Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30]>CO>[C:19]1([S:18]([CH2:17][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:30])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(SCc2[nH]c3ccccc3c2Sc2ccccc2)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=S(Cc1[nH]c2ccccc2c1Sc1ccccc1)c1ccccc1

Procedure:
A solution of 3-phenylthio-2-phenylthiomethylindole (0.750 g, 2.94 mmol) in methanol (100 mL) was cooled to 0° C. with stirring. Monoperoxyphthalic acid magnesium salt (0.908 g 80% peracid) in methanol (50 mL) was added slowly dropwise. After addition, the reaction was stirred an additional 30 min., then quenched with 10% aqueous sodium thiosulfate (2 mL). The methanol was removed in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed successively with water and saturated brine, then dried over magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave an oil which was purified by chromatography on silica gel using 20-30% ethyl acetate in hexane. The title compound was obtained as a foam, mp 71°-74° C. Exact mass calculated for C21H17NOS2 : 364.082982. Found: 364.084549. NMR (DMSO-d6) δ11.82 (1H, s), 7.50 (6H, m), 7.23 (1H, d, J=8 Hz), 7.15 (3H, m) 7.05 (2H, m) 6.90 2H, m), 4.43 (1H, d, J=13 Hz), 4.38 (1H, d, J=13 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26]>>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)NC
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Product: CCC(=O)N(C)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-methylpropanamide using a similar procedure to that described for Description 15.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[PH2+]N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>ClCCl.O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)[PH2+]On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (102 mg, 0.34 mmol) in dichloromethane (10 mL) was treated with benzotriazol-1-yloxy-(dimethylamino)phosphonium hexafluorophosphate (BOP) reagent (223 mg, 0.51 mmol), triethylamine (0.14 mL, 0.52 mmol), and 2-aminothiazole (51 mg, 0.51 mmol) at 25° C. After the resulting brownish-orange solution was stirred 16 h at 25° C., it was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL), and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to furnish rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (115 mg, 88% yield) as a white foam: EI-HRMS m/e calcd for C17H18Cl2O2N2S (M+) 384.0466, found 384.0469.
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].Cl[C:6]([CH3:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].Cl>[Fe](Cl)(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:6]([CH2:7][CH3:8])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=C(Cl)Cl
Reactant: CCCCC(C)(Cl)CC
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: CCCCC(C)(C=C(Cl)Cl)CC
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
1,235 g (12.7 moles) of 1,1-dichloroethene and 630 g (4.23 moles) of 3-chloro-3-methylheptane are taken at 20° C. 85 g of anhydrous iron(III) chloride are added in portions, while cooling. The mixture is then subsequently stirred at 30° C. for 2 hours. It is poured onto ice and dilute aqueous hydrochloric acid. The organic phase is separated off, dried and subjected to fractional distillation. 627 g (71% of theory) of 1,1-dichloro-3-ethyl-3-methyl-hept-1-ene are isolated at boiling point6.1 50°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:18])[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[O:18][C:16]([CH3:17])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1C
Yield: 70.7 %

Procedure:
2.98 g of ethyl 3-(4-chlorobenzoylamino)-3-acetylpropionate, 15 ml of dimethylformamide and 1.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.98 g of ethyl 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetate are thereby obtained. Yield: 70.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[Na]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 100.8 %

Procedure:
To the solution of (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanone 15e (5.0 g, 13.0 mmol) in a dry tetrahydrofuran/methanol mixture (v/v=1/1, 20 mL) was added sodium brohydride (0.98 g, 26.0 mmol) in portions at 0° C. After the addition, the mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (50 mL). The water layer was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15f as pale yellow oil (5.0 g, 99.5%). This material was not further purified.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:14])[N:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:14][CH2:8][CH:9]([OH:14])[CH2:10][N:27]2[CH2:26][CH2:25][N:24]([CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28]2)[N:4]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1cc(C(F)(F)F)nc2cccc(O)c12
Product: Cc1cc(C(F)(F)F)nc2cccc(OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c12

