Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:18](OC3C=CC=CC=3)=[O:19])=[CH:15][C:14]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2].[N:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([NH:17][C:18]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:45][CH:44]=3)=[O:19])=[CH:15][C:14]([C:27]([CH3:28])([CH3:29])[CH3:30])=[N:13]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 60 °C
Yield: 70 %

Procedure:
A mixture of ethyl(4-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate (3.0 g, 7.12 mmol) and 4-(pyridin-4-yloxy)aniline (1.26 g, 6.78 mmol) in THF (50 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and then evaporated at reduced pressure to afford a brown syrup, which was purified by MPLC (25:75 to 70:30 EtOAc/hexane). The desired product was obtained as a white solid (2.42 g) in 70% yield. 1H-NMR (CD2Cl2-d2) δ 8.35 (m, 2H), 8.06 (s, 1H), 7.42 (m, 4H), 7.33 (s, 1H), 7.28 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.88 (d, J=5.8 Hz, 2H), 6.35 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.31 (s, 9H), 1.27 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]+=514.2, RT=2.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:28]([N:11]([CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ncc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (30 mg) in N,N-dimethylacetamide (0.6 mL) were added benzyl bromide (13 mg) and cesium carbonate (26 mg). The mixture was stirred overnight at r.t. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 1:1) to give N-benzyl-2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 534.8 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)n1
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of 2-chloropyrimidine-4-carboxylic acid (1.0 g, 6.31 mmol) in 1:1 benzene (5 mL) and MeOH (5 mL) at 0° C. was added trimethylsilyl-diazomethane (2.0 M solution in hexanes, 3.78 mL, 7.57 mmol) dropwise. The solution was left to stir for 14 hr and concentrated to dryness. Flash chromatography on silica (0-100% EtOAc/hexanes) afforded methyl 2-chloropyrimidine-4-carboxylate (980 mg, 5.68 mmol, 90% yield) as a yellow oil. MS ESI: [M+H]+ m/z 173.0. 1H NMR (500 MHz, CDCl3) δ 8.88 (dd, J=1.5, 4.9, 1H), 7.96 (dd, J=1.5, 4.9, 1H), 4.04 (d, J=1.5, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O>CN(C)C=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([Cl:14])=[O:10])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1snc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 4.0 g (20.3 mmol) of 3,4-dichloroisothiazole-5-carboxylic acid were added 8 ml of oxalyl chloride and a catalytic amount of N,N-dimethylformamide (DMF). The mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under vacuum to obtain 3,4-dichloroisothiazole-5-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)C1CCOCC1
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2nccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloropyrazine (1.45 g, 9.73 mmol) and methyl tetrahydro-2H-pyran-4-carboxylate (2.60 mL, 19.47 mmol) in Toluene (19.47 mL) at room temperature was added LiHMDS (19.47 mL, 19.47 mmol, 1M solution) dropwise. After overnight room temperature stirring, reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. Purification by Biotage (0-10% MeOH/DCM) produced product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]3[CH2:27]O3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:35]>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:24][CH:25]3[CH2:27][S:35]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Reactant: NC(N)=S
Solvent: ClCCl
Solvent: CO
Product: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CS3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 20 (0.40 g, 0.86 mmol) in CH2Cl2 (5 mL) was added a mixture of thiourea (0.10 g, 1.3 mmol, 99%) in methanol (5 mL). The resulting mixture was stirred for 24 h at room temperature, after which the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous Na2SO4 and was filtered. Evaporation of solvent and purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 0.34 g of 21 (83%). 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 2.14 (dd, J=1.8, 5.0 Hz, 1H), 2.52 (dd, J=1.5, 5.9 Hz, 1H), 3.04 (dq, J=5.6, 7.8 Hz, 1H), 3.15 (dd, J=8.0, 14.2 Hz, 1H), 3.47 (s, 3H), 3.51 (dd, J=5.6, 14.4 Hz, 1H), 5.19 (s, 2H), 6.72 (dd, J=2.6, 8.8 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 7.08-7.01 (m, 3H), 7.85-7.80 (m, 2H), 8.16-8.08 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 24.4, 26.2, 28.5, 56.6, 62.7, 80.8, 95.3, 107.3, 114.1, 117.3, 119.4, 126.2, 130.8, 131.6, 146.6, 149.3, 152.8, 163.5. HRMS (FAB) calcd for C22H28NO7S2 (M+H+) 482.1302. found 482.1301.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[O:17]=[S:2]1(=[O:1])[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][O:16][S:34]([C:31]1[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=1)(=[O:35])=[O:36]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2cccnc2S(=O)(=O)N1CCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cccnc2S(=O)(=O)N1CCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 0.73 g of 1,1-dioxido-2-(4-hydroxybutyl)-isothiazolo[5,4-b]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0° C. was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO4. Concentration under reduced pressure gave 1.4 g of crude 1,1-dioxido-2-(4-(4-nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OCCO[C:28]1[CH:40]=[CH:39][C:31]2[N:32]=[C:33]([S:35]([NH2:38])(=[O:37])=[O:36])[S:34][C:30]=2[CH:29]=1)(=O)C.N>C(OCC)C>[S:34]1[C:30]2[CH:29]=[CH:28][CH:40]=[CH:39][C:31]=2[N:32]=[C:33]1[S:35]([NH2:38])(=[O:37])=[O:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCOc2ccc3nc(S(N)(=O)=O)sc3c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CCOCC
Product: NS(=O)(=O)c1nc2ccccc2s1
Reaction time: 8 h

