Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].[P:15](Cl)(Cl)([Cl:17])=[O:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([CH3:12])([CH3:13])[CH2:10][O:11][P:15](=[O:16])([Cl:17])[O:14]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(CO)C(O)c1ccccc1Cl
Solvent: ClCCl
Product: CC1(C)COP(=O)(Cl)OC1c1ccccc1Cl
Yield: 98.3 %

Procedure:
1-(2-Chlorophenyl)-2,2-dimethyl-1,3-propanediol (1.0 g, 4.66 mmol) was diluted with dichloromethane (5 ml) and, under reflux, a solution of phosphorus oxychloride (0.65 g, mmol) in dichloromethane (3 ml) was added dropwise over 40 min. After the dropwise addition, the mixture was refluxed for 6 h. The mixture after completion of the reaction was concentrated, and after addition of ether (dry, 5 ml), concentrated again to dryness to give the title compound (1.23 g, 90%) as colorless crude crystals.
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)(=O)C.OS(O)(=O)=O>CO>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5](=[O:4])[CH2:6]1
Reactant: CC(=O)Oc1coc2ccccc12
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C1COc2ccccc21
Yield: 83 %

Procedure:
To a solution of benzofuran-3-yl acetate (8) (100 g, 1.42 mol) in methanol (350 mL) was added diluted (7.5%) H2SO4 (500 mL) at ambient temperature followed by heating to reflux for 1-3 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled, filtered, and the slurry was washed with water, and vacuum dried to obtain the product meeting the desired specifications. Yield—83-100%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:4][C:3]=2[O:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH:11]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CCCOc1ccc2c(c1)C(=O)CC2c1ccc2c(c1)OCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Yield: 53 %

Procedure:
A solution of 1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy-3-oxo-indane (2.7 g, 9.06 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.45 g, 10.87 mmol) in 1,4-dioxane (80 ml) was stirred at reflux for 2 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in methylene chloride and filtered. The filtrate was concentrated and flash chromatography (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a red solid (1.48 g, 55%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl[C:14]1[N:15]([CH3:27])[C:16](=[O:26])[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[N:19]=1>O1CCCC1>[CH3:27][N:15]1[C:16](=[O:26])[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[N:19]=[C:14]1[O:3][CH2:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(OCC(=O)c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a suspension of sodium hydride (60 wt % in oil, 0.23 g, 6.3 mmol) in tetrahydrofuran (5 ml) was added 2-hydroxyacetophenone (0.92 g, 6.75 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred at room temperature. After 30 minutes, 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (1.0 g, 4.5 mmol) was added. The mixture was stirred under reflux for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-(2-oxo-2-phenyl-ethoxy)-1H-[4,4′]bipyrimidinyl-6-one (75 mg, 0.23 mmol, 5%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29]C)=[O:28])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:36]>CO.O1CCOCC1.Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O-:29])=[O:28])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:36]
Reactant: COC(=O)c1ccccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])c1ccccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (37 mg) in MeOH-1,4-dioxane (1:1, 3 ml) was added iN NaOH solution (1.0 ml) at 5° C. and the mixture was stirred at 80° C. for 3 hours. After cooling, the mixture was acidified with iN HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in MeOH-1,4-dioxane (1:1, 2 ml) and 1N NaOH solution (0.0824 ml) was added thereto. The mixture was evaporated and Et2 was added. The resulting solid was collected by filtration to give sodium 2-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl1methyl}benzoate (19.9 mg).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([Cl:42])[CH:37]=1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[Cl:42][C:38]1[CH:37]=[C:36]([NH:35][C:26](=[O:28])/[CH:25]=[CH:24]/[C:4]2[N:5]([C@@H:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)[C:6]3=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]3[C:3]=2[C:1]#[N:2])[CH:41]=[CH:40][N:39]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccnc(Cl)c3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-amino-2-chloropyridine (209 mg, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate=2:1) to give the objective product as a solid material.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([OH:27])=[O:26].CO.[OH-].[Na+:31].CCOCC>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([O-:27])=[O:26].[Na+:31]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Temperature: 50 °C
Yield: 57.1 %

