deposited precipitate was filtered. The filtrate was applied to a silica gel column chromatography to obtain 0.7 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([CH2:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:29][CH2:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCCc1ccccc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCCc1ccccc1
Yield: 87.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and benzylmethylamine (65 μL, 0.5 mmol) to give 170 mg of the title compound (87%): mp 120°~125° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 and 12.04 (two s, 1H), 7.10~7.41 (m, 7H), 5.09~5.21 (m, 1H), total 2H of 4.63 (s), 4.58 (d, J=16.2 Hz), and 4.47 (d, J=16.2 Hz), 2.95~3.12 (m, 1H), J=2.92 and 2.82 (two s, 3H), 2.78 (dm, 1H, J=17.1 Hz), 2.61~2.73 (m, 2H), 2.22 (dm, 1H, J=13.5 Hz), 1.79~1.94 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([C:20]([O:22]CC)=[O:21])[S:19][C:11]1=2)([O-:3])=[O:2].O.[OH-].[Li+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([C:20]([OH:22])=[O:21])[S:19][C:11]1=2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Yield: 80 %

Procedure:
A mixture of the compound of Example 120 (150 mg, 0.357 mmol) and lithium hydroxide monohydrate (30 mg, 0.714 mmol) in dioxane (3 mL) and water (3 mL) was heated under reflux for 1.5 h. The dioxane was removed in vacuo, the aqueous residue acidified (2M HCl) and the precipitate filtered off and dried to give the title compound as a pale orange solid (112 mg, 80%). δH (DMSO-d6) 13.06 (1H, br s), 8.29 (1H, dd, J 1.3, 8.2 Hz), 8.02–7.93 (2H, m), 7.88–7.84 (1H, m), 7.46–7.35 (6H, m), 6.46 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.137 minutes, 393.0 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:43])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:30]([C:41]#[N:42])[CH:29]=3)[CH:20]=2)=[CH:15][CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:41]([C:30]1[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:20]=[C:19]([C:16]4[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:43])=[CH:18][CH:17]=4)[O:27][C:26]=23)[CH:33]=[CH:32][C:31]=1[O:34][CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)#[N:42]
Reactant: CN(CCNC(=O)c1ccc(-c2cc3nccc(-c4ccc(OC5CCOCC5)c(C#N)c4)c3o2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)c1ccc(-c2cc3nccc(-c4ccc(OC5CCOCC5)c(C#N)c4)c3o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(4-{7-[3-Cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}benzoyl-amino)-ethyl]-methyl-carbamic acid tert-butyl ester (59.0 mg, 0.1 mmol) is dissolved in dichloromethane (1 ml). Trifluoro-acetic acid (1 ml, 12.98 mmol) is added to the solution. The mixture is stirred for 16 h at room temperature. The solvent is removed in vacuum; yield: 20 mg 4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-N-(2-methyl-amino-ethyl)-benzamide trifluoroacetate; HPLC/MS: 1.61 min, [M+H]=497;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[N+:15]([CH3:18])([O-:17])=[O:16]>O>[OH:14][C:7]1([CH2:18][N+:15]([O-:17])=[O:16])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 12 h

Procedure:
5-nitroisatin (0.081 g) and nitromethane (0.15 ml) were added to water (2 ml) and the reaction mixture was vigorously stirred at a temperature of 30° C. for 12 hours. The product was extracted with ethyl acetate and recrystallized with MeOH to afford pure product.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:12][C:11]=2[CH3:29])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](O)(=O)C.C([BH3-])#N.[Na+].C=O>CO>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([N:17]([CH3:30])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:12][C:11]=2[CH3:29])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)CC1CCCC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 97 %

