Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].B(Cl)([C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>>[OH:3][C@H:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccn1
Agent: C[C@@H]1[C@H](B(Cl)[C@@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Product: C[C@H](O)c1cc(C#N)ccn1
Yield: 30.8 %

Procedure:
The title compound was prepared according to General Method B starting from 2-acetyl-isonicotinonitrile (2.00 g, 13.7 mmol) and (−)-DIPCl (6.58 g, 20.53 mmol) to yield the title compound (625 mg, 4.22 mmol) with 90% ee.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([S:16]([NH:19][C:20]2[S:24][N:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F)#[N:8].[I:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[OH:36]>CS(C)=O.C(OCC)(=O)C>[C:7]([C:9]1[CH:10]=[C:11]([S:16]([NH:19][C:20]2[S:24][N:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[O:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=1[I:25])#[N:8]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(C(F)(F)F)cc1I
Temperature: 80 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a suspension of potassium carbonate (0.850 g, 0.006150 mol) and 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 65, 0.500 g, 0.001759 mol) in dimethyl sulfoxide (5.0 mL) was added 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 0.595 g, 0.002066 mol) and stirred at 80° C. under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (10.0 mL) and the organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (5.0 mL) to yield title compound as a white solid, 560 mg, 58% yield.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:31][CH3:32])[CH:28]([CH3:30])[CH3:29]>>[CH2:27]([N:31]([CH3:32])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH:28]([CH3:30])[CH3:29]
Reactant: CNCC(C)C
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CC(C)CN(C)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and isobutyl-methyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 464.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH2:43][CH:44]1[CH2:46][CH2:45]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH2:43][CH:44]1[CH2:45][CH2:46]1)[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:30])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (350 mg, 0.79 mmol) in dimethylformamide (7.5 mL) were added [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) (274 mg, 1.19 mmol) N,N-diisopropylethylamine (0.4 mL), 2.39 mmol) and HATU (364 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 1 h while silica thin layer chromatography was performed (ethyl acetate:hexane=1:1/UV/SiO2, Rf=0.5). The reaction mixture was diluted with ethyl acetate (60 mL), washed with brine (3×30 mL) and dried and concentrated in vacuo to get a crude mass of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (329) (600 mg) which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([NH:14]C(=O)C3C=CC=CC=3)=[S:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([NH2:14])=[S:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(NC(=S)NC(=O)c3ccccc3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc2nc(N)sc2c1
Yield: 66.5 %

Procedure:
A suspension of 1-(2-amino-benzothiazol-6-yl)-3-benzoyl-thiourea (Example 2, 0.2 g, 0.61 mmol) and 2.0 N NaOH (0.67 mL, 1.34 mmol) in 10 mL of THF was heated at reflux for 4 hours. Upon cooling, a yellow solid precipitated which was filtered. Yield: 66.5%, 1H-NMR (DMSO-d6): δ 9.55 (s, 1H); 7.64 (d, 1H, J=1.8 Hz); 7.44 (s, 2H); 7.27 (m, 2H); 7.03 (dd, 1H, J=8.0, 2.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:32]C)[N:21]=[C:22]([C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])[CH:23]=2)[N:18]([CH3:34])[CH:17]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])[NH:21][C:20](=[O:32])[C:19]=2[N:18]([CH3:34])[CH:17]=1
Reactant: COc1nc(-c2c(C)noc2C)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(=O)[nH]1
Temperature: 70 °C
Yield: 82.8 %

Procedure:
The product from Example 94A (0.052 g, 0.094 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 4 hours, cooled and concentrated. Purification by chromatography (silica gel, 0-4% methanol in dichloromethane) afforded the title compound (0.042 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.09 (s, 1H) 7.60-7.64 (m, 2H) 7.41-7.53 (m, 1H) 7.21-7.32 (m, 2H) 7.06-7.16 (m, 1H) 6.81 (d, J=8.48 Hz, 1H) 6.57 (s, 1H) 4.51 (s, 2H) 4.13 (s, 3H) 2.92 (s, 3H) 2.35 (s, 3H) 2.18 (s, 3H). MS (ESI+) m/z 540 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[NH:17]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([Cl:31])[CH:23]=1)=[S:20])[NH2:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14](=[N:18][NH:17][C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([Cl:31])[CH:23]=3)=[S:20])[CH3:16])[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: CC(=O)c1csc(-c2ccc(Cl)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(Cl)cc2)c1O