Procedure:
To a suspension of 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (7.3 g) in N,N-dimethylformamide (120 ml) was added methanol (140 ml) under stirring at 50° C. To this solution was added dropwise sodium hydroxide solution (sodium hydroxide 0.79 g in water 2.37 ml and ethanol 15.8 ml) under stirring for 15 minutes at ambient temperature, and was stirred for 30 minutes at ambient temperature. To this solution ether (250 ml) was added and stirred. The precipitated crystals were collected by filtration and washed two times with water and ether, and dried under reduced pressure to give sodium 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]-quinazoline-3-carboxylate (1 hydrate) (4.4 g).
Reaction SMILES: O=C[C@@H]([C@@H]([C@@H](CO)O)O)O.[OH:11][C@@:12]1([C:19]#[C:20][C:21]2[N:22]=[C:23]([NH:39][CH:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:24]3[N:25]=[CH:26][N:27]([C:37]=3[N:38]=2)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[CH2:13]1>>[OH:11][C@@:12]1([C:19]#[C:20][C:21]2[N:38]=[C:37]3[C:24]([NH:25][CH:26]=[N:27]3)=[C:23]([NH:39][CH:40]([CH2:41][CH3:42])[CH2:43][CH3:44])[N:22]=2)[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[CH2:13]1
Reactant: CCC(CC)Nc1nc(C#C[C@]2(O)CCC[C@@H](C)C2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: CCC(CC)Nc1nc(C#C[C@]2(O)CCC[C@@H](C)C2)nc2nc[nH]c12

Procedure:
Using the representative procedure for ribose cleavage above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenosine (1.03 g) gave the product as a white solid: yield 0.725 g, 98%. LRMS ESI (M+H+) 342.2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mLl) was added saturated aqueous bicarbonate solution (0.88 mL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 4 hours and was quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 75% ethyl acetate in hexane, to give the title compound MS ESI(+) m/z 524.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[N:6]=1
Reactant: Cc1nc(C#N)cs1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nc(=O)c3ccccc3s2)cs1
Yield: 77.9 %

Procedure:
2-Methyl-1,3-thiazole-4-carbonitrile (0.46 g, 3.7 mmol) and methyl thiosalicylate (1.26 g, 7.4 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto. The mixture was refluxed for 15 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.75 g, 78%) as white crystals.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:23][CH2:24][C@@H:25]([C:27]([OH:29])=[O:28])[NH2:26])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:4][CH:3]=1.[CH3:30]C1C=CC(C2(O)C3C=CC=CC=3C=CC3C=CC=CC2=3)=CC=1.COC(=O)[C@H](CO)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:30][C:7]1[CH:6]=[C:5]([C:8]2([O:23][CH2:24][C@@H:25]([C:27]([OH:29])=[O:28])[NH2:26])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2(O)c3ccccc3C=Cc3ccccc32)cc1
Reactant: Cc1ccc(C2(OC[C@H](N)C(=O)O)c3ccccc3C=Cc3ccccc32)cc1
Agent: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: Cc1cccc(C2(OC[C@H](N)C(=O)O)c3ccccc3C=Cc3ccccc32)c1

Procedure:
O-[5-(4-Methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-L-serine: from 5-(4-methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-ol (Example it) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.CCCCCC.[B:23]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])OC(C)C.CC(O)(C(C)(O)C)C.C(O)(=O)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:23]2[O:28][C:29]([CH3:30])([CH3:31])[C:33]([CH3:34])([CH3:35])[O:32]2)=[CH:10][CH:9]=[N:8]1
Reactant: c1cnn(C2CCCCO2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.), stirred solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (prepared as described in the literature: J. Med. Chem. 2004, 47, 2995-3008 and JOC 2008, 73, 4309-4312) (11.8 g, 78 mmol) in anhydrous THF (200 mL), 2.5 M n-BuLi in n-hexane (40 mL, 100 mmol) was slowly added, keeping T<−70° C. After addition the mixture was stirred at −78° C. for 1 h, then triisopropyl borate (23 mL, 100 mmol) was added dropwise, keeping T<−70° C. After addition the mixture was let to reach room temperature in about 2 h, then a solution of 2,3-dimethyl-2,3-butandiol (12.5 g, 105 mmol) in anhydrous THF (30 mL) was added, followed after 10 min by glacial acetic acid (6 mL, 100 mmol). The colorless jelly precipitate was filtered on a thick celite pad and washed thoroughly with diethyl ether. The filtrate was concentrated to yield a colorless oil that crystallized upon addition of n-heptane. The title compound was obtained as colorless crystalline powder (14.7 g, 53%).
Reaction SMILES: [CH3:1][CH:2]([C:7](=[CH:13][CH3:14])[C:8]([O:10]CC)=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>CO.O>[CH3:1][CH:2]([C:7](=[CH:13][CH3:14])[C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC=C(C(=O)OCC)C(C)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC=C(C(=O)O)C(C)CCCC
Yield: 98 %

