Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH:32]1([CH2:35][NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][C:14]([C:18]([N:36]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[CH2:37][CH2:38][CH3:39])=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: CCCNCC1CC1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCN(CC1CC1)C(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylic acid i43 (3.18 g, 10.75 mmol, 1 eq) and triethylamine (1.5 ml, 10.75 mmol, 1 eq) in chloroform (70 ml) is cooled to 0° C. Thionyl chloride (2.3 ml, 32 mmol, 3 eq) is then added dropwise. The mixture is refluxed for 2 h 30 and the solvent is evaporated. The residue is taken up in cold dichloromethane (20 ml, 0° C.) and treated with triethylamine (0.6 ml, 4.3 mmol, 2 eq) and N-(cyclopropylmethyl)propan-1-amine (0.29 g, 2.58 mmol, 1.2 eq). The mixture is stirred at room temperature overnight and then washed two times with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.82 g of 2-[4-(3-chloropropoxy)phenyl]-N-(cyclopropylmethyl)-4-methyl-N-propyl-1,3-oxazole-5-carboxamide i44.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccccc1
Yield: 66.1 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (100 mg; 0.314 mmol), 2-chlorophenylboronic acid (73.6 mg; 0.471 mmol) and tetrakis(triphenylphosphine) palladium(0) (36.2 mg; 0.031 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.193 mL; 1.255 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 82 mg (66%) of the title compound. ESI/APCI(+): 395 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8]C)[O:5][N:4]=1.[OH:10][CH2:11][C:12]([N:14]([CH2:16][C@H:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH3:38])[CH:32]=1)=[N:23][CH:24]=[N:25]2)[CH3:18])[CH3:15])=[O:13]>>[OH:10][CH2:11][C:12]([N:14]([CH3:15])[CH2:16][C@H:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[C:33]([CH3:38])[CH:32]=1)=[N:23][CH:24]=[N:25]2)[CH3:18])=[O:13]
Reactant: CCc1cc(CCl)no1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(COc2ccc(Nc3ncnc4cccc(O[C@H](C)CN(C)C(=O)CO)c34)cc2C)no1
Yield: 7 %

Procedure:
The procedure described in Example 3 was repeated using 3-(chloromethyl)-5-ethylisoxazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 7% yield; NMR spectrum (DMSO-d6 373K) 1.44 (d, 3H), 2.22 (s, 3H), 2.42 (s, 3H), 2.98 (s, 3H), 3.58 (m, 1H), 4.17 (m, 3H), 5.11 (m, 1H), 5.15 (s, 2H), 6.29 (s, 1H), 7.07 (d, 1H), 7.11 (d, 1H), 7.33 (d, 1H), 7.57 (m, 2H), 7.69 (t, 1H), 8.44 (s, 1H), 9.83 (s, 1H); Mass spectrum MH+ 492.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24]([NH:26][C:27]2[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[N:31]=[CH:30]4)=[N:23][CH:22]=[N:21]3)[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[F:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:25]4=[C:17]([CH2:16][N:13]5[CH2:12][CH2:11][CH:10]([NH:9][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH2:15][CH2:14]5)[CH:18]=[CH:19][N:20]4[N:21]=[CH:22][N:23]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.9 %

Procedure:
Acetoxyacetyl chloride (46 mg, 2 equiv) was added dropwise to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) (80 mg, 0.17 mmole) and triethylamine (71 μL, 3 equiv.) in dry DCM (3 mL) at 0° C. under nitrogen. After stirring at 0° C. for 3 hr and at RT for 1 hr, it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded acetic acid (1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-ylcarbamoyl)-methyl ester as a solid (73 mg, 75%). A solution of this ester in THF (0.4 mL) was treated with aq. NaOH (IN, 0.38 mL, 3 equiv.). After 2 hr at RT it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (47 mg, 70%). MS: 529 (M+H)+; HPLC Ret Time: 1.37 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=3)[CH2:13]2)=[O:11])=[C:4]([O:28][C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][C:23]1[N:22]=[C:21]([NH:26][CH3:27])[N:20]=[C:19]([NH:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:10]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:3][C:4]=3[O:28][C:29]([F:32])([F:31])[F:30])=[O:11])[CH2:13]2)[N:24]=1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(Br)cc3OC(F)(F)F)C2)n1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(N4CCOCC4)cc3OC(F)(F)F)C2)n1
Yield: 19 %

