Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH:5]=1.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1.[OH-:22].[Na+]>C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[CH:5]=1.[NH:4]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:15][C:18]([C:19]([OH:22])=[O:20])=[CH:17][CH:21]=2)[N:1]=[CH:5]1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: CCOC(=O)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the obtained ethyl 4-(1,2,4-triazol-4-yl)benzoate (365 mg) in ethanol (4 ml)-THF (4 ml) was added 1 N sodium hydroxide solution (4 ml), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (4 ml). The precipitate was filtered, washed with water and dried to give the title compound, 4-(1H-imidazol-4-yl)benzoic acid (275 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2C(=O)O[C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]2)=[CH:11][CH:10]=1.C(#N)C.Br/[C:29](=[CH:35]\[C:36]([F:39])([F:38])[F:37])/[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([C:21]([F:22])([F:23])[F:24])=[C:35]([C:36]([F:39])([F:38])[F:37])[C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C(Br)=C/C(F)(F)F
Reactant: O=C1OC(C(F)(F)F)=NC1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
Triethylamine (1.1 g, 0.011 mol) is added dropwise to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.64 g, 0.01 mol) and acetonitrile (25 mL). After stirring for 10 minutes at room temperature, a solution of ethyl 2-bromo-4,4,4-trifluorocrotonate (2.47 g, 0.01 mol) and acetonitrile (1 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 2 hours then poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an orange oil which solidifies upon standing. Trituration with hexanes gives the title product as a yellow solid (2.36 g, 61.3%, mp 138°-140° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[O:31])[CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2C[C@H]3CNCCN3C2)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3ccc(Cl)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 57 (50.7 mg, 0.2 mmol) and triethylamine (40 mg, 0.4 mmol) in dichloromethane (1 mL) was added 3-(trifluoromethyl)benzoyl chloride (50 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 hours. The residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.92 (m, 2H), 2.16-2.27 (m, 3H), 2.52 (m, 1H), 2.82-3.25 (m, 2H), 3.60 (m, 2H), 4.45-4.62 (m, 1H), 5.28 (m, 1H), 6.83 (m, 1H), 7.75 (m, 5H), 8.20 (s, 1H); MS (ESI) m/z 426 (M+H)+.
Reaction SMILES: [H-].[K+].O1[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12].ClC/C=C\CCl>O.C(Cl)Cl>[CH3:8][S:9][C:10]1([S:11](=[O:13])[CH3:12])[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: ClC/C=C\CCl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CSC1(S(C)=O)CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Potassium hydride (4.2g) was suspended in 50 ml. of tetrahydrofuran, and 5.464 g of formaldehyde dimethyl mercaptal S-oxide was added dropwise at -10° C. to 0° C. The mixture was stirred for 1 hour at 0° C., and then a tetrahydrofuran solution (6.585 g/30 ml.) of cis-1,4-dichloro-2-butene was added while adjusting the temperature of the reaction mixture to -30° to -40° C. Then, the mixture was stirred for 12.5 hours at room temperature. Methylene chloride (400 ml) and 50 ml. of water were added, and the mixture was shaken. The organic phase was separated, and the aqueous phase was extracted with methylene chloride. The extract and the organic phase were combined, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 3.461g of 3-cyclopentenone dimethyl mercaptal S-oxide in a yield of 45%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCc2cccc(F)c2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-fluorophenyl)ethanamine (300 mg, 2.16 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (160 mg) as a yellow solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.86-2.90 (m, 2H), 3.51-3.56 (m, 2H), 5.39 (s, 2H), 6.04 (s, 2H), 6.29 (s, 1H), 6.97-7.43 (m, 6H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]2[S:10][C:11]([CH2:13][O:14][C:15]3[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=3)[C:18]([NH2:20])=[O:19])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH:2]=[CH2:3]>CO.[Pd]>[F:25][C:16]1[C:15]([O:14][CH2:13][C:11]2[S:10][C:8]3[C:7]([N:12]=2)=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=3)=[CH:23][CH:22]=[C:21]([F:24])[C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
