Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: OCc1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 0 °C

Procedure:
8.7 g. 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole (cf. the preparation of the starting material in Example 15) were dissolved in 50 ml. anhydrous pyridine. To this solution were added dropwise, while stirring and cooling to 5° - 10° C., 5 ml. pivalic acid chloride, 1.5 - 2 hours after the ending of the addition, the reaction mixture was poured into ice water. The aqueous phase was extracted 3 or 4 times with diethyl ether. The ethereal extract was successively washed with 1N sulfuric acid, a saturated aqueous solution of sodium bicarbonate and water, then dried, treated with active charcoal and fullers' earth and subsequently evaporated. The crude (4-(2,3-epoxypropoxy)-6-pivaloyloxymethyl-indole thus obtained (12.5 g.; about 100% of theory) was further reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH2:18][CH2:19][C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:18][CH2:19][C:20](=[O:21])[N:22]([O:24][CH3:25])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: CON(C)C(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCN1CCN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a cooled (0° C.) solution of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester 5.9 g (28 mmol) and 4-bromo-N-methoxy-N-methyl-butyramide 5.4 g (28 mmol) in DMF (220 ml) was added NaH 1.3 g (30 mmol, 55% dispersion in oil), the mixture allowed to reach RT and the mixture stirred for a further 2 h. The reaction was then concentrated, the residue redissolved in EtOAc and washed with 10% aq. KHSO4 solution, brine, dried (MgSO4) and concentrated affording the title compound 9.1 g (quant) as white foam. MS: 330.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 166–168° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34–4.24 (m, 2 H), 4.08–3.99 (m, 1 H), 3.11 (t, J=8.1 Hz, 2 H), 2.12–2.05 (m, 1 H), 1.92–1.76 (m, 1 H), 1.05–1.00 (m, 1 H), 0.94–0.86 (m, 3 H), 0.80–0.71 (m, 1 H), 0.53–0.46 (m, 2 H), 0.33–0.21 (m, 1 H); HRMS (ESI) calcd for C18H19N3OCl3 (M+H)+: 398.0594; found m/z 398.0575.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][O:4][C:5]([C:6]1[C:7]([C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:13]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: COC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
(The following reaction is done in an N2 atmosphere.) To a solution of Methyl-2-bromobenzoate (53) (922 mg, 4.29 mmol) in toluene (11 mL) is added Pd(PPh3)4 (297 mg, 0.26 mmol) and Na2CO3.10H2O (3.43 g, 12.00 mmol) in water (3.8 mL). Degas the resulting mixture is carefully (5 times alternating vacuum and flushing with N2). Add a solution of 3,4,5-Trimethoxyphenylboronic acid (54) (1.00 g, 4.72 mmol) in toluene (10 mL) by syringe, degas the resulting mixture again carefully and stir the resulting mixture overnight at 100° C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Purify the crude product by flash chromatography (silica gel, EtOAc/CyH 1+7, later 1+5) to obtain 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid methyl ester (55) as a yellow solid (1.30 g, 99%). 1H NMR (400 MHz, CDCl3): 3.65 (s, 3H); 3.84 (s, 6H); 3.87 (s, 3H); 6.52 (s, 2H); 7.35-7.42 (m, 2H); 7.50 (t, 1H, J=8.0 Hz); 7.73 (d, 1H, J=8.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:39])(=O)=O)=CC=1>ClCCl>[Cl:39][CH2:21][C:18]1[CH:19]=[CH:20][C:13]2[CH2:12][O:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[O:16][CH2:15][C:14]=2[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C2OCc3ccc(CCl)cc3CO2)cc1
Yield: 37.5 %

Procedure:
1.5 g (5 mmol) of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol in 15 ml of dichloromethane are introduced into a flask. 0.76 g (7.5 mmol) of triethylamine is added and 1 g (5.4 mmol) of p-toluenesulfonyl chloride is added in small solid portions at room temperature. After 20 hours of reaction, the solvent is evaporated off and the crude product is purified by silica gel chromatography (heptane/ethyl acetate: 4/1) to give 0.6 g of 2-chloromethyl-7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocycloheptene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)CCSc1ccc(Br)cc1

