Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:22])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CCNc2ccc(Cl)cc2N1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN1CCC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
20.4 g 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred for 2 hours on a water bath with 12.8 g methyl iodide and 10 g anhydrous potassium carbonate. The inorganic material is removed by filtration under suction and the filtrate is diluted with 200 ml water. The crystalline precipitate is filtered under suction, washed with water, and recrystallized from alcohol. The yield is 20 g of the m.p.=143° C.-144° C. (93% of the theory).
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][PH+](C)C.[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]>COCCOC>[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[CH2:4])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: C[PH+](C)C
Reactant: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Into a three-necked flask, 12.1 g of sodium hydride and 580 ml of 1,2-dimethoxyethane were placed, and 108.5 g of trimethylphosphonium bromide was added thereto with stirring at room temperature. Next, after a drop of absolute alcohol was added, the reaction was allowed to proceed at 70° C. for 4 hours. Then, 100.0 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]benzaldehyde was added to the reaction mixture, to carry out reaction at 700° C. for 5 hours, followed by filtration to collect a cake. The cake was extracted with ether and the extract was put together with the filtrate and washed with water. Then, the ether solution was dehydrated with calcium chloride, and thereafter the ether was removed to obtain a crude product. After twice recrystallized from ethanol, acicular 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was obtained in an amount of 84.5 g (yield: 85.0%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1.CN(C)CCN(C)CCN(C)C.CCOC(C)=O>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To 118B (625 mg, 2.46 mmol) in THF (10 mL) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.77 mL) was added n-BuLi (1.6M in hexane, 1.77 mL) at −78° C. After stiiring for 45 min at −35° C., DMF (0.94 mL) was added at at −78° C. and the reaction was slowly warmed up to rt. The mixture was stirred at rt for 1 h, diluted with EtOAc. The organic extracts were washed with saturated NaHCO3, brine and dried. The crude product was purified by column chromatography to give 118C (615 mg, 89% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.21 (s, 6H) 1.01 (s, 9H) 1.21 (t, J=7.47 Hz, 3H) 2.59 (q, J=7.47 Hz, 2H) 6.99 (dd, J=7.91, 2.20 Hz, 1H) 7.21-7.27 (m, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][C:38]([Cl:44])=[CH:39][CH:40]=3)[N:35]=2)[CH:27]=1)[OH:25])(=[O:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]2[C:41]([CH:42]=[CH:43][C:34]([CH:33]=[CH:32][C:28]3[CH:27]=[C:26]([C@H:24]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:13](=[O:15])[CH3:14])[CH:31]=[CH:30][CH:29]=3)=[N:35]2)=[CH:40][CH:39]=1
Reactant: CC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1CC[C@@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
At -40° C., methanesulfonyl chloride (1.25 mL, 16.2 mmol) and Et3N (2.8 mL, 20 mmol) were added successively to a solution of the hydroxyketone of Step 4 (6.157 g, 13.44 mmol) in 135 mL of CH2Cl2 and the mixture was stirred at -40° C. for 30 min., then at 0° C. for an hour. A saturated solution of NaHCO3 was added and the title mesylate was extracted into CH2CL2, dried over Na2SO4, concentrated and the remaining traces of water were co-evaporated twice with toluene. This mesylate was used as such in Step 7.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>>[CH3:23][C:22]1([CH3:26])[CH2:25][O:20][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:21]1
Reactant: CC(C)(N)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC1=NC(C)(C)CO1
Yield: 79.7 %

Procedure:
Following example 8, 14.9 g (52.4 mmoles) of octadecanoic acid and 9.34 g (104.8 mmoles) of 2-amino-2-methylpropanol gave 14.1 g (79.7%) of product, b.p. 140°-143° C./0.01 mm Hg.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3=[C:25]4[C:20]([C:21](=O)[CH2:22][CH2:23]3)=[CH:19][CH:18]=[CH:17][N:16]4[CH:15]=2)=[CH:10][CH:9]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3=[C:25]4[C:20]([C:21](=[CH2:1])[CH2:22][CH2:23]3)=[CH:19][CH:18]=[CH:17][N:16]4[CH:15]=2)=[CH:10][CH:9]=1
Reactant: O=C1CCc2c(-c3ccc(Cl)cc3)cn3cccc1c23
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCc2c(-c3ccc(Cl)cc3)cn3cccc1c23
Reaction time: 3 h