Procedure:
From 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25.2 mg, 0.1 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (24.5 mg, 0.1 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (41.9 mg, yield 88%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19](O)=[O:20].[C:33](N1C=CN=C1)([N:35]1C=CN=[CH:36]1)=O.CNC.O>O1CCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([N:35]([CH3:36])[CH3:33])=[O:20]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(-c4ccc[nH]4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(-c4ccc[nH]4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 3-(1,3-dioxo-4-pyrrolylisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.29 g, 2.97 mmol), and carbonyldiimidazole (481 mg, 2.97 mmol) in tetrahydrofuran (13 mL) was stirred at room temperature for 2 h. To the mixture was added dimethylamine in tetrahydrofuran (1.7 mL, 2N, 3.4 mmol) and the mixture stirred for an additional 2 h. Water (70 mL) and methylene chloride (50 mL) was added to the mixture. The organic layer was separated, washed with brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a brown solid. This solid was purified by column chromatography (silica gel, 1:5 ethyl acetate:methylene chloride +0.1% MeOH) to give 3-(1,3-dioxo-4-pyrrolylisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a yellow solid (750 mg, 55% yield): mp, 105-107° C.; 1H NMR (CDCl3) δ 1.43 (t, J=7 Hz, 3H, CH3), 2.88 (s, 3H, CH3), 3.00 (s, 3H, 2CH3), 3.04 (dd, J=4.9, 16 Hz, 1H, CHH), 3.82 (s, 3H, CH3), 3.91 (dd, J=10.2, 16.6 Hz, 1H, CHH), 4.09 (q, J=7 Hz, 2H, CH2), 5.82 (dd, J=4.9, 10.2 Hz, 1H, NCH), 6.35 (t, J=2 Hz, 2H, Ar), 6.77-6.81 (m, 1H, Ar), 7.11-7.15 (m, 4H, Ar), 7.52-7.56 (m, 1H, Ar), 7.63-7.71 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.65, 34.71, 35.34, 37.02, 51.52, 55.83, 64.32, 110.48, 111.22, 112.76, 120.24, 120.66, 121.35, 122.02, 129.75, 132.00, 134.06, 134.94, 138.23, 148.15, 148.93, 166.19, 167.34, 169.58; Anal Calcd for C26H27N3O5+0.15 H2O: C, 67.30; H, 5.99; N, 8.85. Found: C, 67.16; H, 5.88; N, 8.92.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:14]([C:32]([O:34]C(C)C)=O)=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1>[C:26]1([CH2:25][O:24][C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]2[C:14]([CH2:32][OH:34])=[CH:13][N:12]=[C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH:1][C:22]([NH:21][CH2:20][CH3:19])=[O:23])[CH:5]=3)[N:16]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)OC(=O)c1cnc(Nc2cccc([N+](=O)[O-])c2)nc1NCCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cccc(Nc2ncc(CO)c(NCCCNC(=O)OCc3ccccc3)n2)c1
Yield: 78.8 %