Procedure:
To 2-cyclopentyl-N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide (4k, 150 mg) dissolved in methanol (20 mL) and acetic acid (2 mL) were added sodium cyanoborohydride (175 mg) and formaldehyde (200 uL) and the reaction mixture was stirred at 25° C. for 70 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate and the product collected by filtration to furnish 151 mg (97% yield) of the title compound as a white solid. LC-MS (m/z) 419 (MH+); tR=3.39, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.61 (m, 2H), 1.75 (m, 2H), 2.02 (s, 6H), 2.24 (m, 3H), 2.97 (s, 3H), 4.63 (s, 2H), 6.42 (s, 2H), 7.41 (d, 2H), 7.68 (d, 2H), 8.83 (s, 1H).
Reaction SMILES: ClC1C(NC2C=C(C)NN=2)=NC(N[C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.[BH4-].[Na+].C[OH:28]>>[F:17][C:14]1[CH:13]=[N:12][C:11]([CH:9]([OH:28])[CH3:10])=[N:16][CH:15]=1
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1-(5-Fluoropyrimidin-2-yl)ethanone (Method 5, 0.77 g) was dissolved in MeOH (15 ml), and the solution was cooled to 0° C. NaBH4 (0.210 g, 5.55 mmol) was added. The mixture was stirred at room temperature for 1 hour and then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound as a yellowish oil (0.79 g, 99%). 1H NMR (CDCl3) δ 8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H), 1.80 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].CC(O)=O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[NH:17][C:18](=[S:19])[NH:20][CH:2]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)c1nn2ccccc2c1-c1c[nH]c(=S)[nH]1
Yield: 121 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 100 μl of HOAc were stirred in 1.5 ml of dioxane at 60-700 C for 30 minutes. 197 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione was obtained after workup. Compound 1085.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[O:20][CH2:21][O:22][CH3:23])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]([Br:25])[C@H:12]1[O:20][CH2:21][O:22][CH3:23])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCO[C@@H]1Cc2ccccc2[C@H]1N(COC)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCO[C@@H]1C(Br)c2ccccc2[C@H]1N(COC)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 2.75 g of tert-butyl[(1R,2R)-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate in 55 ml of carbon tetrachloride was heated at an outer temperature of 100° C., and a mixture of 1.53 g of N-bromosuccinimide and 95 mg of 2,2′-azodiisobutyronitrile was added portionwise thereto over 30 minutes at an interval of 5 minutes, followed by stirring at an outer temperature of 100° C. for 1 hour. The insoluble material was filtered, and an aqueous sodium thiosulfate solution and chloroform were added thereto to carry out a layer separation operation. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 984 mg of tert-butyl[(1R,2S)-3-bromo-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:4]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:5](=[O:13])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)cc(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc(C(F)(F)F)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 39 %

Procedure:
The title compound (138 mg, 40%) was prepared from 2-ethyl-4-trifluoromethyl-1,6-dihydro-6-pyrimidone (200 mg, 1.04 mmol) and 4-[2-bromoethoxy]benzaldehyde (238.5 mg, 1.04 mmol) in presence of K2CO3 (287.5 mg, 2.08 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(=S)=S>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:13][CH:12]=1
Reactant: CCC(=O)Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
294 g of aluminium chloride was added to 1000 ml of carbon disulfide and stirred. The reaction solution was cooled to 0° C. or lower, and 166 g of propionyl chloride was dropwise added thereto. Next, 283 g of bromobenzene was dropwise added thereto. Then, the whole was stirred for one hour at room temperature. After reaction, the reaction solution was poured into a mixture of 300 ml of concentrated hydrochloric acid and 600 g of ice. This was extracted with chloroform and washed three times with water, and chloroform was removed by distillation. By distillation under reduced pressure (b.p. 100° to 105° C./2 mmHg), 301 g of 1-bromo-4-propionylbenzene was obtained.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][Li]>C(OCC)C>[CH2:1]([C:5]1[S:9][C:8]([C:10](=[O:12])[CH3:13])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Solvent: CCOCC
Product: CC(=O)c1ccc(CC(C)C)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-isobutyl-thiophene-2-carboxylic acid (550 mg, 2.99 mmol) in diethyl ether (20 mL), a solution of methyl lithium (3.75 mL, 1.6 M in diethyl ether) is slowly added at rt. The reaction mixture is stirred at rt for 1 h before it is carefully washed twice with water, dried over MgSO4, filtered and evaporated to give the title compound (336 mg) as a slightly yellow oil, LC-MS: tR=0.91 min, [M+1]+=183.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
To a stirred solution of 3.87 g (22.5 mmol) 2.4-difluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 4a was obtained in 55% yield (2.44 g, 12.4 mmol).