Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([OH:21])=O)(=[O:13])=[O:12].C(Cl)(=O)C([Cl:25])=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([Cl:25])=[O:21])(=[O:13])=[O:12]
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
15.6 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxylic acid [Chem, Ber., 35, 3783 (1902)] are dissolved in 120 ml of anhydrous benzene, and 17.5 ml of oxalyl dichloride are added dropwise thereto under stirring. The mixture is allowed to stand at 40° to 50° C. overnight. Then, the mixture is condensed to dryness under reduced pressure, and the residue is recrystallized from a mixture of n-hexane and benzene. 14.3 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride are obtained.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:5]=1[CH2:13][CH3:14].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH2:10]([C:9]1[C:8]([F:12])=[CH:7][CH:6]=[C:5]([CH2:13][CH3:14])[C:4]=1[CH2:3][C:2]1[NH:18][CH2:17][CH2:16][N:19]=1)[CH3:11]
Reactant: NCCN
Reactant: CCc1ccc(F)c(CC)c1C=C(Br)Br
Product: CCc1ccc(F)c(CC)c1CC1=NCCN1

Procedure:
2-(2,6-Diethyl-3-fluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-4-fluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 235.3 ([M+H]+, 100%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[H][H].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][N:10]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[C:7]2=[N:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ncc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
Sodium Hydride (0.667 g, 16.66 mmol) was added portion-wise over 15 mins to a stirred solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (3 g, 15.15 mmol, available from ChemGenx LLC) in N,N-dimethylformamide (30 ml) that had been cooled in an ice bath to 0° C. and placed under nitrogen. The mixture was stirred for 20 mins, until hydrogen evolution ceased, and then benzenesulfonyl chloride (2.148 ml, 16.66 mmol) was added. The mixture was stirred for 18 hours, letting the ice melt over this time. The solution was poured into stirring water (10 ml) and rapidly stirred for 15 mins. The mixture was then poured onto water (70 ml) and filtered. The orange solid obtained was dried in the vacuum oven for 18 h to afford the title compound (3.86 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(C[C@@H]2CCCO2)n1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To the mixture of the product from Example 12C (447 mg, 2.0 mmol) and the product from Step A of Example 11C (410 mg, 2.0 mmol) in CH2Cl2 (8 mL) at about 0° C. was added triethylamine (0.34 mL, 2.4 mmol) dropwise. After stirring for 1 hour at room temperature, water (10 mL) was added to quench the reaction, and CH2Cl2 (20 mL) was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography using an Analogix® IT280™ eluting with ethyl acetate/Hexanes in 0-50% gradient to yield the title compound (330 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 7.81 (d, J=2.71 Hz, 1 H), 7.62 (dd, J=8.98, 2.88 Hz, 1H), 7.28 (d, J=9.15 Hz, 1H), 6.31 (s, 1H), 4.05-4.23 (m, 3H), 3.97 (s, 3H), 3.54-3.72 (m, 2H), 1.83-2.01 (m, 1H), 1.62-1.82 (m, 2H), 1.43-1.60 (m, 1H), 1.24 (s, 9H). MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [C:1]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:3](OCC)=O)=O.[H-].[Na+].[H][H].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]C=1C=O>C1(C)C(C)=CC=CC=1.O>[CH3:14][C:8](=[CH:1][C:3]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)=Cc1ccc2ccccc2c1
Yield: 45.2 %

Procedure:
40 g (0.2 mol) of ethyl α-ethoxalylpropionate are added to a suspension of 5.5 g (0.2 mol) of 80% strength sodium hydride in 300 ml of absolute xylene at 70° C. When the evolution of hydrogen has ended, 31.2 g (0.2 mol) of β-naphthaldehyde, dissolved in xylene, are added dropwise, and when the addition has ended the mixture is heated at the boiling point for 90 minutes. 150 ml of water are added to the cooled reaction mixture and the organic phase is separated off, washed with 7% strength sodium carbonate solution, dried over sodium sulphate and concentrated. The residue is distilled in vacuo. 21.7 g (45.2% of theory) of ethyl 2-methyl-3-β-naphthyl-acrylate of boiling point 110° C./0.13 mbar are obtained.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([CH:17]([CH2:23][C:24]#[CH:25])[C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C1(C)C=CC=CC=1>[CH3:3][C:2]1[NH:5][C:18](=[O:19])[C:17]([CH2:23][C:24]#[CH:25])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: C#CCC(C(=O)OCC)C(=O)c1ccccc1
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#CCc1c(-c2ccccc2)nc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.2 %