Procedure:
A mixture of N-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (60 mg, 0.116 mmol), morpholine (20.21 mg, 0.232 mmol), Pd2(dba)3 (5.31 mg, 5.80 μmol), BINAP (5.42 mg, 8.70 μmol) and cesium carbonate (76 mg, 0.232 mmol) in 1,4-Dioxane (2 ml) was irradiated via microwave reactor for 20 min at 170° C. The crude reaction mixture was passed through a 2 gram SCX ion-exchange column. The column was flushed with MeOH, then it was flushed with 2N NH3 in MeOH. The NH3 solution was collected and the solvent was evacuated to give a residue which was purified by preparative HPLC, resulting in 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-({4-(4-morpholinyl)-2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide (15 mg, 0.022 mmol, 19%). MS (ES) m/e 524 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[CH:9]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][CH:7]1[CH2:34][CH3:35])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:43]([O:45][CH3:46])=[O:44]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[CH:9]([N:18]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:21]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:8][CH:7]1[CH2:34][CH3:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(cc(C)nc2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)CC1CC

Procedure:
This compound can be prepared by reacting, a solution of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6,8-dimethyl-3,4-dihydro-2H-[1,7]naphthyridine-1-carboxylic acid ethyl ester in THF and K2CO3 (2 to 5 eqv) with methyl chloroformate, followed by a typical workup procedure.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([O:31][CH:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH:32]1[CH2:35][CH:34]([NH:36][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1CC(OCc2ccccc2)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC(OCc3ccccc3)C2)cn1
Yield: 43 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (300 mg, 0.97 mmol) was converted, using rac 3-benzyloxy-cyclobutylamine instead of 2-aminoethyl isopropylether, to the title compound (350 mg, 43%) which was obtained as a white solid. MS: m/e=470.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8]1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[C:17]([OH:18])[CH:16]=1>CN(C)C=O.O>[CH:7]1([O:18][C:17]2[CH:16]=[C:15]([CH:23]=[CH:22][C:19]=2[O:20][CH3:21])[CH:14]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Potassium carbonate (27.6 g, 0.20 mole) was added to a solution of cyclopentyl bromide (26.4 g, 0.18 mole) and isovanillin (25.8 g, 0.17 mole) in N,N-dimethyl formamide (80 mL). The resulting suspension was stirred at ambient temperature for 1 week, then diluted with water (about 500 mL) and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with water (5×150 mL), 10% sodium hydroxide (3×50 mL), and water (2×100 mL), then dried over magnesium sulfate and concentrated under vacuum to provide 27.5 g of 3-cyclopentyloxy-4-methoxybenzaldehyde as a viscous yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[C:30]([CH2:29][CH2:28][CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.51 g, 1.61 mmol) and dimethylformamide (15 mL). Add sodium hydride (0.086 g, 60% in oil, 2.15 mmol). Heat to 80° C. After 15 minutes, add ethyl 4-bromobutyrate (0.35 mL, 2.45 mmol) and continue heating at 80° C. After 18 hours, cool and partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29](O)=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:32]([F:35])([F:34])[F:33])=[N:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)=[C:15]([C:29]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:30])[CH:14]=2)=[CH:11][C:10]([C:32]([F:34])([F:35])[F:33])=[N:9]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a suspension of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylic acid (0.52 g, 1 mmol) in DCM (6 mL) was added carbonyldimidazole (2.43 mg, 1.5 mmol) and the mixture was stirred for 2 h at 20° C. Morpholine (0.175 mL, 2 mmol) was added and the mixture was stirred overnight at 20° C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 4:1) to afford (4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)(morpholino)methanone (0.52 g). 1H-NMR (CDCl3): δ 7.97 (m, 2H), 7.77 (d, 1H), 7.64 (m, 1H), 7.58 (m, 1H), 7.46-7.24 (m, 5H), 6.89 (s, 1H), 3.55 (m, 3H), 3.33 (m, 2H), 3.08 (s, 3H), 2.87 (m, 2H), 2.69 (m, 1H). MS(ES): 590 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>>[CH2:1]([NH:5][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:16])=[O:17])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 78.8 %

