Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([CH:16](Cl)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C(OCC)(=O)C.C1C=CC=CC=1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][CH:16]([CH2:14][CH3:15])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Reactant: CCC(Cl)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(Sc1cnn(C(C)(C)C)c(=O)c1C)c1ccc(C(C)(C)C)cc1
Yield: 53.7 %

Procedure:
To a solution of 0.8 g (0.004 mol) of 2-t-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone and 0.84 g (0.004 mol) of α-ethyl-p-t-butylbenzyl chloride dissolved in 20 ml of N,N-dimethylformamide was added 1.0 g (0.01 mol) of sodium carbonate at room temperature under stirring. After addition, the resulting mixture was stirred at 70°~80° C. for four hours. After allowed to cool, the reaction mixture was poured into 200 ml of water and then extracted with 100 ml of benzene. The resulting benzene layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.5 g of crude product. The crude product was fractionated on silica gel column chromatography [developer: a mixed solvent of benzene and ethyl acetate (10:1 mixture)] to obtain 0.8 g of 2-t-butyl-5-(α-ethyl-p-t-butylbenzylthio)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: O.[OH-].[Li+].Br.[C:5]([CH:7]([NH:17][CH2:18][C:19]([NH2:21])=[NH:20])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[Cl:16])#[N:6]>CO>[NH2:6][C:5]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=1
Reactant: N#CC(NCC(=N)N)c1cc(Cl)cc(Cl)c1Cl
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: -10 °C

Procedure:
Lithium hydroxide monohydrate (2.9 kg) was stirred in methanol (269 kg) for 60 minutes at 20° C. and then cooled to −10C. 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide was added in one portion and the resultant mixture stirred vigorously with cooling at −10° C. Compressed air was gassed over the surface of the reaction for at least 6 hours. The mixture was warmed to 25° C. and concentrated to 3 volumes under vacuum. Water (289 kg) was added over at least 1 hour with stirring. The product was isolated by filtration and the cake washed with water (51 kg) and dried in vacuo at 40° C. Yield 12 Kg (91%). HPLC retention time 11.9 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]([CH3:21])([CH3:20])[N:10]=2)=[CH:5][CH:4]=1.C(#N)C>C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]([CH3:21])([CH3:20])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C2=NC(C)(C)[C@@H](c3ccncc3)C2)cc1