Procedure:
To a solution of 1-Methylethyl 2-[(3-nitrophenyl)amino]-4-[[3-[[(phenylmethoxy)carbonyl]amino]propyl]amino]pyrimidine-5-carboxylate (1.7 g) in tetrahydrofuran (100 ml) LiAlH4 (410 mg) was added in portions at 0° C. After 6 h at 0° C. the reaction was quenched by addition of saturated ammonium chloride solution. Ethyl acetate was added and the mixture filtered. After evaporation of the filtrate the residue was partitioned between water and dichloromethane. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. Chromatography of the residue on silica gel (dichloromethane/methanol)) yielded the title compound (650 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(n4cccn4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(n4cccn4)CC3)cnc12
Yield: 53.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(1H-pyrazol-1-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.102 g, 0.229 mmol) obtained in step 2 and methanesulfonamide (0.109 g, 1.14 mmol), the title compound (0.064 g, 53%) was obtained.
Reaction SMILES: C(OC([N:8]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[C:14]([Cl:15])=[C:13]([CH2:16][CH3:17])[N:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(=O)=O.FC(F)(F)C(O)=O>ClC(Cl)C>[Cl:15][C:14]1[C:9]([NH:8][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][CH:11]=[N:12][C:13]=1[CH2:16][CH3:17]
Reactant: CCc1ncnc(N(C(=O)OC(C)(C)C)C2CCNCC2)c1Cl
Agent: O=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCc1ncnc(NC2CCNCC2)c1Cl

Procedure:
20.7 g (0.61 mmol) of 4-(tert-butoxycarbonylpiperidin-4-ylamino)-5-chloro-6-ethylpyrimidine (Example A) were dissolved in 100 ml of dichloroethane and 148.0 g of trifluorocetic acid were added slowly. After the evolution of CO2 had ceased, stirring was continued for 2 more hours. After the solvent and the trifluoroacetic acid had been stripped off, the mixture was concentrated and the residue was taken up in dichloromethane/water. After the mixture had been rendered weakly alkaline by addition of dilute sodium hydroxide solution, the organic phase was separated off, dried and concentrated. This gave 12.3 g (83.9% of theory) of a yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl.Cl[CH2:18][C:19]1[N:23]([CH2:24][CH2:25][CH3:26])[CH:22]=[N:21][CH:20]=1>C(O)C>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH3:26])[CH:22]=[N:21][CH:20]=3)[NH:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: CCCn1cncc1CCl
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
2-mercapto-5-nitrobenzimidazole (2.0 g) was dissolved in ethanol (20 ml), 3N sodium hydroxide (8.2 ml) was added to the mixture, 5-chloromethyl-1-propylimidazole hydrochloride (2.2 g) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and to the obtained residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-5-yl)methyl]thio]benzimidazole (1.6 g).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4]1.[O-]CC.[Na+].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>CCO>[NH2:21][C:20]1[N:7]([CH:3]2[CH2:6][CH2:5][CH2:4]2)[N:8]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: NNC1CCC1
Reactant: CCOC=C(C#N)C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnn(C2CCC2)c1N
Temperature: 25 °C

