Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][CH3:46]>CN(C=O)C>[CH3:46][O:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccc(C)cc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (18 mg, 0.130 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with 1-bromo-2-methoxyethane (14 mg, 0.098 mmol). The mixture was heated at 90° C. for 4 h, cooled to rt and concentrated under vacuum. The residue was purified by preparative HPLC to provide 7-(2-methoxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (12.5 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1H, s), 8.17 (1 H, br. s.), 7.95 (1H, d, J=7.9 Hz), 7.54-7.64 (3H, m), 7.49 (3H, t, J=8.0 Hz), 7.27-7.38 (2H, m), 7.00 (1H, d, J=7.9 Hz), 6.91 (1H, d, J=8.8 Hz), 6.59 (1H, dd, J=8.8, 2.4 Hz), 4.91 (2H, d, J=3.3 Hz), 4.12 (2H, dd, J=5.5, 3.1 Hz), 3.63-3.75 (2H, m), 3.33 (3H, s), 2.44 (3H, s), 1.83 (3H, s). Mass spectrum m/z 520.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCSc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccncc1
Yield: 79 %

Procedure:
To a solution of 4.03 g (15.0 mmol) of 4-[3-(t-butoxycarbonylamino)propylthio]pyridine in 100 ml of methylene chloride, 3.05 g (15.0 mmol) of m-chloroperbenzoic acid was added with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed two times with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to give 3.37 g of the desired compound (78.9% yield, colorless crystals).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Cl.NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[CH:22][N:1]=1
Reactant: N=C(N)N
Reactant: Cn1cc(CC(C#N)=CNc2ccccc2)c2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COCCO
Product: Cn1cc(Cc2cnc(N)nc2N)c2ccccc21
Yield: 41 %

Procedure:
To 100 mL of an ethanolic guanidine solution prepared from 2.10 g (0.022 mole) of guanidine hydrochloride and 1.20 g (0.022 mole) of sodium methoxide was added 5.00 g (0.017 mole) of 3-anilino-2-(1-methyl-3-indolylmethyl)acrylonitrile. The solution was heated under reflux for 1/2 hour and then 100 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 120° by distillation of the ethanol, after which it was heated at this temperature for 4.75 hr. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from 95% ethanol to give two crops of the title compound (total 1.82 g, 41%) mp 253°-256° dec. Anal. Calcd for C14H15N5 : C, 66.38, H, 5.97; N, 27.65. Found: C, 66.05; H, 6.04; N, 27.89.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:12][C:13]([C:15]1[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29](=[O:35])[NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:23])[N:17]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:16]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:31]1([NH:30][C:29]([C@@H:25]2[CH2:26][CH2:27][CH2:28][N:24]2[C:22](=[O:23])[CH2:21][O:20][C:18]2[N:17]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:16]=[C:15]([C:13]([NH:12][C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:42])=[O:5])=[O:14])[CH:19]=2)=[O:35])[CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 422 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-methyl-pentanoic acid tert-butyl ester in 5 ml dichloromethane were added 1.5 ml TFA. After stirring for 16 h it was concentrated and codistilled twice with toluene to give the crude product which was used directly in the subsequent coupling step.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:18]([NH:20][NH2:21])=O>C(O)CCC>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:18]=[N:20][N:21]=3)[N:4]=2)[CH:9]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC=O
Solvent: CCCCO
Product: FC(F)(F)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 6.0 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)pyridazine (prepared as in Example 10), 2.78 g. of formylhydrazine and 75 ml. of butyl alcohol is allowed to stir at reflux temperature for 48 hours. The reaction mixture is concentrated free of solvent and the residue is dissolved in ethyl alcohol, treated with activated charcoal and filtered. The filtrate is cooled in an ice bath and the cream colored solid is collected. The solid is heated with diethyl ether and the mixture is filtered. The solid is recrystallized from ethyl acetate to afford the product of the example as cream colored crystals, m.p. 140°-143° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)(=[O:18])=[O:17])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N:21]1[CH:20]=[C:19]([S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][OH:8])(=[O:17])=[O:18])[CH:24]=[N:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1S(=O)(=O)c1cncnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1cncnc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-[2-(tert-butyl-dimethylsilanyloxymethyl)benzenesulfonyl]pyrimidine (2.1 g) and tetrahydrofuran (2.0 mL) was treated with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (7.5 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound a pale brown solid (0.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](F)=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[NH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:40])[NH:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: NCCN1CCCC1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)F)cc2)N1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)NCCN3CCCC3)cc2)N1
Yield: 81.1 %