Procedure:
148 G. of racemic 4-[2-(p-methoxyphenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine were dissolved in 280 ml. acetonitrile and 450 ml. ethylacetate. 150 G. of (+)-camphersulfonic acid are added and the reaction mixture is heated on a steam bath until all reactants are in solution. The resulting solution is cooled on an ice bath until crystallization begins, then it is allowed to crystallize at room temperature for 2.5 hours. The crystals are filtered and washed with ethyl acetate. The crystals are taken up in water and calcium carbonate is added until a pH 9 is reached and recrystallization occurs. The crystals are filtered, washed with water and taken up in methylene chloride. The organic phase which results is dried over sodium sulfate and evaporated under reduced pressure to obtain crystals of 4-[(4R)-2-(p-methoxyphenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine: [α]D =-152° (CHCl3, c = 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10]Br)[CH:6]=[CH:7][CH:8]=1.[Mg].[CH3:13][C:14]1([CH3:31])[CH2:18][O:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2OC)=[N:15]1.O>O1CCCC1>[CH3:28][O:27][C:21]1[C:20]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:19]([C:16]2[O:17][CH2:18][C:14]([CH3:13])([CH3:31])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1cccc(CCBr)c1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCc2c(C3=NC(C)(C)CO3)ccc(OC)c2OC)c1
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)ethylbromide (12.2 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of magnesium (1.46 g) in dry tetrahydrofuran (20 ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution of 4,5-dihydro-4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (7.95 g) in dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 16 hours. Water (400 ml) was added and the aqueous phase thoroughly extracted with ethyl acetate (2×250 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90% petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200°/1 mm Hg) 9.7 g of the title compound were obtained ms m/e 369.
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1.Cl.[Cl-].[Na+]>C(O)C.C(OCC)(=O)C.O>[F:3][CH2:4][CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COC(=O)c1cnc(OCCF)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(OCCF)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 5 N sodium hydroxide solution (400 μL) was added to a solution of methyl 5-(2-fluoroethoxy)pyrazine-2-carboxylate obtained in Preparation Example 53-(1) (200 mg) in ethanol (4 mL). Water was added until the reaction solution became a complete solution, followed by stirring at room temperature for 10 minutes. The reaction solution was made acidic with 5 N hydrochloric acid. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (150 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].C=O.[C:14]([O-])(=[O:16])C>O.C(O)(=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:14][OH:16])[C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C)c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c(O)c(CO)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
75 g of NaOH were dissolved in 300 ml of deionized (DI) water. 183.3 g 2,4-dimethylphenol were added, and the mixture was cooled to 15°-20° C. 188 g of aqueous formaldehyde (made from 152g 37% formalin diluted with 36 g water) were added over half an hour, while the temperature was maintained below 20° C. After stirring overnight, Thin Layer Chromotography (TLC) in 2:1 hexane/ethyl. acetate showed a single spot, and no remaining 2,4-dimethylphenol. The pH was then adjusted to 6-7 with about 200 ml of 50% aqueous acetic acid. The mixture was transferred to a 2 liter beaker, and extracted with ethyl acetate (400 ml). Removal of the ethyl acetate in a vacuum gave 221.0 g (97.4%) of the desired product as a clear oil or a low-melting solid.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)=[CH:10][N:11]=1)[C:3]([OH:5])=O.[CH:31]([NH:33][NH2:34])=[O:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH:31]([NH:33][NH:34][C:3](=[O:5])[C:2]([CH3:1])([CH3:30])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)=[CH:10][N:11]=1)=[O:32]
Reactant: NNC=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)C(=O)O)s2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)C(=O)NNC=O)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2,2-Dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoic acid (potassium salt) (87% pure, 100 mg, 0.183 mmol), formic acid hydrazide (22.0 mg, 0.367 mmol), HOBT (56.2 mg, 0.367 mmol), and EDC (70.3 mg, 0.367 mmol) were combined with DMF (4 mL) and DIEA (47.4 mg, 0.367 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-10% methanol in ethyl acetate) afforded N′-formyl-2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanehydrazide (70 mg, 80%) as a yellow gum. BSI: [M+H]+ m/z 479.0.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[Si]([O:37][CH2:38][CH:39]=O)(C(C)(C)C)(C)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:39][CH2:38][OH:37])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CCO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.04 mmol) (Example 1, step 7, chiral intermediate from peak 1), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (8.3 mg, 0.048 mmol), and triethylamine (19 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added sodium triacetoxyborohydride resin (38 mg, 0.087 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. The crude product was dissolved in tetrahydrofuran (1 mL) and cooled to 0° C. 1.0 M Tetra-n-butylammonium fluoride in THF (0.44 mL, 0.44 mmol) was added and warmed to room temperature. After 3 h, the solvents were evaporated. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 8.1 mg (40%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C21H28ClN6O2 (M+H)+: m/z=431.2; Found: 431.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH:17](O)=[O:18].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[F:15][C:9]1[CH:10]=[CH:11][C:12]([NH:14][CH:17]=[O:18])=[CH:13][C:8]=1[NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(NC=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (10.0 g, 44.2 mmol) in tetrahydrofuran (60 mL) was added a mixture of formic acid (8.34 mL, 221 mmol) and acetic anhydride (5.01 mL, 53.0 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure to give tert-butyl [2-fluoro-5-(formylamino)phenyl]carbamate as a brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[OH:14].[CH:32]1([CH2:35][O:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][CH2:44][C:45](O)=[O:46])=[O:42])=[CH:39][C:38]=2[CH2:50][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@H:13]([O:14][C:45](=[O:46])[CH2:44][O:43][C:41](=[O:42])[C:40]1[CH:48]=[CH:49][C:37]([O:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:38]([CH2:50][N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)[CH:39]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: O=C(O)COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
EDC (82 mg, 0.429 mmol) was added to a solution of compound (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (120 mg, 0.286 mmol), 2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetic acid (300 mg, 0.859 mmol) and DMAP (18 mg, 0.143 mmol) in DCM (1 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1N and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude was purified through Preparative HPLC to give (S)-3,5-dichloro-4-(2-(2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide (150 mg, 70% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:30]1[CH2:35][CH2:34]O[C@H:32]([CH2:36][C:37]2C=CC=C(Br)C=2)[CH2:31]1)(OC(C)(C)C)=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(C1C=CN=CC=1)=C.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:37][C:36]3[CH:32]=[CH:31][N:30]=[CH:35][CH:34]=3)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Agent: [Pd+2]
Agent: C=Cc1ccncc1
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3ccncc3)c2)C1
Temperature: 140 °C
Yield: 57 %

