Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH:12]([CH3:24])[C:11]=2[NH:10][C:9](=[O:25])[CH:8]=1>CN(C=O)C>[Br:3][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH:12]([CH3:24])[C:11]=2[NH:10][C:9](=[O:25])[CH:8]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2c(O)cc(=O)[nH]c21
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2c(Br)cc(=O)[nH]c21
Temperature: 90 °C
Yield: 50 %

Procedure:
TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: Br[CH:2]1[CH:7]([Br:8])[C:6]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH2:19][F:20])[CH2:17][F:18].[OH-].[Na+].Cl>O1CCOCC1>[Br:8][C:7]1[C:6]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]([CH2:17][F:18])([CH2:19][F:20])[CH:2]=1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)F)cc2C(Br)C1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Yield: 94.3 %

Procedure:
A mixture of 3,4-dibromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-3,4-dihydro-2H-1-benzopyran (10.72 g), a 2 N aqueous solution of sodium hydroxide (60 ml) and dioxane (100 ml) was stirred at room temperature for 2 hours. To the reaction mixture, 2 N HCl was added, followed by extraction with ethyl acetate; the resulting orgnaic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=10/1) to give 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran (8.18 g).
Reaction SMILES: [CH3:1][N:2]([C:4]([F:9])([F:8])[C:5](Cl)=[O:6])[CH3:3].[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:5](=[O:6])[C:4]([F:9])([F:8])[N:2]([CH3:3])[CH3:1])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])([F:9])[F:8])[CH:18]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CN(C)C(F)(F)C(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of dimethylamino-α,α-difluoroacetyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:23]1([NH:22][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:11]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred mixture of aniline (0.306 g) and sodium bicarbonate (0.51 g) in tetrahydrofuran (2 ml) and water (5 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was washed with ethanol to give yellow crystals of N-phenyl3-(2,4-difluorophenylthio)-4-nitrobenzamide (1.1 g).
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCCCCC.C(O)C.C(O)C.O1CCCC1>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (4.18 g) obtained in Example A67(5) was dissolved in hexane-ethanol (1:1, volume ratio), subjected to HPLC using CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), and eluted with hexane-ethanol (1:1, volume ratio) as a mobile phase at 30° C. and at a flow rate 60 mL/min. The resulting fraction containing an optically active form having a longer retention time was concentrated to give an amorphous form (2.04 g, 99.9% ee). The obtained amorphous form (2.04 g) was dissolved in ethanol (9 mL) and tetrahydrofuran (9 mL), 1N aqueous sodium hydroxide solution (8.5 mL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (15 mL) was added, and the mixture was neutralized with 1N hydrochloric acid (8.5 mL) under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration, and dried to give the title compound (1.88 g, 98%, 99.9% ee) as a colorless amorphous form.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C@@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CC(Nc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccccc1

Procedure:
2-Chloro-6-[(α-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R)-α-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[CH:5][N:4]=1.CC(C[AlH]CC(C)C)C>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(SC)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CSc1ncc(CO)cn1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a cold suspension of methyl 2-(methylthio)pyrimidine-5-carboxylate (1.74 g, 9.4 mmol) in dichloromethane (20 mL, −70° C.) was added DIBAL (20.8 mL, 20 mmol) dropwise via an addition funnel. The mixture was stirred under nitrogen at −70° C. for 1 hour and then at −50° C. for 3 hours. The reaction was diluted with dichloromethane (50 mL) and quenched with a suspension of sodium sulfate decahydrate (10 g) in water (50 mL). The slurry was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel) using 100% ethyl acetate to afford the desired compound (0.7813 g, 39%) as a yellow solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.53 (s, 2H), 4.56 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 157.0409 (M+H C6H8N2OS requires 157.0430).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:14]=3[CH3:13])[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: Cc1cccc(B(O)O)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: Cc1cccc(-c2cccc3c2C(=O)C(C)C3)c1C
Temperature: 125 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
Using a method similar to Example 16 d), 2.0 g (0.011 mol) of (1), 1.95 g (0.013 mol) of 2,3-dimethylphenylboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.9 g of 2-methyl-7-(2,3-dimethylphenyl)-1-indanone as solid.
Reaction SMILES: FC1C=CC=CC=1C=O.[CH:10]([S:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])(C)[CH3:11]>>[CH2:10]([S:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[CH3:11]
Reactant: CC(C)Sc1ccccc1C=O
Agent: O=Cc1ccccc1F
Product: CCSc1ccccc1C=O
Yield: 78 %

