Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([S:24][CH2:16][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 167, Step 1, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl mercaptan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:8]3=[N:9][C:10]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH:23]([OH:24])[C:26]([F:28])([F:27])[F:25])[C:6]=4[N:7]3[CH2:14][CH2:13][CH2:12]2)=[C:16]([CH3:22])[CH:17]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a suspension of 9-chloro-1-(4-bromo-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (4.54 g, 11.2 mmol), trifluoromethyltrimethylsilane (4.97 mL, 33.7 mmol) in tetrahydrofuran (150 mL) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran 1.12 mL, 1.12 mmol), and the mixture was stirred at 0° C. for 15 min. To the reaction mixture was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran 1.12 mL, 1.12 mmol), and the mixture was stirred at 0° C. for 15 min. To the reaction mixture was added trimethyl(trifluoromethyl)silane (4.97 mL, 33.7 mmol), and the mixture was stirred at 0° C. for 30 min. 1N hydrochloric acid (20 mL 20 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo to give the title compound as a colorless powder (3.24 g, 6.83 mmol, 61%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[N:3][CH:4]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cnc1N1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-chloro-5-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) prepared in Step 4 and sodium carbonate (1.25 g, 9.06 mmol) were added to anhydrous N,N-dimethylformamide (50 ml). 1,2,3,4-tetrahydroisoquinoline (712 μg, 5.66 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 100° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 1.34 g of the titled compound as yellow solid. (Yield: 86%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[S:39]1[CH:43]=[C:42]([CH2:44][CH2:45][NH2:46])[N:41]=[CH:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][CH2:44][C:42]1[N:41]=[CH:40][S:39][CH:43]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCc1cscn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(thiazole-4-yl)ethylamine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (11.8 mg, 0.022 mmol, 47.0% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.46-7.69 (7 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.50-3.69 (2 H, m), 3.03 (2 H, t, J=6.90 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[C:10]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:9]=[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:7]=1)=[CH2:5])C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[C:11]([CH3:12])=[C:10]([CH2:13][O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:9]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: C=C(OCC)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(COCC(F)(F)F)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1

Procedure:
A solution of 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine (52 mg, 0.11 mmol) in dioxane (4 mL), water (0.5 mL) and concentrated hydrochloric acid (0.028 mL, 0.33 mmol) was heated at 40° C. for 35 min. Sodium bicarbonate (40 mg) and water (2 mL) were added. The volatiles were removed in vacuum, the residue was coevaporated with dioxane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[N:38][C:33]([Cl:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)nc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 6-chloro-pyridine-3-sulfonyl chloride. Purity (ELSD, based on MW=597.1)=98%.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: C[C@@H](N)[C@@H](O)c1cccc(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1cccc(Br)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid was coupled with (1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt (EXAMPLE 108, Part E) as in Example 1, Part C (11 mg, 16%). HPLC: RT=10.19 min. MS (ESI−): mass calcd. for C22H18BrIN4O4S2, 673.34; m/z found, 671/673 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.45 (s, 1H), 8.37 (d, J=7.0, 1H), 8.23 (d, J=8.8, 1H), 8.08 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.33 (dd, J=8.2, 1.5, 1H), 7.31-7.21 (m, 3H), 6.99 (d, J=8.3, 1H), 6.19 (d, J=8.6, 1H), 4.95-4.94 (m, 1H), 4.44-4.40 (m, 1H), 2.60 (s, 1H), 1.03 (d, J=6.9, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[CH3:14][C:15]1([CH3:26])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:19]2([OH:21])[CH2:18][CH2:17][CH:16]([C:22]([O:24][CH3:25])=[O:23])[C:15]([CH3:14])([CH3:26])[CH2:20]2)=[N:8][CH:9]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COC(=O)C1CCC(=O)CC1(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(O)(c2ccc(Br)cn2)CC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi was added dropwise to a solution of 2,5-dibromopyridine in toluene (30 mL) at −78° C. The reaction mixture was stirred for 1 hour at −78° C., then a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate in toluene (5 mL) was added. The reaction mixture was warm to room temperature, quenched with saturated aqueous ammonium chloride, extracted with CH2C12 (3×), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford methyl 4-(5-bromopyridin-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate as a colorless oil. MS ESI calc'd for C15H21BrNO3 [M+H]+ 342 and 344. found 342 and 344.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][O:19][C:20]([NH:22][N:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][O:19][C:20]([NH:22][N:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cccc2c1CCCC2COC(=O)NN(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)COc1cccc2c1CCCC2COC(=O)NN(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
A solution of 2-[(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methoxycarbonyl]-1,1-diphenylhydrazine (0.17 g) and 1N-aqueous sodium hydroxide (1 ml) in dioxane (1.5 ml) was stirred at room temperature for 30 minutes and partitioned between 5% hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was washed with isopropanol to afford 2-[(5-carboxymethoxy-1,2,3,4-tetrahydro-1-naphthyl)-methoxycarbonyl]-1,1-diphenylhydrazine (0.08 g) as a colorless powder.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[CH:45]=[C:46]([CH3:50])[C:47]([CH3:49])=[CH:48][C:42]=2[N:41]=1>C(#N)C>[CH3:50][C:46]1[C:47]([CH3:49])=[CH:48][C:42]2[NH:41][C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])=[N:44][C:43]=2[CH:45]=1
Reactant: Cc1cc2nc(CCl)[nH]c2cc1C
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2nc(CN(CCCCN3C(=O)c4ccccc4C3=O)C3CCCc4cccnc43)[nH]c2cc1C
Temperature: 60 °C
Yield: 28 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (154 mg, 0.441 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (15 mg, 0.090 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-5,6-dimethyl-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. patent application U.S. Ser. No. 09/535,314) (77 mg, 0.426 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with saturated aqueous NaHCO3 (1×20 mL) and brine (2×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (60 mg, 28%). 1H NMR (CDCl3) δ 1.34-1.51 (m, 2H), 1.53-1.73 (m, 3H), 1.81-2.06 (m, 2H), 2.12-2.22 (m, 1H), 2.34 (s, 6H), 2.55-2.89 (m, 4H), 3.51 (t, 2H, J=7.3 Hz), 3.93-4.08 (m, 3H), 7.1 (dd, 1H, J=7.5, 4.8 Hz), 7.31-7.39 (m, 3H), 7.63-7.67 (m, 2H), 7.72-7.77 (m, 2H), 8.58 (d, 1H, J=4.0 Hz).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].BrN1[C:21](=O)[CH2:20][CH2:19]C1=O>O1CCCC1>[CH:13]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][C:7]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:20]([CH3:21])[CH3:19])[CH:1]([CH3:3])[CH3:2])=[CH:6]1)([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: C1CCOC1
Product: CC(C)[Si](c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 137.4 %

