Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[F:25][C:26]([F:35])([F:34])[C:27](I)([F:32])[C:28]([F:31])([F:30])[F:29]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[F:25][C:26]([F:35])([F:34])[C:27]([F:32])([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=1)[C:28]([F:31])([F:30])[F:29]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
100 g (0.608 mol) of 2-(trifluoromethyl)aniline, 131 g (0.639 mol) of 85% sodium hydrosulfite, and 20.9 g (0.0608 mol) of tetrabutylammonium hydrogen sulfate were charged to a mixed solution of 1500 ml of ethyl acetate and 1500 ml of water, and 53.9 g (0.639 mol) of sodium hydrogen carbonate was added thereto. 198 g (0.669 mol) of heptafluoroisopropyl iodide was added dropwise thereto at room temperature, followed by stirring at room temperature for 6 hours. After the liquid separation, the solvent of the organic layer was evaporated under reduced pressure, and 500 ml of ethyl acetate was charged thereto. 160 g (0.608 mol) of a 4 M hydrogen chloride/ethyl acetate solution was added dropwise thereto, followed by stirring at room temperature for 30 minutes, and then stirring at 5° C. for 1 hour. After the filtration, the filtrate was washed with water and a saturated aqueous sodium hydrogen carbonate in this order, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1) to prepare 60.0 g (yield 30%) of a target compound.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6](/[CH:7]=[CH:8]/[N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][C:10]2=[O:18])=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][C:10]2=[O:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(/C=C/n2c(=O)sc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1sc2ccccc2n1/C=C/c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a 10 mL round bottomed flask equipped with a magnetic stir bar containing DCM (4 mL) was placed 6 (0.1 g, 0.39 mmol), the reaction mixture was cooled to 0° C., BBr3 (1.0 mL of 1M in DCM) was added drop wise and was stirred at RT for 3 hrs. The reaction was neutralized with sat. NaHCO3, extracted into DCM (3×15 mL). The combined organic extracts were washed with water (15 mL), brine (15 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel using EtOAc:Hexanes (1:4) as an eluent to afford 7 (0.09 g, 95%) as a white solid.
Reaction SMILES: O.CC(C)([O-])C.[K+].[CH:8]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=4)[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:20]=3[C:40]([O:42]CC)=[O:41])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1.Cl>C(OCC)C.C(OCC)(=O)C>[CH:8]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=4)[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:20]=3[C:40]([OH:42])=[O:41])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC)ccc2n1Cc1cccc(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc2c(c1)c(-c1ccc(OCC3CC3)cc1)c(C(=O)O)n2Cc1cccc(OC)c1
Temperature: 0 °C
Yield: 14.3 %

Procedure:
Water (5 uL) was added to a cooled (0° C.) and stirred suspension of potassium t-butoxide (90 mg, 0.80 mmol) in ethyl ether (5 mL). The slurry was stirred for 5 min and then a solution of ethyl 3-[4-(cyclopropylmethoxy)phenyl]-5-ethoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 144, 52 mg, 0.10 mmoL) in ethyl ether (2+1 mL rinse) was added. The mixture was warmed to rt and stirred for 16 h. The solution was adjusted to pH=7 with 1 M hydrochloric acid and diluted with ethyl acetate (50 mL). This mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC, using 1:1 ethyl acetate/hexane as the eluent, to afford 7.0 mg (14%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.45-7.37 (m, 3 H), 7.18 (t, 1 H), 6.99-6.91 (m, 4 H), 6.77 (dd, 1 H), 6.70 (m, 2 H), 5.85 (d, 2 H), 3.99-3.86 (m, 4 H), 3.69 (s, 3 H), 1.36-1.28 (m, 4 H), 0.63-0.59 (m, 2 H), 0.39-0.37 (m, 2 H); mass spectroscopy gave MH+=472.2 (calcd exact mass for C29H29NO5=471.20).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:15]([CH3:16])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
The mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 mL of 60% aqueous dimethylamine solution is stirred at 100° C. for 6 hours. The reaction mixture is evaporated, the residue dissolved in 15 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated yellow crystalline material is filtered off, washed with water and dried, to obtain 3.4 g of the title compound. Mp.: 189° C.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCC3CCCCC3)cc2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3CCCCC3)cc2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.5 mg, 0.016 mmol) and dimethylglyoxime (70.1 mg, 0.6 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (384.6 mg, 10 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.02 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-(2-cyclohexylethoxy)benzyl)thiazolidine-2,4-dione (Derivative 113 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [CH:1]([CH:3]1[C:8](=O)[C:7](C2CCCC2)=[C:6](OC)[CH2:5][CH2:4]1)=O.C(=O)(O)O.[NH2:21][C:22](N)=[NH:23]>CN(C=O)C>[NH:21]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:1]=[N:23][CH2:22]1