Procedure:
In a manner similar to the method described in example 55b, racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.28 mmol) was reacted with N-(2-aminoethyl)pyrrolidine (0.4 g, 3.5 mmol), N-methylmorpholine and 4-dimethylaminopyridine in tetrahydrofuran to give racemic(2′R, 3R, 4′S)-2′-{5-bromo-2-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-phenyl}-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.17 g, 83%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH2:23]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH2:1])[CH2:8][CH2:7]1)=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
Trans-4-(aminomethyl)-cyclohexane carboxylic acid (50 g (0.318 moles)), p-toluenesulfonic acid (61.7 g (0.324 mmoles)), benzyl alcohol (250 mL; 2.4 moles) and toluene (250 mL) were combined and stirred. The resulting mixture was refluxed for 24 hours and the liberated water was removed azeotropically using a Dean-Stark apparatus. A clear solution was obtained after 5 hours of refluxing. The solution was allowed to cool to room temperature and the product crystallized. The mixture was vacuum filtered, washed with ether and dried in a vacuum oven to give 128.12 g (96% yield) of the above-identified product. 1H NMR (CD3OD) δ1.05 (, 2H), 1.43 (m, 2H), 1.59 (m, 1H), 1.85 (m, 2H), 2.03 (m, 2H), 2.33 (m, 1H), 2.35 (s, 3H), 2.75 (d, 2H, 5.09 (s, 2H), 7.23 (d, 2H), 7.32 (m, 5H), 7.69 (d, 2H). M.P. 154°-156° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH2:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: Nc1ccccc1B(O)O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccc4N)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 2-aminophenylboronic acid. Mass spectrum (ESI) 437.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[CH3:9][C:10]1([CH3:43])[N:14](CCCC(O)=O)[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][O:32][C:28]=3[C:27]=2[CH2:39][CH2:40][CH3:41])[C:11]1=[O:42]>>[CH3:43][C:10]1([CH3:9])[N:14]([CH:3]([CH3:2])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][O:32][C:28]=3[C:27]=2[CH2:39][CH2:40][CH3:41])[C:11]1=[O:42]
Reactant: O=C([O-])CCCCBr
Reactant: CCCc1c(OCCCN2C(=O)N(CCCC(=O)O)C(C)(C)C2=O)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)N(C(C)CCC(=O)O)C(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
4-[5,5-Dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoic acid was prepared as for Example 37, substituting 5-bromovalerate for the 4-bromobutyrate of Example 37.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[NH3:22]>>[CH2:14]([O:13][C:11]([NH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][C:4]([NH2:22])=[O:3])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: N
Product: CC(C)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
2.23 g of 3(S)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 6N ammonia (in methanol) are stirred for 6 days at 75° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate. The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.20; m.p. 171°-172° C.
Reaction SMILES: C([C:3]([CH2:16][CH3:17])(P(=O)([O-])[O-])/[C:4](/[CH3:11])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C([Li])CCC.[CH3:23][C:24]1([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:30]2[CH:29]=[C:28](/[C:41](/C)=[CH:42]/C=O)[CH:27]=[CH:26][C:25]1=2>C1COCC1.CCOCC>[CH3:11]/[C:4](/[CH:3]=[CH:16]/[CH:17]=[C:41](/[C:28]1[CH:27]=[CH:26][C:25]2[C:24]([CH3:23])([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:30]=2[CH:29]=1)\[CH3:42])=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C(\C)C(CC)(CC)P(=O)([O-])[O-]
Reactant: C/C(=C\C=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of diethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate [prepared in accordance with J. Org. Chem. 39: 821 (1974)] 264.0 mg, (1.00 mmol) in THF (2 ml) was added 26.0 mg (0.41 mmol, 0.65 ml)of n-butyllithium in hexanes (1.6M solution) followed immediately by the addition of (E)-3-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalen-yl)-2-butenal (Compound X) 82.0 mg, 0.26 mmol) in THF (3 ml). After 1 hour, the reaction mixture was diluted with ether (60 ml), washed with water (5 ml), saturated aqueous NaCl (5 ml) and dried over MgSO4. After removal of the solvents under reduced pressure, the title compound was isolated as an oil by column chromatography (5% EtOAc/hexanes, followed by HPLC using 1% EtOAc/hexanes). 1H NMR (acetone-d6): δ 7.36-7.43 (2H, m), 7.18-7.27 (4H, m), 7.17 (1H, d, J=1.7 Hz), 7.08 (1H, dd, J=11.2, 15.2 Hz), 6.46 (1H, d, J=11.2 Hz), 6.38 (1H, d, J=15.2 Hz), 5.98 (1H, t, J=4.7 Hz), 5.78 (1H, s), 4.10 (2H, q, J=7.1 Hz), 2.35 (3H, s), 2.33 (3H, s), 2.32 (2H, d, J=4.7 Hz), 2.12 (3H, s), 1.31 (6H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]1[N:7]2[N:12]=[C:13]([CH3:15])[CH:14]=1.[NH2:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:20]=[CH:19][C:18]=1[S:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>C(O)C>[CH3:15][C:13]1[CH:14]=[C:6]2[N:5]=[CH:4][C:3]3[C:8](=[N:9][CH:10]=[N:11][C:2]=3[NH:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[S:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[N:7]2[N:12]=1
Reactant: Cc1cc2ncc3c(Cl)ncnc3n2n1
Reactant: Nc1cc(OCc2cccc(C(F)(F)F)c2)ccc1Sc1ccc(O)cc1
Solvent: CCO
Product: Cc1cc2ncc3c(Nc4cc(OCc5cccc(C(F)(F)F)c5)ccc4Sc4ccc(O)cc4)ncnc3n2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.5 %