To a solution of 3-(5-Allyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.018 g, 0.049 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 5 mg) and the reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and the filtrate was evaporated to dryness under reduced pressure to give the title compound as white solid (0.0078 g, 43%). 1H NMR (DMSO-d6, 400 MHz); δ 0.91 (m, 3H), 1.65 (m, 2H), 2.74 (m, 2H), 5.69 (s, 2H), 7.12 (m, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.27 (br s, 1H) and 8.52 (br s, 1H). MS ES+(364.11), HPLC (method I) Rt=15.85 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:38]([OH:44])[CH2:39][C:40]([NH:42][NH2:43])=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ON1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:38]([OH:44])[CH2:39][C:40]([NH:42][NH:43][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NN
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NNC(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
66 mg (0.1 mmole) of 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoic acid hydrazide (prepared as described in Example 5) were dissolved in 3 ml of dimethylformamide, and then 31 mg (0.1 mmole) of N-hydroxysuccinimide 4-benzoylbutyrate were added and the mixture was stirred for 2 days at room temperature. The resulting reaction mixture was concentrated by evaporation under reduced pressure, and water was added to the resulting residue. After the water had been added to the residue, the precipitate was separated by filtration. It was washed with water, and the powder obtained after drying was washed with ethyl acetate, to give 63 mg of the title compound as a white powdery solid melting at 158°-160°, [α]27 -44.4° (C=0.5, methanol).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([F:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:19][O-:20].[Na+].O>C1COCC1>[F:18][C:9]1[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:11][C:2]([O:20][CH3:19])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(OCC(F)(F)F)nc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a stirred solution of methyl 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate (1.1 g, 3.9 mmol, Step-1 of Amine-42) in THF (35 mL) is added sodium methanolate (0.32 g, 5.8 mmol) at 0° C. The mixture is stirred at 60° C. for 2 hours and cooled to room temperature. The mixture is poured into water and extracted with dichloromethane (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (9:1) to give 310 mg (28% yield) of the title compound as a white solid.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])C(C)=CC=1.Cl.NO.C(N(CC)CC)C.N.[OH-].[Na+]>CC(O)C.O.CO.C(Cl)Cl>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([NH2:3])[CH:9]=2)[NH:13][CH:12]=1
Reactant: Cc1ccc(C)n1-c1ccc2[nH]cc(CC[C@@H]3CCCN3C)c2c1
Agent: Cl
Agent: N
Agent: NO
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(C)O
Product: CN1CCC[C@H]1CCc1c[nH]c2ccc(N)cc12
Temperature: 25 °C

Procedure:
To an argon purged round bottom flask fitted with a magnetic stirbar and containing a yellow solution of 145 (94 g, 0.292 mmol) in anhydrous 2-propanol (6 mL) and water (2 mL) was added solid hydroxylamine hydrochloride (406 mg, 5.84 mmol) in one portion. Triethylamine (407 μL, 2.92 mmol) was added via syringe and the flask was fitted with a condensor. The vessel was placed in an oil bath and heated to reflux. The reaction was stirred at reflux under argon for 6 hours. TLC (10% 2M NH3 in MeOH, 90% CH2Cl2) revealed the reaction was complete, and so the reaction was cooled to room temperature. Sodium hydroxide pellets (120 mg, 3.0 mmol) were added slowly. The reaction was stirred vigorously overnight. The reaction was filtered through celite, followed by washing of the celite with 2-propanol (40 mL) and absorption of the filtrate onto silica gel. The product was purified by column chromatography (5-10% 2M NH3 in MeOH, 90% CH2Cl2) using a silica gel plug approximately 15 mm in diameter by 30 mm in height to afford an orange solid. This product was partitioned between brine (5 mL) and ethyl acetate (10 mL). The organic was dried with anhydrous sodium sulfate before being decanted. Concentration afforded an orange oil, compound 146. Yield: 48 mg of orange oil (68%) 1H NMR (DMSO-d6) δ 10.19 (s, 1H), 7.02-6.99 (d, J=5.4 Hz, 1H), 6.90-6.89 (d, J=2.1 Hz, 1H), 6.64-6.63 (d, J=1.5 Hz, 1H), 6.47-6.43 (dd, J=1.8, 8.7 Hz, 1H), 4.42 (bs, 1H), 2.97-2.90 (m, 1H), 2.59 (m, 2H), 2.20 (s, 3H), 2.05-1.97 (m, 4H), 1.69-1.40 (m, 4H).