Procedure:
The product from step (a) (102.6 g) was dissolved in tetrahydrofuran (600 ml) and treated with N-bromosuccinimide (89 g) at -78° C. under nitrogen for 15 minutes. The reaction was allowed to come to ambient temperature over one hour, concentrated, diluted with hexane, filtered and the solvent removed. The residue was dissolved in tetrahydrofuran (600 ml), cooled to -78° C., and tert-butyl lithium in pentane (588 ml 1.7M) was added. After one hour elemental sulfur (16 g) was added and the mixture was stirred for one hour at ambient temperature. The reaction was cooled to -78° C. and triisopropyl silyl chloride (98 g) was added and the reaction was allowed to warm to room temperature. After 24 hrs the solvent was removed under reduced pressure and the residue in diethyl ether was washed with water, dried over sodium sulfate, filtered, concentrated and distilled at 160°-205° C. (0.2 mm) to give a colorless viscous oil (119.8 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:34])[C@H:13]([CH3:33])[NH:14][C:15]([C:29]([O:31][CH3:32])=[O:30])([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:32][O:31][C:29]([C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:35])=[O:5])=[O:34])[CH3:33])([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:30]
Reactant: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)OC
Reaction time: 2 h

Procedure:
A mixture of N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester (Example 31; 1.5 g.) and trifluoroacetic acid (20 ml.) was kept at laboratory temperature for 2 hours and then evaporated to dryness under reduced pressure at less than 30° C., using toluene as described in Example 20. There was thus obtained as an oil N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline trifluoroacetate.
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:5])[CH2:3][OH:4].[H-].[Na+].I[CH3:19]>CN(C)C=O>[CH3:19][O:4][CH2:3][C:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])([CH3:1])[CH3:5]
Reactant: CI
Reactant: Cc1cc2ccccc2n1C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)n1c(C)cc2ccccc21
Temperature: 0 °C
Yield: 96.9 %

Procedure:
To a solution of 2-methyl-2-(2-methyl-1H-indol-1-yl)propan-1-ol (780 mg, 3.8 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (919 mg, 38.3 mmol) at 0° C. The resultant reaction mixture was allowed to stirred at 0° C. for 1H. Iodomethane (5.4 g, 38.3 mmol) was added dropwise at 0° C., And then the resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was quenched with water. The pH was adjusted to around 6 by progressively adding 2N hydro chloride below 0° C. extracted with acetic ester (50 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 10:1→5:1) to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole (800 mg, 96%) as a light yellow oil. LCMS (M+H+) m/z: calcd. 217.15. found 217.9.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].O[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: Oc1cccnc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2cccnc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and 3-hydroxypyridine. White solid (34%). MS (EI): 478.1 (M+H)+.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH:5]([C:7]([O:9]C)=[O:8])[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.[OH-].[Na+]>CO>[C:18]([O:17][C:15]([N:1]1[CH2:2][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH:5]([C:7]([OH:9])=[O:8])[CH2:6]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CC(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.3 %

Procedure:
1-tert-Butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate (75 g) was dissolved in methanol (375 ml), and 2 M aqueous sodium hydroxide solution (125 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 14 hr, and methanol was evaporated under reduced pressure. The concentrated solution was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with ethyl acetate. The basic aqueous layer was acidified (pH 2) with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (71 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[N:20]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(Quinolin-2-ylmethoxy)-phenylamine (1.73 g) in 30 mL of concentrated HCl at 0° C. was added sodium nitrite (531 mg). After 3 h, tin chloride (3.95 g) was dissolved in 20 mL of concentrated HCl and added slowly dropwise and the reaction mixture stirred at ambient temperature for 18 h. The reaction mixture was filtered and the solid dried to provide the title compound as the HCL salt (3.94 g). MS: (M+H m/z=266.3).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([N:26]=[C:27]=[S:28])=[O:25])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:27]([NH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[S:28])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Yield: 75 %

Procedure:
1.20 g (4.0 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylaminobenzenesulfonamide is dissolved in 5 ml of anhydrous DMF, and 0.60 g (4.3 mmol) of 95% strength ethoxycarbonyl isothiocyanate is added. After 3 h at room temperature the mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The residue is taken up in a little ethyl acetate and precipitated with heptane at -25° C. The precipitate is filtered off with suction and dried to give 1.29 g (75% of theory) of colorless N-tert-butyl-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 110° C.