Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:33]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([NH:40]O)=[NH:39])#[N:34]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]1[O:17][N:40]=[C:38]([C:37]2[CH:42]=[CH:43][CH:44]=[C:35]([C:33]#[N:34])[CH:36]=2)[N:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCCC(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(C(=N)NO)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCCC(c2nc(-c3cccc(C#N)c3)no2)N1C(=O)OC(C)(C)C
Yield: 48.6 %

Procedure:
2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-piperidine-1-carboxylic acid tert-butyl ester (340 mg, 46.2%) was prepared according to the procedure in Example 25 from 6-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (486 mg, 2 mmol) with isobutyl chloroformate (273.16 mg, 2.0 mmol) and triethylamine (1.14 g, 8 mmol) in THF (6 mL). Then 3-cyano-N-hydroxy-benzamidine (306 mg, 1.9 mmol) and DMF (5 mL) were added and the mixture was heated at 130˜135° C. for 3 h. 1H NMR (CDCl3), δ(ppm): 8.38 (d, 1H), 8.32 (dd, 1H), 7.77 (dd, 1H), 7.61 (t, 1H), 5.58 (d, 1H), 4.43 (m, 1H), 2.55 (m, 1H), 1.50–1.98 (m & s, 14H), 0.96 (d, 3H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]/[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C@:14]12[CH2:4][C@H:21]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])=[CH:24][CH:23]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of NaH (84 mg, 2.1 mmol) in DMF (5 mL) at 0° C. was added trimethylsulfoxonium iodide (154 mg, 0.70 mmol). The resulting mixture was stirred at rt for 30 min followed by the addition of (E)-5-Methoxy-3-((3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one in DMF (2 mL). The reaction mixture was then heated to 55° C. for 3 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give yellow viscous oil. The crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow powder, which was triturated with EtOAc to give the title compound as a pale yellow powder (93 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 10.45 (br. s, 1H), 8.71 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.73 (d, J=5.4 Hz, 1H), 6.56 (d, J=6.0 Hz, 1H), 5.86-5.75 (m, 3H), 3.71 (br s, 4H), 3.52 (br s, 4H), 3.40-3.16 (m, 6H), 2.42 (br. s, 1H), 2.00 (br. s, 1H), 0.79 (br s, 2H), −0.13 (s, 9H); MS ESI 598.4 [M+H]+, calcd for [C33H39N5O4Si+H]+ 598.28.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CC#N>[CH:24]([N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]1[CH3:8])([CH3:26])[CH3:25]
Reactant: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Yield: 45.9 %