Procedure:
Following the same procedures as in Example 1-(a) and (b), reaction and treatment were carried out using 2-trifluoromethyl-4-methyl-5-hydroxyquinoline prepared in Example 54 and N-diphenylmethylpiperazine in order to obtain the desired compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.O.[OH-].[Li+]>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH˜4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]pentanedioic acid as a white crystalline powder (31.8 μm, 80%), LC/MS (M+H)+: 446, 1H NMR (DMSO-d6) δ 8.85 s 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 5.71 (s, 2H), 5.18 (m, 1H), 3.65 (t, 2H), 3.05 (m, 4H), 0.92 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[F:11][C:12]([F:34])([F:33])[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:17]([C:30](O)=[O:31])=[CH:16]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[CH:3][C:2]([NH:1][C:30]([C:17]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:12]([F:33])([F:11])[F:34])=[CH:21][CH:20]=3)=[O:31])=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Reactant: CN(C)c1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NC(=O)c2cc3cc(C(F)(F)F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 8 h
Yield: 40 %

Procedure:
0.185 g (1.35 mmol) of 3-amino-6-(dimethylamino)pyridine (WO2005/028452) in 2 ml of dry dimethylformamide is added dropwise at 20° C. under argon to a solution of 0.35 g (1.04 mmol) of 5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736), 0.198 g (1.14 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.165 g (1.14 mmol) of 1-hydroxybenzotriazole monohydrate in 6 ml of dry dimethylformamide. The reaction mixture is stirred overnight, run onto 100 ml of water and then extracted three times with 50 ml of ethyl acetate. The organic phases are subsequently combined, washed three times with 20 ml of water, dried over sodium sulfate and then concentrated under reduced pressure. The expected product is purified by chromatography on a silica column, elution being carried out with a mixture of dichloromethane and methanol. 0.19 g of the expected compound is thus isolated.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH2:10]([SH:13])[CH2:11][CH3:12].[OH-].[K+]>CCO>[CH3:8][C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([S:13][CH2:10][CH2:11][CH3:12])[N:7]=1
Reactant: CCCS
Reactant: Cc1nc(F)ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1ccc(N)c(C)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture of 6-fluoro-2-methyl-pyridin-3-ylamine (2.01 g, 16 mmol), propane-1-thiol (3.0 mL, 33 mmol), and potassium hydroxide (1.8 g, 32 mmol) in 3 mL EtOH were heated under microwave irradiation at 100° C. for 1 h and then at 150° C. for 2 h. Mixture was extracted with CH2Cl2 and brine. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (hexane/AcOEt 2:1) to give 2-methyl-6-propylsulfanyl-pyridin-3-ylamine (2.18 g, 75% yield) as a colorless oil. 1HNMR (CDCl3, 400 MHz) δ 0.99-1.03 (t, J=7.3 Hz, 3H), 1.64-1.73 (m, 2H), 2.39 (s, 3H), 3.02-3.05 (t, J=7.3 Hz, 2H), 3.48 (s, 2H), 6.82-6.84 (d, J=8.2 Hz, 1H), 6.93-6.95 (d, J=8.2 Hz, 1H). Exact mass calculated for C9H14N2S 182.09 found 183.0 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:28][CH2:27]2)[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine, to give 1-[3,5-di(trifluoromethyl)phenyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(OCc2ccccc2)CC1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(OCc2ccccc2)CC1F
Yield: 92.7 %

Procedure:
A methanol (200 mL) solution of 4-(Benzyloxy)-2-fluorocyclohexanone (6.46 g, 29.1 mmol) was cooled in and ice bath under nitrogen. Sodium borohydride (1.66 g, 43.6 mmol) was added and the reaction aged 0.5 h. Hydrochloric acid (1 N) was slowly added after which methanol was removed under reduced pressure. Water was added and the resulting mixture was extracted with ethyl acetate (4×) and the combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 4-(Benzyloxy)-2-fluorocyclohexanol as a pale oil (6.05 g, 93% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:1]2([C:11]3[CH:10]=[CH:9][C:8]([OH:15])=[CH:13][CH:12]=3)[CH2:6][CH2:5][C:4]([C:11]3[CH:12]=[CH:13][C:8]([OH:15])=[CH:9][CH:10]=3)([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[CH2:3][CH2:2]2)=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1CCC(=O)CC1
Agent: Cl
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)cc1