Procedure:
The unpurified 6-[2'-(2",3",4",6"-tetra-O-acetyl-β-glucopyranosyl)oxyethoxy]-2-benzothiazolesulfonamide (3.02 g.; 5.00 mmole) was dissolved in anhydrous diethyl ether (100 mL) and combined with cold (0° C.) saturated methanolic ammonia (100 mL) and stirred overnight with the temperature rising to room temperature over a six hour period. The solution was evaporated to dryness at reduced pressure and chromatographed on a silica gel column (150 g.) and eluted with chloroform/methanol (9.1). The product fractions (UV light and charring positive) were combined and evaporated to dryness at reduced pressure, and lyophilized to yield 6-[β-glucopyranosyl)oxyethoxy]-2-benzothiazolesulfonamide. The product conformed to accepted standards of purity and its structural assignment verified by standard spectroscopic methods (mass spec, 13C and 1H nuclear magnetic resonance).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:9][CH:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:13])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1

Procedure:
Valine tert-butyl ester hydrochloride is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give tert-butyl 2-{[(4-methoxyphenyl)sulfonyl]amino}-3-methylbutanoate.
Reaction SMILES: [CH:1]1([C@H:4]([OH:9])[CH2:5]/[CH:6]=[CH:7]/[CH3:8])[CH2:3][CH2:2]1.[CH2:10]([O:12][CH:13]([O:29][CH2:30][CH3:31])[CH2:14]O[C@H](CC=C)COCC1C=CC=CC=1)[CH3:11]>>[CH2:10]([O:12][CH:13]([O:29][CH2:30][CH3:31])[CH2:14][O:9][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5]/[CH:6]=[CH:7]/[CH3:8])[CH3:11]
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Reactant: C/C=C/C[C@@H](O)C1CC1
Product: C/C=C/C[C@@H](OCC(OCC)OCC)C1CC1