Procedure:
114A (10.4 g, 78% yield) was prepared from 2-fluorobezaldehyde (10 g, 81 mmol) and thioethane (5.5 g, 89 mmol) using a procedure similar to that used in the preparation of 11A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.23-1.42 (m, 3H) 2.98 (q, J=7.34 Hz, 2H) 7.17-7.37 (m, 1H) 7.38-7.64 (m, 2H) 7.81 (dd, J=7.70, 1.59 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a stirred solution of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (0.143 g, 0.000488 mol) in tetrahydrofuran at 15° C. was added in one portion a 1.0 M aqueous solution of sodium hydroxide (0.50 mL, 0.00050 mol), and the mixture was allowed to stir at room temperature for 18 hours. The THF was rotary evaporated, and the residue was partitioned between water and chloroform. The aqueous layer was washed with additional chloroform. The aqueous layer was acidified with 1.0 M aqueous hydrochloric acid (0.50 mL), and extracted with dichloromethane-tetrahydrofuran (50/50 v/v). The extract was washed with brine, dried (Na2SO4) and rotary evaporated. The residue was dried in vacuo to give 0.130 g of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid as a pale yellow solid; mp 191-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:8]1[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[CH3:18]
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CC(=O)NC(=O)N1Cc1ccc(Cl)cc1
Yield: 50 %

Procedure:
Into a 50 ml round bottomed flask equipped with an efficient condenser sealed with a calcium chloride tube were placed 10 ml of ethylchloroformate and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione. The mixture was refluxed for 3 hours, the solvent was removed in vacuum and ice water was added cautiously to the residue. The solution was adjusted to a neutral pH with a saturated solution of sodium bicarbonate. The crystals thus formed were filtered off by suction and recrystallized from isopropanol to yield 0.8 g (50%) of 1-ethoxycarbonyl-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 135°.
Reaction SMILES: [N:1]([C@@H:4]([CH3:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]([CH3:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH2:15][C:13]3=2)[CH:8]=[N:7]1
Reactant: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@H](C)N=[N+]=[N-])c3c2C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@H](C)N)c3c2C1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of the product from step E (0.20 g, 0.56 mmol) and palladium-on-carbon (10%, 0.02 g) in methanol (20 mL) was placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered, evaporated, and treated with 2 N HCl in ethanol. Evaporation of this solution to dryness to give an amorphous solid (0.18 g, 80%): LCMS (+ESI) m/z 333 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[C:2]([F:14])([F:15])[F:1])[CH3:22]
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccccc1C(F)(F)F
Yield: 95 %

Procedure:
2-Trifluoromethylcinnamic acid (10.1 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.8 g, 95%) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:3]1([CH2:2][O:17][C:16]2[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=2[O:14][CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)ccc1OCC1CCCCC1
Reaction time: 64 h
Yield: 93.5 %