Procedure:
To a mixture of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6 mmol) and K2CO3 (1.3 g, 9.2 mmol) in CH3CN (10 mL) was added 2-iodopropane (2.3 mL, 22.9 mmol) and the reaction was stirred at reflux temperature overnight. Additional 2-iodopropane (2.3 mL, 22.9 mmol) and K2CO3 (1.3 g, 9.2 mmol) were added and the reaction was continued to reflux overnight. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, to afford 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.550 g, 46%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+].[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24].CCO>O.Cl>[C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[N:15]=1)([CH3:27])([CH3:26])[CH3:19]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(Oc3ccccc3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a 250 mL Erlenmeyer flask with a magnetic stir bar, 3-phenoxyphenylamine (4.81 g, 0.026 mol) was added to 6 N HCl (40 mL) and cooled with an ice bath to 0° C. A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop wise. After 30 min, SnCl22H2O (52.0 g, 0.23 mol, 8.86 eq.) in 6 N HCl (100 mL) was added and the reaction mixture was allowed to stir for 3 h, and then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for 4 h, concentrated in vacuo and the residue extracted with EtOAc (2×100 mL) and purified by column chromatography using hexane/EtOAc/Et3N (8:2:0.2) to yield 3-tert-butyl-1-(3-phenoxyphenyl)-1H-pyrazol-5-amine (1.40 g, 17%). mp: 108-110° C.; 1H NMR (CDCl3): δ 7.3 (m, 10H), 5.7 (s, 1H), 4.9 (brs, 2H), 1.3 (s, 9H).
Reaction SMILES: S(Cl)(Cl)=O.F[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH3:15].[CH3:16][S-:17].[Na+].[CH3:19]O>>[CH3:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[S:17][CH3:16])[C:10]([O:12][CH3:19])=[O:11]
Reactant: C[S-]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(SC)c(C)c1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (5.8 g, 3.5 mL, 48.7 mmol) was added dropwise to a solution of 4-fluoro-3-methyl-benzoic acid (5.0 g, 32.4 mmol) in methanol (40 mL). The reaction mixture was stirred at 35° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resulting methyl 4-fluoro-3-methylbenzoate was used in the next step without further purification. ESI-MS m/z calc. 167.1. found 168.2 (M+1)+; Retention time: 1.57 minutes (3 min run). The crude ester was dissolved in DMF (20 mL) and powdered sodium thiomethoxide (2.3 g, 32.4 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and at 80° C. for 1 hour. The reaction mixture was concentrated in vacuo, the residue was partitioned between 1M HCl solution and ethyl acetate. The layers were separated and the organic was washed with 1M hydrochloric acid solution. The ethyl acetate layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 3-methyl-4-(methylthio)benzoate. ESI-MS m/z calc. 182.2. found 183.1 (M+1)+; Retention time: 1.48 minutes (3 min run). Methyl 3-methyl-4-(methylthio)benzoate (32.4 mmol) was heated in a mixture of acetic acid (80 mL) and hydrogen peroxide (40 mL of 30% w/w,) at 80° C. for 30 minutes. The reaction mixture was cooled, concentrated in vacuo and then partitioned between water and ethyl acetate. The layers were separated and the organic was washed sequentially with water (1×20 mL), sat. NaHCO3 (1×20 mL) and brine (1×20 mL), then dried over MgSO4 and concentrated in vacuo. The residue was triturated with ethyl ether to give methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g) as a white solid. The mother liquor was concentrated in vacuo then triturated with hexanes (3×) to give a second crop (1.2 g) (combined yield 95%). ESI-MS m/z calc. 228.3. found 229.5 (M+1)+; Retention time: 1.04 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.20-8.09 (m, 1H), 8.04-8.00 (m, 2H), 3.96 (s, 3H), 3.10 (s, 3H), 2.77 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:15]C(=O)C)=[CH:9][C:8]=2[N+:19]([O-:21])=[O:20])=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[OH:15][CH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:19]([O-:21])=[O:20])[CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2
Reactant: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(CO)cc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
5-Acetoxymethyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (3.5 g, 12.0 mmol) prepared in Step B was dissolved in a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 100 mL). Lithium hydroxide hydrate (1.5 g, 35.9 mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, methanol and tetrahydrofuran were removed by distillation under reduced pressure. 1N hydrochloric acid was added to the residue. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography to give the title compound (2.3 g, Yield 81%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Yield: 51.4 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 810 mg (2.89 mmol) of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide and 656 mg (3.47 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane/ethyl acetate to afford 670 mg (49% yield) of the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:34]([C:36]1[S:40][C:39]([O:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:34][C:36]1[S:40][C:39]([O:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(Oc2ccc(C#N)cc2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine a solution of methoxy methyl triphenyl phosphonium chloride (358 mg, 1.047 mmol) in THF (3.6 mL) with a solution of KHMDS (0.5M in toluene, 2 mL, 1.047 mmol) at 0° C. for 20-40 min. Cool the resulting orange solution to about −78° C., then add a solution of 4-(5-formyl-thiophen-2-yloxy)-benzonitrile in THF (1 mL) dropwise over about 10 min. Stir at about −78° C. for 45 min, then allow the reaction mixture to warm to room temprature and quench with H2O (5 mL). Extract the reaction mixture with ether (5 mL), wash with H2O, dry over magnesium sulfate, filter and concentrate. Purify the crude product by flash chromatography (CH2Cl2) to provide 155 mg of 4-[5-(2-methoxy-vinyl)-thiophen-2-yloxy]-benzonitrile. Redissolve the product in i-PrOH (about 0.8 mL)—H2O (about 0.8 mL) and add pTsOH.H2O (4 mg, 0.018 mmol). Stir the reaction mixture at reflux for 2-3 hours. Cool the reaction mixture to room temprature, dilute with H2O (5 mL) and extract with diethyl ether (6 mL). Wash the organic layer with sodium bicarbonate, brine, dry over magnesium sulfate, filter and concentrate under reduced pressure to give the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].Cl[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(OCC)(=O)C.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(C)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
Potassium tert-butylate (11.22 g, 2 eq) is added to a solution of DMF (80 ml) cooled down to 0° C. A solution of 1-chloro-2-nitrobenzene (7.87 g, 1 eq) and ethyl 2-chloropropanoate (7 ml, 1.1 eq) is added dropwise over 45 minutes to the mixture whilst keeping the reaction temperature below 5° C. At the end of the addition, stirring is maintained for 2 hours at 0° C., then the mixture is hydrolyzed at this temperature with a 1N solution of hydrochloric acid and ethyl acetate is added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent:heptane/dichloromethane 8:2 to 6:4) produces the expected compound in the form of a yellow oil (8.28 g; 64% yield).
Reaction SMILES: C(OCC)(=O)C.C(O)(C)C.[CH:11]1([NH:14][C:15](=[O:30])[C@@H:16]([OH:29])[C@@H:17]([NH:21]C(OC(C)(C)C)=O)[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1.[ClH:31].C(O)(C)C>CCCCCC>[ClH:31].[CH:11]1([NH:14][C:15](=[O:30])[C@@H:16]([OH:29])[C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (46.1 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (34.82 g). Hexane (20 g) was added to the solution and the mixture was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (9.1 g) was dropwise added, taking 1 hour. Then, after stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 4 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (15 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (3.48 g, yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:11])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 28.5 %