Procedure:
The procedure described in Example 1A was performed using isobutylamine (0.396 g, 5.41 mmol) and 3-nitrobenzenesulfonyl chloride (1.0 g, 4.5 mmol) to give N-isobutyl-3-nitrobenzenesulfonamide (0.916 g, 78%). 1H NMR consistent with structure.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[O:21])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1)N1CCCC1
Reaction time: 15 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxylic acid (340 mg, 1.18 mmol), pyrrolidine (102 mg, 1.44 mmol) and diisopropylethylamine (372 mg, 2.88 mmol) in THF (5 mL) was added PyBop (1.25 g, 2.4 mmol) portionwise at 25° C. After stirring for 15 h, the mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 141 mg (35%) of [2-(4-cyclopropylpiperazin-1-yl)benzooxazol-5-yl]pyrrolidin-1-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5]>O1CCCC1.O>[ClH:1].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: CN(C)CC1CC2(CCC1(O)c1ccccc1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CC(=O)CCC1(O)c1ccccc1
Reaction time: 16 h
Yield: 65 %

Procedure:
215 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-phenyl-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (85 g, 259 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The resulting colorless solid was filtered out with suction and dried. 47.5 g (65%) of the product were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[N:11][C:10]([Cl:29])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:30]>>[ClH:29].[ClH:30].[NH2:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:29])[N:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(N)CC1
Yield: 56 %

Procedure:
Following general procedure IV-1, tert-butyl {trans-4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]cyclohexyl}carbamate (360 mg, 0.86 mmol) was reacted with HCl (5 mL, 2 M in ether) to afford the desired product (190 mg, 56%) as a white solid. ESI MS m/z 318 [M+H]+
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO[C:21](C)(C)[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH:17]=[CH:21][CH3:22]
Reactant: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](OC)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.65 g of ethyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature with 797 mg of potassium tert.butylate and stirred for 1 hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.1 g of 3-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]propionaldehyde in 15 ml of tert.butyl methyl ether and then left to warm slowly to room temperature while stirring. After 2 hours the pale yellow suspension was partitioned between diethyl ether and water. The aqueous phase was separated and washed three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the yellow, solid crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.91 g of trans-4-(3-pentenyl)-1-(trans-4-methoxycyclohexyl)cyclohexane with a Z/E ratio of 86:11.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:28])[CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl>[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[S:6][C:5]([CH:7]([OH:28])[CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
While stirring zinc chloride (7.76 g, 57.0 mmol) in diethyl ether (150 ml), sodium borohydride (4.31 g, 114 mmol) was added at room temperature, and the mixture was stirred at it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added ethyl 3-(5-chloro-2-thienyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (12.50 g, 28.48 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−1/1) to give the objective substance.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[CH:23]=[C:22](I)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.[C:27]1([CH2:33][SH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C(N(CC)CC)C>[CH2:33]([S:34][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([NH:13][C:12]2[CH:25]=[CH:26][C:9]([F:8])=[CH:10][CH:11]=2)[CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To toluene 4.0 mL suspension of methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.40 g, 1,1′-bis(diphenylphosphino)ferrocene 0.072 g and tris(dibenzylideneacetone)dipalladium(0) 0.050 g were added triethylamine 0.30 mL and phenylmethanethiol 0.15 mL, and it was stirred under argon atmosphere at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent, hexane:ethyl acetate=10:1] to give methyl 4-(benzylthio)-2-(4-fluoroanilino)benzoate 0.36 g of white solid.