Procedure:
Into a molten mixture of 300 g (3.2 mole) of phenol and 22.4 g (0.2 mole) of 1,4-cyclohexanedione (m.p. 78° C.) was introduced hydrochloric acid gas at a temperature of 50° C. to saturation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CN1C=CC(NC(=O)[C@@H](N2[CH2:33][C:32]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[CH:36]=3)=[CH:31][C:30]2=[O:46])CC(C)C)=N1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([N:14]1[CH2:33][C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[CH:36]=2)=[CH:31][C:30]1=[O:46])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](N)C(=O)Nc1cnccn1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
A mixture of (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (prepared as in Example 245, 0.400 g, 1.92 mmol), (E)-4-bromo-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 235, 0.462 g, 1.29 mmol) and N,N-diisopropylethylamine (0.734 g, 5.69 mmol) in acetonitrile (16.6 mL) were sealed in a tube and heated at 100° C. for 12 h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), sealed in an Emry Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% to 35% ethyl acetate/hexanes) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (127 mg, 22%) as a tan solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 1.04 (s, 6H), 1.39-1.70 (m, 2H), 1.72-1.87 (m, 1H), 2.66 (s, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 6.94-7.19 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 11.16 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[N:4]=1.[NH:18]1[CH2:23][CH2:22]N[CH2:20][C@@H:19]1[CH2:24][CH2:25][OH:26].C(N(C(C)C)CC)(C)C.CS(C)=O>C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:22][CH2:23][NH:18][C@@H:19]([CH2:24][CH2:25][OH:26])[CH2:20]3)[C:5]=2[N:4]=1
Reactant: OCC[C@H]1CNCCN1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCO)C1
Yield: 13.9 %

Procedure:
Combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.458 g, 1.72 mmol), (S)-2-piperazin-2-yl-ethanol (0.518, 3.98 mmol), diisopropylethylamine (0.346 mL, 1.99 mmol), dimethyl sulfoxide (1.5 mL) and toluene (4.5 mL) and heat to 110° C. for 48 hours. Evaporate the mixture and apply the material to 20 g of SCX, elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and finally 100% 2N ammonia-methanol. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 10% 2N ammonia-methanol in dichloromethane, to obtain (S)-2-[4-(2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-yl)-piperazin-2-yl]-ethanol (0.082 g, 0.239 mmol, 14%): mass spectrum (APCI): m/z=344.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([C:23]#[N:24])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.CO>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Reaction time: 18 h

Procedure:
Combine 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic diethyl ester (1.3 g, 3.24 mmol) and cobalt(II)chloride hexahydrate (1.54 g, 6.48 mmol) in methanol (50 mL). While maintaining the temperature at or below 20° C. with an ice-bath, add portionwise sodium borohydride (2.17 g, 57 mmol). After the addition is complete, allow the reaction mixture to stand at ambient temperature for 18 hours. Evaporate the reaction mixture invacuo to obtain a residue. Partition the residue between dichloromethane and 1M hydrochloric acid solution. Extract the aqueous layer several times with dichloromethane, combine the organic layers, dry over Na2SO4, filter, and concentrate invacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 20/1 ethyl acetate/methanol. Remove residual solvent inuacuo at 82° C. to give the title compound: Rf= 0.74 (silica gel, 5/1 ethyl acetate/methanol); mp; 116°-118° C. Elemental Analysis calculated for C16H21NO5 : C 62.53; H 6.89; N 4.56; Found: C 62.52; H 6.85; N 4.50.
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=O)(C)(C)C>C(O)C>[ClH:1].[ClH:1].[ClH:1].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Concentrated hydrochloric acid (1.5 ml) was added to N-[1-[3-(4-tert-butoxycarbonylaminophenyl)propan-1-yl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (350 mg, 0.656 mmol) and the mixture was stirred at room temperature for 2 hours. Ethanol was added to the mixture to give N-[1-[3-(4-aminophenyl)propan-1-yl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride as orange crystals (251 mg, 71%), which were collected by filtration and washed with ethanol.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24](I)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C)C=O.[Pd](Cl)Cl.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.[Cu]I>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reaction time: 8 h

Procedure:
A solution of the product of Stage b), (0.8 g, 1.69 mmoles), bis(triphenylphosphine) palladium (II) chloride (25 mg) and copper (I) iodide (25 mg) in dry triethylamine (40ml) and N,N-dimethylformamide (3 ml) was degassed thoroughly with nitrogen. (Trimethylsilyl) acetylene (0.47 ml, 3.37 mmoles) was added and the mixture stirred under N2 at 50° for 8 hours. The solvent was removed under reduced pressure, the residue dissolved in methylene chloride (40 ml) and the solution washed with 2% aqueous disodium EDTA solution (4 ml), water (50 ml) and dried (sodium sulphate). Evaporation of the solvent and purification of the residue by silica column chromatography eluting with 2% MeOH/CH2Cl2 afforded the title compound. Trituration with ether/hexane afforded analytically pure title compound as an off-white powder.