Procedure:
To a stirred suspension of 8.00 g (84.6 mmol) of acetamidine hydrochloride in 100 mL of methanol was added 4.56 g (84.4 mmol) of solid sodium methoxide. The mixture was stirred for 40 min at room temperature and rotovaped to remove the methanol. The residue was suspended in 75 mL of ethanol and a solution of 6.19 g(26.9 mmol) of ethyl 2-benzoyl-pent-4-ynoate in 75 mL of toluene was added. The mixture was heated to reflux with a Dean Stark trap and the first 80 mL of distillate was collected and discarded. An 80 mL portion of toluene was added and the mixture was heated at reflux for two weeks. The mixture was allowed to cool, diluted with 70 mL of ether and extracted with two 50 mL portions of 5% aqueous sodium hydroxide. The aqueous extracts were acidified to pH 1 and washed with two 75 mL portions of ethyl acetate. The pH of the aqueous phase was adjusted to 10 and the white precipitate that formed was collected by filtration. Drying furnished 1.76 g (29%) of 2-methyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone, mp 220°-225° C., 1H-NMR (d6-DMSO) δ2.3 (3H, s), 2.68(1H, t,J=4), 3.20(2H, d,J=4), 7.45(3H,m), 7.65 (2H,m).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:7][CH:6]=1)=[O:4].[CH2:18]1[N:23]2[CH2:24][N:25]3[CH2:27][N:21]([CH2:22]2)[CH2:20][N:19]1[CH2:26]3>C1(C)C=CC=CC=1>[Br-:1].[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:19]23[CH2:20][N:21]4[CH2:27][N:25]([CH2:24][N:23]([CH2:22]4)[CH2:18]2)[CH2:26]3)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2F)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Product: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ccc(-c2ccccc2F)cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a stirred solution of 34.8 g of 2-bromo-1-(2'-fluoro[1,1'-biphenyl]-4-yl)ethanone in 1600 ml of toluene was added 17.34 g of hexamethylenetetramine. The mixture was stirred at 60° C. for 4 hours and then cooled. The resulting solid was collected, washed with toluene and ether and dried, giving 48.7 g of 1-[2-(2'-fluoro[1,1'-biphenyl]-4-yl)-2-oxoethyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1. 13,7 ]decane bromide as a white solid mp 174°-178° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH3:10][N:11]([CH2:54][CH:55]=O)[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1.[BH3-]C#N.[Na+].C(O)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:55][CH2:54][N:11]([CH3:10])[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1
Reactant: COCCNCCOC
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCN(CCOC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using bis(2-methoxyethyl)amine in place of L-proline-tert-butyl ester. Into a 25-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (1 mL), bis(2-methoxyethyl)amine (25 mg, 0.19 mmol, 1.20 equiv), NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv), acetic acid (1.0 mg, 0.02 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 47.9 mg product was obtained. This resulted in 47.9 mg (40%) of (S)—N1-(2-(bis(2-methoxyethyl)amino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 747 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.24 (s, 1H), 9.50 (s, 1H), 9.20 (d, J=9 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.24-8.32 (m, 2H), 7.99 (d, J=6 Hz, 2H), 7.86 (d, J=6 Hz, 1H), 7.60-7.69 (m, 3H), 7.30 (s, 1H), 7.10-7.24 (m, 4H), 5.25 (t, J=6.9 Hz, 1H), 3.80 (d, J=33 Hz, 5H), 3.63 (s, 6H), 3.33 (s, 12H), 2.97 (s, 4H), 2.74 (s, 2H), 1.96-2.00 (m, 2H), 1.73-1.88 (m, 6H), 1.60 (d, J=6 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[Br-:1].[CH2:2]([P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-bromotridecane (100 g, 0.4 mol) and triphenyl phosphine (100 g, 0.4 mol) in 500 ml of xylenes was refluxed overnight. The reaction mixture was then cooled to room temperature and poured into diethyl ether. The resulting oil was washed three times with ether, dissolved in methylene chloride and then concentrated in vacuo. The oil was left standing in diethyl ether at 0° C. overnight and then concentrated in vacuo to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 96 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 96%). 1H NMR (300 MHz, CDCl3): δ 3.18-3.26 (m, 4H), 3.76 (s, 3H), 4.11-4.14 (m, 4H), 6.84-6.87 (d, J=8.7 Hz, 2H), 7.22-7.34 (m, 3H), 7.41-7.53 (m, 1H), 7.65-7.66 (m, 1H), 7.79 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.O1CCOCC1.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1
Reactant: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (24.3 mg, 0.058 mmol, 1 eq) in DCM (4 mL) was added 4M HCl in dioxane (0.290 mL, 1.16 mmol, 20 eq). The reaction mixture was allowed to stir at RT for 5 mins. MeOH (100 uL) was added to the mixture. The mixture was then concentrated to dryness to give N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanamide (8.1 mg, 37% yield). LC-MS M+H+338.5.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2c1CCC(CC=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cccc2c1CCC(CC=C(Br)Br)C2
Reaction time: 0.17 h