Reactant: COC1=C(C2CCCC2)C(=O)C(C=O)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: C1=NCNc2ccccc21
Temperature: 150 °C
Yield: 148.4 %

Procedure:
A mixture of 6-formyl-2-cyclopentyl-3-methoxycyclohex-2-en-1-one (2.0 g, 10.2 mmol) and guanidine carbonate (4.6 g) in DMF (30 mL) was heated at 150° C. for 4 hours. The solvent was removed under reduced pressure and to the residue ice-cold water was added. The product was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with water and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to give 2.0 g of crude dihydroquinazoline. The dihydroquinazoline was aromatized to the title compound by heating in nitrobenzene at 150° C. in the presence of 10% Pd-C. To a solution of dihydroquinazoline (2.0 g, 8.2 mmol) in nitrobenzene (20 mL), 200 mg of 10% Pd-C was added, and the reaction mixture was heated at 150° C. for 3 days. The Pd-C was removed by filtration. The filtrate was concentrated, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as an off-white solid (1 g, 50% yield), mp 181–183° C.; 1H NMR (CDCl3): δ 1.6–2.2 (complex, 8H, 4×CH2), 3.9 (s, 3H, OCH3), 4.27 (t, 1H, CH), 5.02 (brs, 2H, NH2), 7.02 (d, 1H, Ar-H, J=9 Hz), 7.54 (d, 1H, Ar-H, J=9 Hz), 8.87 (s, 1H, Ar-H); MS m/z 244.07, C14H17N3O (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH2:5][CH:6]1[CH2:8][O:7]1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1.O>CN(C)C=O>[OH:7][CH:6]([CH2:5][C:4]1[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([OH:12])=[C:2]([CH3:1])[CH:3]=1)[CH2:8][N:21]1[C:17](=[O:23])[CH2:18][CH2:19][C:20]1=[O:22]
Reactant: O=C1CCC(=O)N1
Reactant: Cc1cc(CC2CO2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC(O)CN2C(=O)CCC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 6.6 g (0.03 mol) of 3-methyl-5-tert.-butyl-4-hydroxybenzyl-oxirane and 3 g (0.03 mol) of succinimide in 30 ml of dimethylformamide is stirred for 18 hours at a temperature of 150°-55° C whilst passing a slight stream of nitrogen through the mixture. After cooling to room temperature, the reaction mixture is poured into 150 ml of water and the oily reaction product which precipitates is dissolved in toluene. Successive extraction of the toluene phase with dilute hydrochloric acid, 5% strength aqueous sodium bicarbonate solution and water, drying over sodium sulphate and evaporation of the solvent gives the crude product. After recrystallisation from methylcellosolve, 6.5 g (68% of theory) of N-[2-hydroxy-3-(3-methyl-5-tert.-butyl-4-hydroxyphenyl)-propyl]-succinimide of melting point 217.5°-218° C are obtained in the form of colourless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a solution of 9-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Preparation 90) (80 mg, 0.189 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.066 ml, 0.378 mmol) followed by ethyl 3-bromopropanoate (0.048 ml, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. The residue was purified by column chromatography on silica. Elution with 40-60% ethyl acetate in cyclohexane to give the title compound as an olive green coloured oil (28 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:20][N:21]1[CH2:25][C:24](=[O:26])[N:23]=[C:22]1SC.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[N:21]([CH3:20])[CH2:25][C:24](=[O:26])[N:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC1=NC(=O)CN1C
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CC(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
3-(3-Piperidinomethylphenoxy)propylamine (2.61 g), 1-methyl-2-methylthioimidazolin-4-one hydroiodide (2.85 g) and triethylamine (3.635 g) were refluxed in ethanol (25 ml) for 5 hours.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])/[C:9]1=[O:24])=O)(C)(C)C.[Cl:25][C:26]1[C:27]([F:39])=[C:28](/[CH:32]=[N:33]/[CH2:34][Si](C)(C)C)[CH:29]=[CH:30][CH:31]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:24])[C:10]3([CH:18]([CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:34][NH:33][CH:32]3[C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=3[F:39])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 4 (2.5 g, 7.1 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 5 (2.4 g, 9.9 mmol), acetic acid (0.6 g, 10 mmol) and H2O (0.2 g, 11 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.6 g, 20%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23](Cl)[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C.C1COCC1>[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COCCCOc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxypropan-1-ol (0.500 mL, 5.23 mmol) in t-butanol (5 mL) was added a 60% dispersion of NaH in oil (70 mg, 1.75 mmol). The resulting suspension was permitted to stir for 30 minutes at which time the reaction was placed at 0° C. and charged with 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS#778574-06-4, 300 mg, 1.02 mmol) as a solution in THF (1.5 mL). After 20 minutes the mixture was quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers were then separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel flash chromatography to provide 6-benzyl-2-chloro-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Nc2ncccc2N)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