Procedure:
Bromomethylcyclohexane (0.78 mL, 4.2 mmol) was added to a suspension of vanillin (0.43 g, 2.8 mmol) and potassium carbonate (1.17 g, 8.47 mmol) in EtOH (7.0 mL) and treated according to Procedure 3 for 64 h. 4-Cyclohexylmethoxy-3-methoxybenzaldehyde (0.65 g, 93%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.05 (m, 2H, CH2), 1.15-1.36 (m, 4H, CH2), 1.73 (m, 2H, CH2), 1.87-1.98 (m, 2H, CH2, CH), 3.88 (d, J=6.0 Hz, 2H, OCH2), 3.92 (s, 3H, OCH3), 6.95 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (d, J2,6=2.0 Hz, 1H, H2), 7.42 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 25.6, 26.4, 29.8, 37.3, 56.1, 74.5, 109.3, 111.4, 126.8, 129.8, 149.9, 154.4, 190.9; vmax 1133, 1265, 1508, 1586, 1683, 2853, 2925 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[CH2:10][S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[S:14])[CH2:10][S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSc2cccc(Cl)c2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccncc1
Product: S=C1CSc2cccc(Cl)c2N1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 195.8 %

Procedure:
5-Chloro-2,3-dihydro-1,4-benzothiazine-3-one (2.0 g) and phosphorus pentasulfide (2.0 g) were added to pyridine (5 ml), followed by stirring at 120° C. for 20 minutes. The reaction mixture was then poured into a dilute hydrochloric acid (50 ml), and the precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to obtain 1.9 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-thione (m.p. 138°-140° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1.[C:8]12([C:18](Cl)=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[Cl:7][C:4]1[S:3][C:2]([NH:1][C:18]([C:8]23[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]2)[CH2:9]3)=[O:19])=[N:6][CH:5]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(Cl)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 48 h
Yield: 51.3 %

Procedure:
A mixture of 2-amino-5-chlorothiazole (2.00 g, 14.9 mmol), 1-adamantanecarbonyl chloride (3.54 g, 17.8 mmol), 4-dimethylaminopyridine (1.10 g, 0.90 mmol) and triethylamine (4.15 mL, 23.0 mmol) in 80 mL of THF was stirred at 80° C. for 48 hours The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed with brine. The layers were separated and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, dichloromethane) afforded 2.27 g of the title compound: MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: C(OC([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1
Yield: 94.5 %

Procedure:
5 g of methyl (Z)-2-[(benzyloxy)carbonyl]amino-3-(3-[(tert-butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-propenoate was dissolved in methanol. 0.7 g of 10% palladium-carbon was added thereto, followed by stirring for 16 hours in a hydrogen atmosphere. The reaction solution was filtered and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), to give 3.4 g of methyl 2-amino-3-(3-[(tert-butoxycarbonyl)amino]methyl-4-methoxyphenyl)propanoate was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])=[CH:37][CH:36]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])=[CH:39][CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Reactant: C=CC(=O)Nc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)n2)cc1
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Example 3, Step 3) (80.0 mg, 0.238 mmol) in IpOH (3.0 ml) was added DIEA (0.062 mL, 0.356 mmol) and N-(4-aminophenyl)acrylamide (Example 2, Step 2) (42.4 mg, 0.261 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fells out of solution, was filtered off and dried under reduced pressure to give N-{4-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=463[M+H]+. Calc'd for C26H22N8O: 462.19.
Reaction SMILES: Cl.N[C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.N([O-])=O.[Na+].[N:26]1C=CC=C[CH:27]=1>S(=O)(=O)(O)O.O>[N+:19]([C:16]1[O:15][C:14]([C:4]2[C:3]([C:27]#[N:26])=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: c1ccncc1
Reactant: Nc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 90 °C

Procedure:
Add a solution of 0.25 g of 4-amino-3-(5-nitro-2-furyl)-1-phenylpyrazole hydrochloride in 2 ml of pyridine dropwise over a period of from 1 to 2 hours to a solution of 0.22 g of sodium nitrite in 3 ml of concentrated sulfuric acid and 1.75 ml of water at 0° C. Stir the resulting reaction mixture for 0.5 hour, and then precipitate the diazonium salt by adding ice and water to the reaction mixture. Add the precipitate to a heated (90° C) solution of 300 mg of potassium cyanide and 200 ml of copper(I)cyanide in 20 ml of water. Stir the prepared admixture for 15 minutes at 90° C, cool down, draw off the formed precipitate and chromatograph with methylene chloride on silica gel to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].