Procedure:
A mixture of 15 g (79 mmol) of 4-bromo-thiophenol (Compound 42), 3.16 g (79 mmol) of powdered sodium hydroxide and 150 ml of acetone was heated at reflux for 15 minutes. The refluxing mixture was then treated dropwise with a solution of 12 g (79 mmol) of 1-bromo-3-methylbutane (Compound 51) in 25 ml of acetone and then refluxed for a further 18 hours. The mixture was allowed to cool and the solvent removed in-vacuo. The residue was taken up in 25 ml of water and the mixture basified with 2 N NaOH solution. The mixture was extracted with ether and the combined ether extracts washed successively with 1 N NaOH, water and saturated NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled (113-117 degrees C., 0.2 mm) to give the title compound as a colourless oil. PMR (CDCl3): & 0.93 (6H, d, J~6.6 Hz), 1.47-1.58 (2H, m), 1.65-1.80 (1H, m), 2.90 (2H, t, J~7.8 Hz), 7.18 (2H, d, J~8.6 Hz), 7.39 (2H, d, J~8 6 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:13][CH3:12])=[O:5]
Reactant: CO
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1Cl
Yield: 86 %

Procedure:
2,5-dichloronicotinic acid chloride (5.0 g) was dissolved in methanol (30 ml) with stirring under ice cooling and then stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in ether and washed with saturated sodium hydrogen carbonate water solution and brine. The extract was dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (30/1), to give the title compound (4.2 g, 86%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+])=[O:32].Cl.ClCCl>C1COCC1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([CH2:36][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:26])([F:27])[F:25])=[CH:18][CH:19]=2)[CH:34]=1
Reactant: COC(=O)c1cccc(C[Zn+])c1
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Br)cc3)n(Cc3ccccc3)nc12
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cccc(Cc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Benzyl-3-(4-bromo-phenyl)-7-trifluoromethyl-2H-indazole (43 mg, 0.1 mmol) and 4 mg of bis[triphenylphosphine]palladium(II) chloride were dissolved in THF. After 5 minutes, 0.4 ml of a 0.5M solution of 3-(methoxycarbonyl)-benzylzinc bromide in THF (0.2 mmol) were added and the reaction mixture was stirred at room temperature overnight. 1M HCl-solution and dichloromethane were added, and the phases were separated. The resulting product was obtained after flash chromatographic purification using n-heptane/ethyl acetate, 90:10, as eluent. Yield: 47 mg.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][C:14](=[O:16])[CH3:15])[CH3:11])=[CH:6][CH:5]=1>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])[CH3:11])=[CH:8][CH:9]=1
Reactant: CC(=O)CN[C@@H](C)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)CN[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Sodium borohydride (2.39 g) was added to a solution of 1-[(S)-1-(4-fluorophenyl)ethylamino]propan-2-one (2.5 g) in ethanol (25 mL) under ice-cooling, and then the reaction solution was stirred at room temperature for one hour. The reaction solution was diluted with ice water and ethyl acetate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:2-propanol=100:1 to 0:100) to obtain 1.18 g of the title compound as a diastereomer mixture.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([CH:13]=[CH2:14])[C:5]([OH:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH:18]=[CH2:19]>CN(C=O)C.CCOCC>[CH2:19]([O:12][C:5]([CH3:11])([C:4]([F:15])([F:3])[CH:13]=[CH2:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: C=CC(F)(F)C(C)(O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(C)(C(=O)OCC)C(F)(F)C=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH (48.5 mg, 1.212 mmol) was added to a cold (−20° C.) solution of ethyl 3,3-difluoro-2-hydroxy-2-methylpent-4-enoate (214 mg, 1.102 mmol) in DMF (2 mL) and the mixture was allowed to warm to rt (˜30 min) and then 3-bromoprop-1-ene (0.113 mL, 1.323 mmol) was added. The mixture was stirred at rt overnight, diluted with ether (20 mL) and washed with water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (2:1 DCM-hexanes) to afford ethyl 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate as a clear oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][CH2:21][CH2:22][C:23]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:24]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2-c2ccccc2-c2ccccc21
Yield: 94 %