57 g (0.23 mol) of N-(3-fluoro-4-methylphenyl)-3-nitro-2-pyridylamine was dissolved in ethyl acetate (250 ml), and water (125 ml) and acetic acid (80 ml) were added thereto, and the solution was heated to 50° C. 77 g (1.40 mol) of iron powder was added to the reaction solution so that the temperature thereof would not exceed 60° C., and then stirred for 1 hour at 60° C. The reaction solution was cooled to room temperature, and the inorganic matter was separated by filtration. The solution was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was washed with hexane to obtain 45 g (yield: 90%) of N2-(3-fluoro-4-methylphenyl)-2,3-pyridinediamine.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[CH:38](=O)[CH3:39]>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH2:38][CH3:39])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC=O
Product: CCN1CC(NC(=O)c2cc(OC)c(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)C1

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and acetaldehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.20 Hz, 3H) 1.61 (br. s., 6H) 1.96 (br. s., 2H) 2.40 (q, 2H) 2.88 (t, J=6.32 Hz, 2H) 3.52 (t, J=5.81 Hz, 2H) 3.91 (s, 3H) 4.08 (t, J=13.77 Hz, 2H) 4.33-4.48 (m, 1H) 4.71-4.89 (m, 1H) 7.20 (d, J=4.04 Hz, 1H) 8.05 (s, 1H) 8.26 (d, J=13.39 Hz, 1H) 8.31 (d, J=3.28 Hz, 1H) 8.43 (d, J=7.07 Hz, 1H). [M+H] calculated for C26H32F3N7O3, 548. found 548.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N[C:13]1C=CC(Cl)=NC=1>>[CH3:13][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)nc1
Product: CNc1cncc(C(F)(F)F)c1

Procedure:
The reaction procedure of Reference Example 24 was repeated except that 3-amino-5-trifluoromethylpyridine was used in lieu of 5-amino-2-chloropyridine to obtain the title compound as white crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[O:13][C:12](=[O:18])[CH2:11][CH2:10]2.[O:19]1[CH2:23][CH2:22][O:21][CH:20]1[CH:24]1[CH2:29][CH2:28][CH:27]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>C1COCC1.[Br-].[Zn+2].[Br-]>[F:17][C:15]1[CH:16]=[C:7]([C:33]2([OH:36])[CH2:34][CH2:35][CH:30]([CH:27]3[CH2:26][CH2:25][CH:24]([CH:20]4[O:21][CH2:22][CH2:23][O:19]4)[CH2:29][CH2:28]3)[CH2:31][CH2:32]2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:18])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(Br)cc(F)c2O1
Reactant: O=C1CCC(C2CCC(C3OCCO3)CC2)CC1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C1CCc2cc(C3(O)CCC(C4CCC(C5OCCO5)CC4)CC3)cc(F)c2O1
Temperature: -100 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
Butyllithium (1.6 ml, 1.5 M) was added dropwise to a solution of 6-bromo-8-fluoro-3,4-dihydrocoumarin (4.8 g) in THF (50 ml) as cooled at −100° C. in an argon gas stream. After completion of the dropwise addition, the temperature of the reaction mixture was raised to −78° C., and a solution of zinc bromide (5 g) in THF (100 ml) was added dropwise thereto. After completion of the dropwise addition, the temperature of the reaction mixture was raised to −30° C., and a solution of 4-(4-(1,3-dioxolan-2-yl)cyclohexyl)cyclohexanone (5.0 g) in THF (50 ml) was added dropwise thereto. After completion of the dropwise addition, the temperature of the reaction mixture was raised to room temperature, followed by stirring for 18 hours. The reaction mixture was added in ice water, extracted with toluene, washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a colorless crystal of 1-(8-fluoro-3,4-dihydrocoumarin-6-yl)-4-(4-(1,3-dioxolan-2-yl)cyclohexyl)cyclohexanol (4.5 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=1)=[O:2]
Reactant: O=CO
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1NC=O
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, 98% formic acid (12.75 g) was added to acetic anhydride (22.97 g) using an dropping funnel, the obtained mixture was stirred at 50-60° C. for 2 hrs, and cooled to room temperature. Tetrahydrofuran (25 mL) was added to the obtained mixture and a solution of ethyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (20.00 g) in tetrahydrofuran (20 mL) was added. The obtained mixture was stirred at room temperature for 3 hrs and concentrated. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-(formylamino)-1-phenyl-1H-pyrazole-4-carboxylate as colorless needle crystals (20.89 g, yield 93%). melting point: 135-136° C.