Procedure:
Ethyl (2-hexyl)but-2-enoate (12 g, 0.06M) in methanol (150 ml) was treated with sodium hydroxide (15 g, 0.375M) in water (100 ml) under reflux for 6 hours. The solvents were then removed in vacuo and the residue taken up in water and extracted with dichloromethane. The aqueous phase was separted, acidified in pH1 with concentrated hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulphate and concentrated in vacuo to an oil which was distilled in vacuo to afford E and Z (2-hexyl)but-2-enoic acid (10.1 g, 0.06M) as the main fraction (b.p. 100°-110° C. at 0.5 mm Hg) (Found: C, 68.2; H, 10.4. C10H18O2 +0.5H2O requires: C, 68.5; H, 9.7%); δ(CDCl3) 0.88 (3H, m, CH3); 1.3 (8H, m, (CH2)4); 1.84 and 2.04 (3H, each m, each CH3CH); 2.32 (2H, t, J=8 Hz, CH2) 6.14 and 6.94 (1H, each q, each J=8 Hz, CH).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:30]=[CH:29][C:10]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:31][CH3:32])[CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C.Cl>C1COCC1>[C:25]([Si:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:11][C:10]1[CH:29]=[CH:30][C:7]([B:37]([OH:38])[OH:36])=[CH:8][C:9]=1[O:31][CH3:32])([CH3:27])([CH3:28])[CH3:26]
Reactant: COc1cc(Br)ccc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C., 140 ml n-BuLi (1.6 M in hexane, 223.8 mmol) in 600 ml THF are added to a solution of 89.92 g (203.4 mmol) (4-bromo-2-methoxy-phenoxy)-tert-butyl-diphenyl-silane over a period of 30 minutes. After further 30 minutes at −78° C., 140.9 ml (610.4 mmol) triisopropylborate are added over a period of 30 minutes. The mixture is allowed to warm up to room temperature and is then hydrolysed at 0° C. with a 10% HCl solution within 30 minutes. After separation of the water phase, the organic phase is dried over MgSO4, condensed and the residue is crystallized-from ethyl acetate and a mixture of ethyl acetate/heptane, yielding. 4-(tert-butyl-diphenyl-silanyloxy)-3-methoxy-phenyl-boronic acid is isolated as a light yellow solid (m.p. 193–196° C.).
Reaction SMILES: [Br:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[N:3]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1ccc(-n2c(Br)c(C#N)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 0 °C

Procedure:
2-Bromo-1-(4-methoxy-phenyl)-1H-indole-3-carbonitrile was dissolved in dry DCM and cooled to 0° C. 5 eq BBr3 (1.0 M solution in hexane) was added and the mixture was stirred over night. Still at 0° C., the reaction was quenched with the addition of MeOH. The mixture was diluted with H2O and the phases were partitioned. The organic phase was concentrated and the crude product purified on silica using n-heptane:EtOAc (4:1) as mobile phase. ES/MS m/z: 313, 315 (M+H), 311, 313 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.69 (m, 1H), 7.38-7.30 (m, 4H) and 7.16-7.10 (m, 3H).
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1>>[CH3:1][O:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1
Reactant: O=Cc1cccc2c1ccn2CC(O)c1ccccc1
Reactant: CI
Product: COC(Cn1ccc2c(C=O)cccc21)c1ccccc1
Yield: 93 %