Procedure:
To a solution of carbon tetrabromide (19.5 g) in methylene chloride (50 ml) was added triphenylphosphine (30.8 g) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 2-formylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.09 g; the compound prepared by method described in the specification of the Japanese Patent Application No. 3-130467) in methylene chloride (25 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was gradually added n-hexane, and filtrated to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (6.42 g) having the following physical data.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].O>C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Sodium metal (3.80 g, 165 mmol) was dissolved in absolute ethanol (66 mL) at 0° C. The 3-nitro-o-xylene (10 g, 66.2 mmol) and diethyl oxalate (18 mL, 132 mmol) were then added and the reaction was warmed to room temperature and stirred for 18 hours. The reaction was refluxed for 30 minutes, then cooled and water (22 mL) was added and the reaction was stirred at room temperature for one hour. The reaction was concentrated to remove the ethanol, then extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide the desired product (13.92 g, 94%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[K+].[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH-:35])(=[O:34])=[O:33])=[N:30][CH:31]=1)([CH3:25])[CH3:24]>CN(C=O)C>[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:3]=2)(=[O:34])=[O:33])=[N:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A mixture of 654 mg of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine and 1051 mg of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1e) in 20 ml of DMF was stirred for 16 h at room temperature. Eventually, the solvent was distilled off under reduced pressure and the resulting residue was treated with 100 ml of 10% aqueous acetic acid and 100 ml of DCM. The layers were separated. The aqueous layer was extracted two more times with DCM. The combined organic layers were washed once with water, dried over MgSO4 and evaporated. The remaining residue was crystallised from isopropanol:diethyl ether. The yellow crystals were collected, washed with cold isopropanol and diethyl ether, and dried under high vacuum to furnish 870 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.06 min, [M+1]+=480.40, [M−1]−=478.48.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[N:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[CH3:15][C:16]([CH3:39])([CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH:13]([C:10]1[N:11]=[CH:12][C:7]([C:26]2[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH2:21][C:16]([CH3:15])([CH3:39])[C:17]([O:19][CH3:20])=[O:18])=[N:24][CH:25]=2)=[N:8][CH:9]=1)=[O:14]
Reactant: O=Cc1cnc(Cl)cn1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(C=O)cn2)cn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
N,N-dimethylformamide (10 mL) was added to 5-chloropyrazine-2-carbaldehyde (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (1410 mg) and 2N aqueous sodium carbonate solution (5.26 mL), and after replacing the atmosphere with nitrogen, palladium chloride (dppf) methylene chloride complex (143 mg) was added to the mixture and the resulting mixture was stirred at 65° C. for 2 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. After filtration with Celite, the organic layer was separated, washed with water and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30) to obtain methyl 3-{[5-(5-formylpyrazin-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (855 mg).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:25](=[O:26])[C:24]3[C:19]([Cl:18])=[CH:20][CH:21]=[C:22]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C:23]=3[F:28])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(C)(C)C)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(NC(C)(C)C)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 21.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)-2-methylquinazoline-4,8-diamine (Intermediate-58, 100 mg, 0.43 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.52 mmol), oxalyl chloride (82 mg, 0.65 mmol), DMF (1 drop) and DIPEA (166 mg, 1.29 mmol) in CH2Cl2 (3 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.66 (d, J=7.4 Hz, 1H), 8.15 (t, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.44-7.33 (m, 4H), 4.31 (d, J=5.8 Hz, 2H), 2.48 (s, 3H), 1.14 (s, 9H); MS (m/z): 500.60 (M+H)+.
Reaction SMILES: I[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.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>[CH3:20][N:4]1[C:3](=[O:21])[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]1=[O:19]
Reactant: OB(O)c1cccs1
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccsc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 50.9 %

Procedure:
To a solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (60.0 mg), 2-thiophen boronic acid (84.6 mg), sodium carbonate (84.6 mg) in tetrahydrofuran (2.0 ml)/water (0.3 ml) was added tetrakis(triphenylphosphine)palladium (25.2 mg) and the resulting mixture was stirred with heating under reflux for five hours. The reaction mixture was filtered through Celite (trade mark) and thereto was added water (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (27.3 mg).