Procedure:
The product from Example 4a (88 mg, 0.40 mmol) was reacted with 4-[2-Amino-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-phenol (151 mg, 0.40 mmol) in 5 mL of ethanol at 70° C. with stirring for 6 hours. After cooling to room temperature the product was isolated by suction filtration and was triturated with diethyl ether to give the title compound as a pale yellow solid (123 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.45 (s, 1H) 9.65 (s, 1H) 9.34 (s, 1H) 8.57 (s, 1H) 7.62-7.85 (m, 4H) 7.09-7.21 (m, 4H) 7.02 (dd, J=3.02 Hz, J=8.74 Hz, 1H) 6.74 (s, 1H) 6.65 (dd, J=2.19 Hz, J=8.74 Hz, 2H) 5.23 (s, 2H) 2.48 (s, 3H); (ESI+) m/z 575 (M+H−Cl)+; (ESI−) m/z 573 (m−H−Cl)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1C2N=C(N3CC[O:63][C@@H:62]4CCC[C@@H]34)N(C[C@H]3CC[C@H](C)CC3)C=2C(C2C=NC=C(Cl)C=2)=NC=1C(=NO)N.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35]3[NH:36][C:62](=[O:63])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3:1 mixture of 4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide and 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33 mg, 0.06 mmol) in acetonitrile (2 mL) was added 1,1′-carbonyldiimidazole (19.7 mg, 0.122 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL, 0.244 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford pure 3-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31ClFN7O3 [M+H]+=568. found=568. 1H NMR (600 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.43 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.78-3.87 (m, 2H), 3.63 (dd, J=14.4, 3.6 Hz, 1H), 3.56 (d, J=12.6 Hz, 1H), 3.39 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.27 (m, 1H), 1.86 (m, 1H), 1.69 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.80 (m, 1H), 0.63-0.74 (m, 6H), 0.47 (m, 1H), 0.29-0.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11]C(OC(C)(C)C)=O)[S:8][CH:9]=1)=[O:4].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH2:11])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1csc(CN)n1
Reaction time: 12 h
Yield: 71.5 %

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-thiazole-4-carboxylic acid methyl ester (1.1 g, 3.9 mmol) was dissolved in methanol (15 mL). HCl in dioxane (4 M, 5 mL) was added. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo, re-dissolved in methanol, and stirred with Bio-RAD AG 1-X8 resin (4 g, 20-50 mesh, hydroxide form, pre-washed with methanol and air dried) for 35 min. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (0.48 g, 73% over two steps): 1H NMR (400 MHz, d6-DMSO): 8.38 (s, 1H), 3.97 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].BrC1[S:26][CH:27]=[CH:28]N=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[S:26][CH:27]=[CH:28][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2nccs2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 2.37 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide, there is added under nitrogen at less than 30° C., 0.38 g. of sodium borohydride. The mixture is stirred at 20°-30° C. for 1 hour, then 3.2 ml. of 2-bromothiazole is added. The mixture is heated to 130°-135° C. for 1 hour, then cooled and diluted with water. The crude product is filtered off and recrystallized from methanol yielding 1-acetamido-2-nitro-4-(thiazol-2-ylthio)benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[C:23]([O-:26])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:3]2[CH:4]=[N:5][C:6]([O:26][CH3:23])=[CH:7][CH:2]=2)=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(Cl)cc2)cn1
Temperature: 150 °C
Yield: 101.6 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.05 g, 0.13 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)pyridine (0.09 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.26 mmol) in water (0.34 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 27 mg of the title compound as a yellow solid. MS: [M+H]+=409.