Procedure:
(1R,3E)-1-Cyclopropylpent-3-en-1-ol (C24) was converted to the product according to the method used for the synthesis of ({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2) in Preparation P1, except that all reagents were combined at 0° C. The product was obtained as a colorless oil. Yield: 550 mg, 2.27 mmol, 48%. 1H NMR (400 MHz, CDCl3) δ 5.44-5.59 (m, 2H), 4.62 (dd, J=5.3, 5.3 Hz, 1H), 3.66-3.76 (m, 3H), 3.54-3.63 (m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.65 (dt, J=8.5, 5.9 Hz, 1H), 2.28-2.33 (m, 2H), 1.65-1.68 (m, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 0.79-0.88 (m, 1H), 0.53-0.60 (m, 1H), 0.42-0.50 (m, 1H), 0.34-0.41 (m, 1H), 0.06-0.13 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)=[O:7].[C:17]([C:20]1[C:21](=[O:29])[N:22]([CH3:28])[C:23]([CH3:27])=[CH:24][C:25]=1[OH:26])(=[O:19])[CH3:18]>C(O)C>[OH:26][C:25]1[CH:24]=[C:23]([CH3:27])[N:22]([CH3:28])[C:21](=[O:29])[C:20]=1[C:17](=[O:19])[CH:18]=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([NH:8][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH:10]=1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: COCCOC(=O)Nc1cccc(C=O)c1
Solvent: CCO
Product: COCCOC(=O)Nc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Yield: 60.7 %

Procedure:
According to the same manner as that of Example a-1 except that 1.00 g of 3-[(2-methoxyethoxy)carbonylamino]benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.742 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, and 20 ml of ethanol was used in place of pyridine, 0.96 g of 4-hydroxy-3-[3-[3-[(2-methoxyethoxy)carbonylamino]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (42a)] was obtained as a yellow crystal.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:25][C@@H:26]1[O:31][C@H:30]([CH3:32])[CH2:29][N:28]([C:33]([C:35]2[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=2)=[O:34])[CH2:27]1>O1CCCC1.CCOCC>[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][N:28]([C:33]([C:35]2[CH:36]=[C:37]([S:41]([N:9]3[CH2:10][CH2:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:8]3=[O:12])(=[O:42])=[O:43])[CH:38]=[CH:39][CH:40]=2)=[O:34])[CH2:27]1
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)c2cccc(S(=O)(=O)Cl)c2)C[C@H](C)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2cccc(S(=O)(=O)N3CCC(c4ccccc4)(c4ccccc4)C3=O)c2)C[C@H](C)O1
Reaction time: 0.5 h

Procedure:
To 3,3-diphenylpyrrolidin-2-one (166 mg, 0.7 mmol; Example 1A) in anhydrous tetrahydrofuran (6 mL) was added potassium tert-butoxide (1 mL, 1.0 M in tetrahydrofuran) at room temperature followed by stirring for 30 minutes. Then the crude 3-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)benzene-1-sulfonyl chloride (0.7 mmol; Example 147A) in tetrahydrofuran (8 mL) was added slowly. The mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=1:1) to give crude material. The crude material was dissolved in ether (60 mL), the insoluble solid was removed, and the ether solution was concentrated to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (m, 3H), 1.10 (m, 3H), 2.83 (m, 3H), 3.30-3.60 (m, 4H), 3.80 (m, 2H), 4.37 (m, 1H), 7.00 (m, 4H), 7.20 (m, 6H), 7.71 (t, 1H, J=7 Hz), 7.88 (m, 1H), 8.00 (m, 2H); MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:13]2)[CH:7]=[N:6][CH:5]=1
Reactant: FC(F)(F)c1cncc(I)n1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Under N2, 2-iodo-6-(trifluoromethyl)pyrazine (CAS 141492-94-6) (0.137 g, 500 μmol, Eq: 1.00), ethyl 1H-pyrazole-4-carboxylate (CAS 37622-90-5) (70.1 mg, 500 μmol, Eq: 1.00) and potassium carbonate (138 mg, 1.00 mmol, Eq: 2) were combined in DMSO (2.4 ml). The orange solution was stirred at 120° C. over 1 hour. Control with TLC: the reaction was finished. At RT, the RM was partitioned between water and EtOAc; extracted; the organic layer was washed with water and brine; dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 5% to 25% EtOAc in heptane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:25])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](OCC)=[O:21])[CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:25])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][CH2:19]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(CC(C)Cc2ccc(C(C)(C)C)cc2)CC1
Solvent: O
Solvent: CCOCC
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCC(CO)CC1
Yield: 57.8 %