Procedure:
Intermediate (b) N-Boc-(R)-2-(3-bromobenzyl)morpholine (103 mg, 0.29 mmol), was dissolved in CH3CN (2 mL) with palladium acetate (3.2 mg, 14 umol), tris(ortho-tolyl)phosphine (8.8 mg, 29 umol), 4-vinylpyridine (61 mg, 0.58 mmol) and triethyl amine (58 mg, 0.58 mmol). The reaction was then subjected to microwave heating at 140° C. for 5 minutes. The reaction was cooled to room temperature, partitioned between ethyl acetate (20 mL) and water (20 mL) and separated. The organic layer was washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20-30% ethyl acetate/isohexane) to yield the desired intermediate (a), N-Boc-(R)-2-(3-(2-(4-pyridinyl)vinyl)-benzyl)morpholine as a colorless gum (63 mg, 57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:19])[CH:3]=1.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>CN(C)C=O>[CH:24]1([CH2:23][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=3)[C:4](=[O:19])[CH:3]=2)[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2ccc(OCC3CC3)cc2=O)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate (1.00 g, 3.56 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added sodium hydride (0.14 g, 5.70 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, then (bromomethyl)cyclopropane (0.58 g, 4.28 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed at high vacuum and the residue was diluted with dichloromethane (30 mL), washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid (1.15 g, 97%): mp 180-183° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.68-8.65 (m, 1H), 6.19-6.16 (m, 1H), 5.93 (d, J=2.6 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.81 (d, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.31-1.19 (m, 1H), 0.70-0.64 (m, 2H), 0.38-0.33 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 162.2, 156.6, 155.6, 131.3, 119.6, 104.5, 96.7, 60.9, 17.3, 14.3, 9.8, 9.5, 3.3; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH2:11][OH:12])[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CN1CCCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2CO)CC1

Procedure:
A mixture of (2-fluoro-5-nitrophenyl)methanol (4.500 g, 26.3 mmol), diisopropylethylamine (6.89 mL, 39.4 mmol), and 1-methyl-1,4-diazepane (4.25 mL, 34.2 mmol) in acetonitrile (150 mL) was refluxed for 24 hours. The solvent was evaporated. The residue was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4 and filtered. The title compound was crystallized from the organic layers.
Reaction SMILES: [F:1][C:2]1([F:58])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:58][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:46]([F:57])[C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:54])([F:56])[F:55])=[CH:51][CH:52]=2)[CH2:6][CH2:7]1
Reactant: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 57.9 %

Procedure:
To a solution of 68 mg (0.085 mmol) of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 21, in 1 ml of dichloromethane, 46 μl of anisole and 130 μl of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 19 hours. Then, 100 μl of trifluoroacetic acid was further added and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 34 mg of the title compound as a white solid (yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6](=[O:14])[NH:5]2.C(Cl)([Cl:17])=O.C1(C)C=CC=CC=1.O>CN(C)C=O>[Cl:17][C:7]1[C:6](=[O:14])[NH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1Cl
Reaction time: 20 h

Procedure:
To a solution of 2.5 g (~10.8 mmol) 6,7-dichloro-quinoxaline-2,3(1H,4H)-dione in 100 ml of dry N,N-dimethylformamide was added at 0° C. 8.5 ml of 1.93 M phosgene in toluene (~16.3 mmol). Stirring was continued at 24° C. for 20 h. Addition of 100 ml H2O gave a precipitate (2.4 g). Purification by column chromatography (silica gel) by using ethyl acetate as eluent gave the title compound (1.5 g; 56%), m.p. >300° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C([O-])(O)=O.[Na+].[CH3:18][N:19](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1)#[N:19]
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 80 °C
Yield: 92 %

Procedure:
A mixture of 5-iodo-2-aminobenzene-sulfonamide (17.9 g; 60 mmol), Zn(CN)2 (4.9 g; 41.9 mmol) and Pd(PPh3)4 (2.5 g; 2.2 mmol) in DMF (150 ml) under N2 was heated to 80° C. for 2 h. The reaction mixture was poured into NaHCO3 (sat. aq., 600 ml) and extracted with EtOAc (9×200 ml). The combined organic fractions were washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.), dried (Na2SO4), filtered and evaporated to dryness. The remanense was washed with water and hexane and filtered of to give 10.9 g (92%) of product.