Procedure:
A suspension of cyclobutylhydrazine dihydrochloride (11.63 g, 73.12 mmol) in EtOH (110 mL) was cooled in an ice bath and treated portion-wise with solid sodium ethoxide (9.95 g, 146 mmol) over 45 mins, while keeping the internal temp of the reaction mixture at approximately 0° C. The mixture was stirred in the ice bath for an additional hour, and then a solution of (ethoxymethylene)malononitrile (8.93 g, 73.1 mmol) in EtOH (70 mL) was added drop-wise over about 1.5 h, at a rate which maintained the internal temperature of the reaction mixture between 0° C. and 5° C. The reaction was then allowed to warm to room temp over about 18 h, after which it was heated at reflux for 1.5 h. After cooling to room temp, solvents were removed in vacuo, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with additional EtOAc, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide crude C14, which was used in the next step without purification. Yield: 14.1 g, >100% mass recovery. 1H NMR (300 MHz, CDCl3) δ 1.9 (m, 2H), 2.4 (m, 2H), 2.65 (m, 2H), 4.25 (br s, 2H), 4.45 (m, 1H), 7.5 (s, 1H).
Reaction SMILES: B1(C=C)OB([CH:7]=[CH2:8])OB(C=C)O1.C1C=CN=CC=1.Br[C:20]1[C:21]([C:35]([NH:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:36])=[N:22][O:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH:38]1([NH:37][C:35]([C:21]2[C:20]([CH:7]=[CH2:8])=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:23][N:22]=2)=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(NC1CCCC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Br
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (57.9 mg, 0.05 mmol) was added to a stirred suspension of 2,4,6-trivinylcyclotriboroxane pyridine complex (121 mg, 0.50 mmol), 4-bromo-N-cyclopentyl-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxamide (202 mg, 0.50 mmol) and potassium carbonate (138 mg, 1.0 mmol) in DME (4.7 mL) and water (1.6 mL) and heated to 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and ethylacetate. The organics were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography eluting with heptane to 20% ethylacetate in heptane to obtain N-cyclopentyl-5-(4-(trifluoromethyl)phenyl)-4-vinylisoxazole-3-carboxamide (140 mg, 0.40 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[CH2:19][O:18][C:11]2([CH2:17][CH2:16][C:14](=[O:15])[CH2:13][CH2:12]2)[O:10][CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][C:8]1([CH3:20])[CH2:9][O:10][C:11]2([CH2:12][CH2:13][CH:14]([OH:15])[CH2:16][CH2:17]2)[O:18][CH2:19]1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC2(CCC(O)CC2)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To the suspension of lithium aluminum hydride (748 mg, 19.7 mmol) in tetrahydrofuran (40 ml), a tetrahydrofuran solution of 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (3.9 g, 19.7 mmol) was added at 0° C. The mixture was stirred at room temperature for 3 hours. After water (0.7 ml), a 5N aqueous sodium hydroxide solution (0.7 ml), and water (2.1 ml) were sequentially added at 0° C. to the mixture, the mixture was dried over sodium sulfate, filtrated, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane=1/2, 1/1, 2/1) to obtain the title compound (3.6 g, yield: 91.2%) as a colorless oil.
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([C:10]1[S:14][C:13]([C:15]2[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH:28](Cl)([Cl:30])[Cl:29]>C1COCC1.CN(C=O)C>[Cl:29][CH:28]([Cl:30])[C:11]1[CH:12]=[C:13]([C:15]2[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=2)[S:14][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: ClC(Cl)Cl
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])s2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C(Cl)Cl)c([N+](=O)[O-])s2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of t-BuOK (9.07 g, 81 mmol) in THF (50 mL) was cooled to −78° C. before adding DMF (70 mL). A solution of 3-(5-nitro-2-thienyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (6.60 g, 20.22 mmol) and CHCl3 (1.79 mL, 22.24 mmol) in DMF (35 mL) was added dropwise over 1 h. After complete addition, the reaction was stirred at −78° C. for 30 min, quenched with 2 N HCl, allowed to warm to room temperature, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification of the crude residue by flash chromatography (0-25% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([CH3:20])[N:15]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CCOCC.CCCCCC.O>[OH:28][CH:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([CH3:20])[N:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cncc(C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COc1ccc(C(O)Cc2cncc(C)n2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 5.05 grams (50 mmole) of diisopropylamine in 40 milliliters of ether was added to 47.1 mole butyllithium in hexane at 0° C. After stirring the resulting solution for 15 minutes, 5.4 grams (50 mmole) of 2,6-dimethylpyrazine in 50 milliliters of ether were added slowly and the reaction mixture was stirred at 0° C. for 30 minutes. A solution of 5.4 grams (40 mmole) of p-methoxybenzaldehyde in 40 milliliters of ether was added, and stirring at 0° C. was continued for an additional 30 minutes. Water was added, the organic phase was separated, washed with water and dried over magnesium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH3:42])[C:20]3[CH:40]=[CH:39][C:23]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[C:22]([CH3:41])[CH:21]=3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH3:42])[C:20]3[CH:40]=[CH:39][C:23]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[C:22]([CH3:41])[CH:21]=3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)C(=O)C2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)C2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)ccc1CN1CCN[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl (2S)-4-{4-[({4-[(4-chlorophenyl)sulfonyl]cyclohexyl}carbonyl)(methyl)amino]-2-methylbenzyl}-2-methylpiperazine-1-carboxylate (80.2 mg, 0.13 mmol) synthesized in (10D) in dichloromethane (1 mL), trifluoroacetic acid (10 mL) was added at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10 (v/v)), whereby the title compound was obtained as an oil (50.1 mg, yield: 100%).