Procedure:
A solution of 41.4 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-carbethoxy-piperidine in 100 ml of absolute diethyl ether is added dropwise to a suspension of 10 g of LiALH4 in 100 ml of absolute ether. An exothermic reaction ensues and the ether refluxes. When the reaction has subsided, the mixture is heated under reflux for 4 hours. 100 ml of water are then slowly added dropwise, with ice cooling. 500 ml of diethyl ether are added, the top layer is decanted and the smeary residue is triturated twice more with ether. The combined ether phases are washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gives 21 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-hydroxymethylpiperidine [B]. Boiling point 175°-178° C./0.2 mbar.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[N:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:24]=[O:25].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:24]([NH:23][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:25])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: COC(=O)CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
A suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.2 g.), methyl 2-isocyanatoacetate (1.4 g.) and triethylamine (1.2 g.) in acetonitrile (50 cc.) is stirred for 18 hours at a temperature of about 20° C. A further amount of methyl 2-isocyanatoacetate (0.7 g.) is added and stirring is continued for a further 3 hours. The precipitate is filtered off and is dissolved in methylene chloride (35 cc.). Decolourising charcoal (0.5 g.) is added. After filtration, diisopropyl ether (105 cc.) is added to the filtrate. The crystalline precipitate which forms is filtered off, washed with diisopropyl ether (15 cc.) and then dried to give 2-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxycarbonylmethylaminocarbonyloxy-isoindolin-1-one (2.5 g.) melting at 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][NH:20][C:17]([C@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:12]2)=[O:19])=[C:23]([C:30]([F:31])([F:33])[F:32])[CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(CN)c(C(F)(F)F)c1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(C#N)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.264 mmol) in N,N-Dimethylformamide (DMF) (4 ml) was added 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (0.053 g, 0.264 mmol) followed by diisopropylethylamine (0.101 ml, 0.580 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.128 g, 0.290 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-N-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (83 mg, 0.148 mmol, 56%). MS (ES) m/e 448 [M+H]+. 1H NMR (400 MHz, DMSO-D6) □ 7.8 (bs, 1H), 7.3 (bs, 1H), 7.2 (m, 1H), 6.9 (m, 1H), 3.8 (bs, 2H), 3.3 (bm, 1H), 2.2 (bm, 4H), 1.8-1.5 (bm, 4H), 1.3-1.1 (bm, 4H), 0.8-0.5 (bm, 4H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][CH:16]([CH3:32])[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1.P(C#N)(=O)(OCC)OCC.O>ClCCCl>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH2:17][CH:16]([CH3:32])[CH3:15])[CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]1)=[O:6]
Reactant: CC(C)CNC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCCl
Solvent: O
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-amino-4-(trifluoromethyl)benzoic acid (0.32 g) and tert-butyl 3-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.4 g) were dissolved in 1,2-dichloroethane (20 ml), diethyl phosphorocyanidate (0.31 g) was added and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-1:1) was concentrated under reduced pressure to give the object compound (0.33 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16].F[B-](F)(F)F.[H+].[CH3:26][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH3:26])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(Br)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 106.1 %

Procedure:
6-Bromo-7-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-108) (912.6 mg, 2.79 mmol) and (514 mg, 1.57 mmol) were separately dissolved in methylene chloride (9 ml and 5 ml), and aqueous 42% tetrafluoroboric acid solution (420 μl, 2.79 mmol) and (240 μl, 1.57 mmol) were individually added to each, then with cooling with ice, trimethylsilyldiazomethane (2 M hexane solution, 2.8 ml, 5.58 mmol) and (1.6 ml, 3.14 mmol) were dropwise added, followed by stirring at 0° C. for 40 minutes; but since the reaction did not finish, the same amount of aqueous 42% tetrafluoroboric acid solution and trimethylsilyldiazomethane were added, followed by stirring for 19 hours with heating up to room temperature. After the reaction, the two reaction solutions were combined, water was added, followed by extraction with ethyl acetate and washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (10:1, v/v) to obtain the entitled compound (1.01 g, 68%) as a white solid.