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH2:22][C:23]2[C:24]([NH2:31])=[N:25][C:26]([NH2:30])=[N:27][C:28]=2O)=[C:16]([O:32][CH3:33])[CH:15]=1)=[O:13].P(Cl)(Cl)([Cl:36])=O>>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH2:22][C:23]2[C:24]([NH2:31])=[N:25][C:26]([NH2:30])=[N:27][C:28]=2[Cl:36])=[C:16]([O:32][CH3:33])[CH:15]=1)=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(OC)c(Cc2c(N)nc(N)nc2O)c(OC)c1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(OC)c(Cc2c(N)nc(N)nc2Cl)c(OC)c1
Reaction time: 48 h

Procedure:
2.4 G. of N,N-dimethyl-aniline were added dropwise with stirring to a suspension of 3.4 g. of α-(2,4-diamino-6-hydroxy-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester in 25.6 g. of phosphorus oxychloride. The resulting mixture was brought to the boiling temperature in the course of 1 hour and then boiled at reflux for 4 hours. Thereafter, two thirds of the phosphorus oxychloride were removed by distillation under reduced pressure. The residue was poured onto 80 g. of ice with stirring and left to stand for two days at room temperature. The suspension was treated with 38 ml. of 25% aqueous ammonia, while the temperature did not exceed 20°C. After 2 hours, the solid material was removed by filtration with suction, rinsed with a small amount of water in a flask and separated from the N,N-dimethyl-aniline with steam. After cooling, the compound in suspension was removed by filtration with suction and taken up in ethyl acetate. The solution was dried over magnesium sulfate and the solvent evaporated. The dark residue (1.6 g.) was purified by column chromatography on 60 g. of silica gel (Merck) using chloroform/n-propanol/25% ammonia (80:20:1) as the eluant, whereby there was obtained α-(2,4-diamino-6-chloro-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester having a m.p. of 228°-229°C. (from methanol).
Reaction SMILES: [OH:1][C:2]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.[BH4-].[Na+]>>[OH:7][CH2:6][CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC1(O)CN(C)CCO1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCC(O)CN(C)CCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 2-Hydroxy-4-methyl-2-pentadecylmorpholine (1 g, 3.06 mmol) at 0° C. was added NaBH4 (349 mg, 9.17 mmol) over a period of 10 minutes at 0° C., and the reaction mixture was stirred at 0° C. for 6 hours. Then methanol was removed by rotavap, the residue was taken in ether (100 mL) washed with water (2×25 mL), brine, and dried over sodium sulphate. Evaporation of the solvent gave a pure product. Yield (0.98 g, 97%), NMR 1H (CDCl3, 200 MHz) 0.89 (3H, t, CH3) 1.25 (26H, s, CH2) 1.38 (2H, m. CH2) 2.32 (3H, s, N--CH3) 2.3-2.7 (4H, m, CH2) 3.67 (3H, m, CH2OH, CHOH). NMR 13C (CDCl3, 50 MHz) 67.6 64.1, 59.7, 59.3 42.4, 34.9, 31.9, 29.7, 29.3, 25.6, 22.7, 14.1 IR cm--1 3392, 2922, 2853, 1466, 1265, 878, 740.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:7][CH2:6]2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.[F-].[Cs+]>CN(C)C=O.O>[CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Reactant: BrCC1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(CC2CC2)CC=C(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-triisopropylsilanylsulfanylcyclohex-3-enecarbonitrile (20.5 g, 58.5 mmol) and (bromomethyl)cyclopropane (15.8 g, 117 mmol) in anhydrous N,N-dimethylformamide (65 ml) was added cesium fluoride (17.8 g, 117 mmol) and the mixture left to stir at ambient temperature for 15 hours. The mixture was diluted with water (500 ml) and extracted with diethyl ether (3×200 ml). The combined organic layer was washed with water (2×300 ml) and brine (200 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to give an orange oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (10-40%). Collecting appropriate fractions gave a colourless oil (10.7 g, 74%). 1H NMR δ (ppm) (CDCl3): 5.53 (1H, t, J=1.6 Hz), 2.69-2.51 (4H, m), 2.30-2.11 (3H, m), 1.71-1.67 (1H, m), 1.60-1.45 (2H, m), 1.05-0.99 (1H, m), 0.92-0.88 (1H, m), 0.60-0.56 (4H, m), 0.26-0.18 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[O:10])=[C:4]([F:28])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.Cl>C(OCC)(=O)C.C(O)CC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:11][N:12]=[C:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 140 °C