Procedure:
9H-Tribenz[b,d,f]azepine (0.17 g, 0.70 mmol, prepared similarly as described by H. C. Axtell et al., J. Org. Chem. 56, 3906 (1991)) was suspended in dry toluene (5 ml). 3-Chloropropionyl chloride (0.13 g, 1.0 mmol) and triethylamine (0.1 ml) were added and the mixture was heated at reflux temperature for 1.5 hour. Saturated aqueous sodium bicarbonate (10 ml) was added, and the phases were separated. The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo, affording 220 mg, (94%) of crude 3-chloro-1-(9H-tribenz[b,d,f]azepine-9-yl)propan-1-one as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[O:20][C:21]1[CH:26]=[C:25]([O:27]C)C=C[C:22]=1CCC(C1CCCC1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][C:25](=[O:27])[CH2:26][C:21](=[O:20])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(86), Step 2 substituting 3-(3-chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one from Step 1 above in place of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one. 1H NMR (CDCl3): δ 1.41-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H), 2.61 (t, J=8.6 Hz, 2H), 2.81 (s, 2H), 3.40 (s, 2H), 3.89, (s, 3H), 6.45 (d, J=8.5 Hz, 1H), 7.0 (d, J=8.5 Hz, 1H), 7.15 (brs, 1H). ESIMS (MH+): 351.8
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][N:32]([CH2:35][C@H:36]([C@H:39]([OH:41])[CH3:40])[CH2:37][OH:38])[C:31](=[O:42])[N:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH2:37][C@H:36]([CH2:35][N:32]2[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[N:30][C:31]2=[O:42])[C@H:39]([OH:41])[CH3:40])=[CH:3][CH:4]=1
Reactant: CC(=O)Nc1ccn(C[C@@H](CO)[C@@H](C)O)c(=O)n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
DMTCl (0.79 g, 2.34 mmol) was added to a stirred solution of 46 (0.5 g, 1.96 mmol) in 20 ml of anhydrous pyridine. After being stirred at room temperature overnight the reaction was quenched with MeOH (2 ml) and concentrated to an oil. The oil was partition between dichloromethane and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resulting material was chromatographed on silica eluting with a gradient of methanol (5-7.5%) in ethyl acetate. Concentration of the pure product fractions afforded 0.99 g (90%) of 47 as a white amorphous solid. 1H NMR (DMSO-d6): δ 10.78 (s, 1H), 7.73 (d, J=7 Hz, 1H), 7.27 (m, 5H), 7.16 (m, 4H), 6.98 (d, J=7 Hz, 1H), 6.82 (m, 4H), 4.60 (d, J=5 Hz, 1H), 3.84 (d, J=7 Hz, 2H), 3.76 (m, 1H), 3.72 (s, 6H), 3.08 (m, 1H), 2.99 (m, 1H), 2.20 (m, 1H), 2.09 (s, 3H), 1.03 (d, J=6 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>C(Cl)Cl>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:3]1
Reactant: OC1CCNC1
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(O)C1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 3-hydroxypyrrolidine (0.35 g, 4.02 mmol) and Et3N (1.16 mL, 8.04 mmol) in CH2Cl2 (20 mL) was added allyl chloroformate (0.47 mL, 4.43 mmol) at 0° C. The mixture was kept at 0° C. for 0.5 hr and more CH2Cl2 was added. It was then washed with 5% NaHCO3, water and brine, dried over Na2SO4 and concentrated to give the product (0.34 g) as a yellow liquid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28]OS(C)(=O)=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:3])[CH3:2].[C-:35]#[N:36].[K+]>CN(C=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28][C:35]#[N:36])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:2])[CH3:3]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CC#N)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
A mixture of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester (16 mg, 0.033 mmol) and KCN (21 mg, 0.33 mmol) in DMF was stirred for 24 h at ambient temperature. The solvent was evaporated and the residue was purified by prep-HPLC (gradient 10%-100% B) to give 12 mg (88%) of [2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-yl]-acetonitrile as a colorless gum.
Reaction SMILES: [O-]CC.[K+:4].[CH:5]([O:7][CH2:8][CH3:9])=[O:6].C([O:12][C:13](=O)[CH2:14][N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])C>C(OCC)C.CCO>[CH2:8]([O:7][C:5]([C:14]([N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:13][O-:12])=[O:6])[CH3:9].[K+:4]
Reactant: CCOC(=O)CN=C(C)OCC
Reactant: CCOC=O
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C[O-])N=C(C)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred suspension of 3.222 g (36 mmol, 1.05 eq) of potassium ethoxide in 30 mL diethyl ether and 5 mL EtOH at 0° C., a solution of 3.849 g (52 mmol, 1.5 eq) ethyl formate and 6 g (35 mmol) (1-ethoxy-ethylideneamino)-acetic acid ethyl ester in 30 mL diethyl ether and 5 mL EtOH is then slowly added. The reaction mixture is stirred for one hour at 0° C. After addition of 40 mL diethyl ether, the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the obtained solid was washed with diethyl ether and dried under vaccum to yielded 5 g (60%) of potassium 2-ethoxycarbonyl-2-(1-ethoxy-ethylideneamino)-ethenolate as an orange solids.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[O:14][N:13]=1)=[O:11])[CH3:8].[CH:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](Cl)=[S:28])=[CH:22][CH:21]=1>ClCCl>[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][O:19][C:27]([O:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[S:28])[O:14][N:13]=1)=[O:11])[CH3:8]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1cc(CCO)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CCOC(=S)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Pyridine (2.4 g, 31 mmol) was added to a stirred solution of 5-hydroxyethylisoxazole-3-carboxylic acid ethyl ester (4.75 g, 26 mmol) (prepared analogously to Example 64 part a) in dichloromethane (150 ml) under nitrogen at room temperature. The mixture was cooled to 0° C. and phenyl chlorothionoformate (5.3 g, 31 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hand at room temperature for 2 h, then diluted with dichloromethane (200 ml) and washed with water (×2). The organic layer was dried MgSO4) and evaporated in, vacuo. Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane, gave the title-compound (6.7 g, 81%), 1H NMR (250 MHz, CDCl3) δ 1.43 (3H, t, J=7.1 Hz, CH3), 3.37 (2H, t, J=6.3 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, CH2), 4.83 (2H, t, J=6.3 Hz, CH2), 6.60 (1H, s, Ar—H), 7.08-7.11 (2H, m, 2 of Ar—H), 7.29 (1H, m, Ar—H), 7.38-7.46 (2H, m, 2 of Ar—H); MS (ES+) m/e 322 [MH]+, m/e 168 [MH—154]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:24][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16][CH:13]1[O:12][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:15][CH2:14]1
Reactant: CCCCCC(O)CCC1CCC(CCCCCCCC(=O)OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(O)CCC1CCC(CCCCCCCC(=O)O)O1
Yield: 94.6 %