Procedure:
(Method B) A mixture of 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone (471 mg), 4-chloropyridine hydrochloride (225 mg) and triethylamine (405 mg) in ethanol (20 ml) was reacted in a sealed tube at 150° C. for 18 hours. The reaction mixture was concentrated, and the residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=12:1) and crystallized from a mixture of ethanol and diethyl ether to obtain the title compound (156 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[C:10]1([Mg]Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: Cn1ncc(Br)c1C=O
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-methyl-2H-pyrazole-3-carbaldehyde (1.00 g; 5.29 mmol) was dissolved in 5.0 ml of anhydrous THF and cooled down to −78° C. Phenylmagnesium chloride 2 mol/l (6.61 ml; 13.23 mmol) was dropped and stirred for 1 hour. It was warmed up to 0° C. and quenched carefully with water, then extracted with DCM. The organic layers were pooled, dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]=[C:11]([CH3:22])[N:12]([S:13]([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:15])=[O:14])[C:8]=2[CH:7]=1.COC(=O)[C@H](NC(OCC1C=CC=CC=1)=O)CC1C=CC2N(S(CC[Si](C)(C)C)(=O)=O)C(C)=NC=2C=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH2:25])[CH2:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]=[C:11]([CH3:22])[N:12]([S:13]([CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])(=[O:14])=[O:15])[C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2nc(C)n(S(=O)(=O)CC[Si](C)(C)C)c2c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)[C@@H](Cc1ccc2c(c1)nc(C)n2S(=O)(=O)CC[Si](C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc2nc(C)n(S(=O)(=O)CC[Si](C)(C)C)c2c1
Yield: 80 %

Procedure:
A methanol (50 mL) suspension of (R)-2-benzyloxycarbonylamino-3-[2-methyl-3-(2-trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-propionic acid methyl ester and (R)-2-Benzyloxycarbonylamino-3-[2-methyl-1-(2-trimethylsilanyl-ethanesulfonyl)-1H-benzoimidazol-5-yl]-propionic acid methyl ester (1:1 mixture, 600 mg), and 10% palladium on charcoal (180 mg) was agitated on a Parr apparatus overnight under 40 psi of hydrogen at room temperature. After replacing the hydrogen atmosphere with nitrogen, the mixture was filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a tan solid (80%). 1H-NMR (CD3OD, 500 MHz) δ 7.81 (d, J=8.5, 0.5 Hz, 0.5H), 7.70 (s, 0.5H), 7.58 (d, J=8.5 Hz, 0.5H), 7.49 (s, 0.5H), 7.25 (d, J=9.0 Hz, 1H), 3.89 (dd, J=14.0, 6.5 Hz, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.55-3.51 (m, 2H), 3.18 (d, J=6.0 Hz, 1H), 3.22-3.18 (m, 0.5H), 3.14-3.09 (m, 0.5H), 2.81 (s, 1.5H), 2.80 (s, 1.5H), 0.92-0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H); 13CNMR (CD3OD, 125 MHz) δ 174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, 119.7, 119.0, 114.1, 113.4, 55.6, 51.8, 51.7, 51.6, 40.2, 39.8, 15.83, 15.77, 9.9, −3.07, −3.11. Mass spec.: 398.20 (MH)+.
Reaction SMILES: [NH:1]1[C:7](=O)[CH2:6]C[CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH2:13]([NH2:16])[CH:14]=[CH2:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:13]([NH:16][CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:2]=1[NH:1][CH:7]=[CH:6]2)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: O=C1CCCc2ccccc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCNCc1cccc2cc[nH]c12
Temperature: 22 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
To a solution of indole-7-carboxaldehyde 1 (4.00 g, 27.6 mmol) in 1,2-dichloroethane (120 mL) at 20-24° C. was added allylamine (2.50 mL, 33.1 mmol), acetic acid (3.4 mL), and sodium triacetoxyborohydride (5.85 g, 27.6 mmol). The resulting mixture was stirred at 20-24° C. for 5 hours. An additional 1.5 g (7.1 mmol) of sodium triacetoxyborohydride was added and the resulting mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL), washed carefully with aqueous sodium bicarbonate (100 mL), and the layers were separated. The organic layer was washed with water (100 mL), saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 4.21 g (82%) of the desired compound as a light yellow oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][S:27]([O:18][CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)(=[O:29])=[O:28]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-ol (20.0 g, 83.68 mmol) and Et3N (12.68 g, 125.52 mmol) in DCM (200 mL) at 0° C., MsCl (11.447 mg, 100.41 mmol) was added in portions and the resulting solution was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product (26.526 g, 100% yield).
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])([C:9]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[N:12][CH:13]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[C:9]2[NH:10][CH:11]=[N:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(O)(c1ccccc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(c1ccccc1)c1cnc[nH]1
Yield: 53 %

Procedure:
Phenyl-o-tolyl-(3-trityl-3H-imidazol-4-yl)-methanol, (Intermediate 8) (620 g, 1.2 mmol) in dichloromethane (30 mL) was reacted with TFA: trifluoroacetic acid (4.0 ml) and triethylsilane (TES) (6.0 ml) at rt for 24 h. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-(Phenyl-o-tolyl-methyl)-1H-imidazole 162 mg (53%). 1HNMR (CD3OD, 300 MHz) δ 7.8 (s, 1H), 7.12-7.38 (m, 9H), 6.82 (s, 1H), 6.40 (s, 1H), 5.60 (s, 1H), 2.21 (s, 1H).