Yield: 41.2 %

Procedure:
Into a 250 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate (4.35 mmol). Added to the flask was K2CO3 (21.71 mmol), water (100 mL), and 1-propanol (10.00 mL). The solution was stirred at reflux (140° C.) for 16 h and then cooled to room temperature and filtered to remove an undetermined solid. The filtrate was concentrated in vacuo. Added to the white solid was 1N aq NaOH (10 mL) followed by the addition of Boc2O (4.35 mmol). The solution was stirred at room temperature overnight. The solution was diluted with 100 mL ethyl acetate and brought to a pH=7 with the addition of 1N aq HCl. The organic layer was separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel purification (100% dichloromethane, 0-100% ethyl acetate, and 0-10% methanol:ethyl acetate) provided the title product (790 mg, 39%). MS(ES)+ m/e 442.0, 443.0 [M+H]+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=O)[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=[S:2])[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of P4S10 (36.1 g, 81.1 mmol) and Na2CO3 (8.6 g, 81.1 mmol) in 1,2-DCE (700 mL) at room temperature was stirred for 2 h before Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound D) (16.8 g, 45.1 mmol) was added. The resulting mixture was stirred at 70° C. for 2 h before being cooled and filtered. The solid was washed twice with DCM and the filtrate washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash-chromatography on silica gel (DOM/MeOH: 99/1) to afford the title compound (17.2 g, 98% yield) as a yellowish solid. LC/MS (Method D): m/z 389 [M(35Cl)+H]+, Rt 2.64 min
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: Br
Product: O=C1CCCc2ccc(O)cc21
Temperature: 100 °C
Yield: 110.1 %

Procedure:
The 7-methoxy-1-tetralone (Aldrich, Cat. #163368) (0.75 g, 4.2 mmol) was dissolved in conc hydrobromic acid (3.0 ml) and was heated to 100° C. for 8 h. The reaction was allowed to cool to r.t. and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.75 g, 100%) as a semisolid.Analytical LCMS (M+H)+: m/z=163.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:14]([S:16](Cl)(=[O:18])=[O:17])[CH3:15]>>[CH2:14]([S:16]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:18])=[O:17])[CH3:15]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and ethylsulfonyl chloride using the procedure described in example 12.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)[C:15]3[N:16]=[C:17]([CH3:20])[NH:18][CH:19]=3)=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:15]3[N:16]=[C:17]([CH3:20])[NH:18][CH:19]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(NC(=O)Cc2ccc(C3CC3)cc2)c2c[nH]c(C)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(C(NC(=O)Cc2ccc(C3CC3)cc2)c2ccc(O)cc2)c[nH]1
Temperature: -10 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a 10 ml round bottom flask containing −78° C. solution of 2-(4-cyclopropylphenyl)-N-[(4-methoxyphenyl)(2-methyl-1H-imidazol-4-yl)methyl]acetamide (80.00 mg, 0.213 mmol) in 2.0 ml of CH2Cl2 was added drop-wise 1.0 N BBr3 in CH2Cl2 (1.065 ml, 1.065 mmol). The resulting solution was stirred at −10° C. for 2 hours. The reaction mixture was quenched with diethyl ether. Water was added and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (10-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 15.20 mg (20%) of the title compound. 1H NMR (CD3OD, 400 MHz) δ 7.136 (m, 4H), 7.012 (m, 2H), 6.938 (d, J=1.10 Hz, 1H), 6.797 (m, 2H), 6.067 (s, 1H), 3.523 (s, 2H), 3.344 (s, 1H), 2.552 (s, 3H), 1.868 (m, 1H), 0.932 (m, 2H), 0.635 (m, 2H). ES-MS [M+1]+: 362.3.