Procedure:
VI (1.78 g, 0.00500 mole), methanol (20 ml), and 20% aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 90 minutes. The methanol was removed from a water bath (60° C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. An emulsion was formed, which was extracted with ether (25 + 25 ml). The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (60° C, 1 mm Hg) to give 1.62 g (95%) of VII as a light yellowish oil, nD25 1.4682.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])=[CH:5][CH2:6]OC(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:33]([N:35]([CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])[CH2:36][CH3:37])[CH3:34]
Reactant: CCNCC
Reactant: COC(OC)C(C)=CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN(CC)CC=C(C)C(OC)OC

Procedure:
A mixture of 56.4 g (0.30 mol) of 4-acetoxy-2-methyl-2-butenal dimethyl acetal, 150 ml of diethylamine, 675 mg (3 mmol) of palladium (II) acetate and 3.9 g (15 mmol) of triphenylphosphine was boiled under reflux for 15 hours under argon. AFter concentrating the mixture, the residue was suspended in 170 ml of ether/pentane (1:1), the solution was treated with active carbon, filtered over Hyflo and concentrated. The residual oil was firstly distilled at 40°-55°/0.3 mmHg over a 5 cm Vigreux column, there being obtained 57.1 g of N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine as a 90:10 (E/Z) mixture. This mixture was then fractionated over a 30 cm packed column. There were firstly obtained a total of 34.8 g (58%) of mixed fractions [(E/Z)=86:14] and then 14.5 g (24%) of pure (E)-N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine of boiling point 30°-32°/0.06 mmHg.