Procedure:
The same procedures used in Example 324 were repeated except for using 113 mg of methyl iodide and 189 mg of 1-(2-hydroxy-2-phenylethyl)indole-4-carbaldehyde prepared in Example 321 as a starting material to give 185 mg of 1-(2-methoxy-2-phenylethyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][C@@H:13]2[CH2:12][C:11](=O)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][C@@H:13]2[CH2:12][CH:11]([NH2:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of (1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (0.9 g, 3.73 mmol) in methanol (112 mL) was added ammonium acetate (28.3 g, 373 mmol), stirred for 15 minutes at room temperature and sodiumcyano borohydride (1.87 g, 30.8 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine (89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the residual mass was quenched with water (50 mL) and the aqueous layer was extracted again with ethyl acetate (3×100 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 2.4 g of crude oil, which was purified by preparative HPLC to give 600 mg (66%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 0.92-0.99 (2H,m), 1.27 (1H,m), 1.78-1.83 (3H,m), 2.04-2.15 (2H,m), 2.57-2.74 (3H,m), 3.98-4.01 (1H,m), 7.11-7.14 (1H,m), 7.36-7.41 (2H,m). 13CNMR(CD3OD) δ: 145.92, 133.22, 131.50, 130.76, 129.77, 129.30, 127.57, 127.06, 54.35, 40.52, 37.67, 35.74, 34.36, 33.53, 31.10, 28.25, 26.08, 25.87, 18.50. Purity: 99.15% (a/a) by HPLC. MS, M+(241).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][N:8]([CH3:10])C.C(N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[CH3:19][O:18][C:16]([C:4]1[C:3](=[O:20])[N:8]([CH2:10][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C=CN(C)C)=C(C(=O)OC)C(=O)OC
Solvent: CCO
Product: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1C(=O)OC
Temperature: 25 °C
Yield: 104.6 %

Procedure:
A mixture of 5-dimethylamino-3-ethoxycarbonyl-2-methoxycarbonyl-penta-2,4-dienoic acid methyl ester (5 g, 17.5 mmol) and benzylamine (2 mL, 18.4 mmol) in EtOH (30 mL) was refluxed for 5 h. The mixture was cooled to r.t., concentrated in vacuo, and taken up in ether. The solution was washed with 1M HCl and water, and then dried over MgSO4. Evaporation of the solvent in vacuo afforded 5.77 g of the title compound as a viscous orange oil. MS: (+) m/z 338.06 (M+Na).
Reaction SMILES: C([O:8]C(N1CCC[C@H]1C(NC(P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1)CC1C=CC(C#N)=CC=1)=O)=O)C1C=CC=CC=1.Br.N1(C(OCC2C=CC=CC=2)=O)CCC[C@H]1C(O)=O.[CH2:64]1[CH2:69][CH2:68][CH:67]([N:70]=[C:71]=[N:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)[CH2:66][CH2:65]1>C(Cl)Cl.C(N(CC)CC)C>[C:71]([NH:70][CH:67]1[CH2:66][CH2:65][CH2:64][CH2:69][CH2:68]1)([NH:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N#Cc1ccc(CC(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: Br
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Diphenyl 1-(N-Benzyloxycarbonyl-L-prolyl)amino-2-(4-cyanophenyl)ethanephosphonate {Cbz-Pro-(4-CN-Phe)P (OPh)2 }. To a cooled solution of the phosphonate 4-CN-PheP (OPh)2.HBr (0.41 g, 0.9 mmole) and Cbz-Pro-OH (0.25 g, 1.0 mmole) in 20 mL CH2Cl2 was added 0.14 mL triethyl amine. After stirring for 10 min, DCC (0.21 g, 1.0 mmole) was added and the mixture was stirred at 0° C. for 2 h and at r.t. for 24 h. During this period, dicyclohexylurea (DCU) formed, was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 mL ethyl acetate, filtered, the filtrate was washed with 50 mL 1N HCl, water, 6% NaHCO3, and water. The organic layer was dried, filtered, and evaporated to give crude product which was then recrystallized from ether to give white crystals, yield 52% (0.29 g); mp 131-132° C.; 1H NMR (DMSO) δ 8.75(m, 1H), 7.8-7.2(m, 19H), 5.06 (m, 2H), 4.95 (m, 1H), 4.6 (q, 1H), 4.2 (m, 1H), 3.5-3.1 (m, 3H), 2.0-1.4 (m, 4H); MS (FAB+) m/e 610 (M+1). Anal. (C34H32N3O6P) C, H, N.