Procedure:
Methyltriphenylphosphonium bromide (3.8 g) was added to 25 ml of anhydrous tetrahydrofuran. To this mixture was added the solution of potassium t-butoxide (1.2 g) in 25 ml of tetrahydrofuran at ambient temperature. After stirring for 3 hours, to this solution was added the solution of 1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one (1.5 g), which was obtained in example 2, in 15 ml of tetrahydrofuran. After stirring for 30 min., to this solution was added water and extracted with ethyl acetate. The organic solution was washed with brine and dried over anhydrous sodium sulfate. After removing drying agent by filtration and organic solvent by evaporation under reduced pressure, the residue was purified by alumina column chromatography, and the title compound was obtained as yellow crystals (1.1 g) .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11](O)[C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:21])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([Cl:21])[C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])cc1OC

Procedure:
A mixture of 6.2 g of 1-(3,4-dimethoxyphenyl)-2-methyl-2-nitropropanol, 3 ml of thionyl chloride and 40 ml of anhydrous benzene is refluxed for 4 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (dark brown oil) is distilled at 145° C. under reduced pressure (0.15 mm Hg). 4.6 g of 1-(3,4-dimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane are thereby obtained as pale yellow prisms.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14](=O)[CH3:15])[CH:13]=1.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14]([CH3:1])=[CH2:15])[CH:13]=1
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (58.92 g, 162 mmol) in tetrahydrofuran (400 ml) was treated at room temperature with potassium tert-butylate (18.51 g, 162 mmol), and the mixture was stirred for 30 minutes. While cooling with ice, a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone [CAS No. 198477-83-3] (29.23 g, 135 mmol) in tetrahydrofuran (50 ml) was added. Thereafter, the mixture was warmed to room temperature and stirred for 1.5 hours. For the workup, the mixture was treated with ethyl acetate (650 ml) extracted with water (450 ml). The organic layer was separated, washed with brine (220 ml), dried over sodium sulfate and evaporated at reduced pressure. After chromatography on silica gel using a mixture of hexane and ethyl acetate as the eluent, the 4-bromo-1-fluoro-2-isopropenyl-benzene (intermediate C2A) was obtained as a yellow oil (28.49 g, 98% of theory). Rf: 0.7 (silica gel; eluent: heptane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[CH:8]=[CH2:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:8]=[CH2:7]
Reactant: C1CCNCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The piperidine from Example 114 (56 mg, 0.15 mmol) was dissolved in dimethylformamide (2 mL) and was treated with allyl bromide (17 μL, 0.18 mmol), and potassium carbonate (63 mg, 0.45 mmol) and the mixture was stirred at r.t. for 4 hrs. The mixture was diluted with water (2 mL) and the solution washed with ethyl acetate (3×10 mL). The organic phase was dried (MgSO4) and evaporated to give a pale oil which was purified by column chromatography on silica gel eluting with 80% ethyl acetate in hexanes to give the N-allylpiperidine. 1H NMR (CDCl3) 7.42-7.37 (4H, m), 7.13-7.02 (2H, m), 6.90-6.83 (1H, m), 5.83-5.71 (1H, m), 5.12-5.08 (2H, m), 2.99-2.95 (2H, m), 2.86 (2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and 1.91-1.85 (2H, m); MS MH+=412(414).
Reaction SMILES: C1([Li])C=CC=CC=1.[C:8]1([S:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)=[CH:23][CH:22]=1>O.O1CCCC1>[C:8]1([S:14][CH2:15][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CCCCCCI)cc1
Reactant: CSc1ccccc1
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCCCCCSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyllithium (378 ml., 0.755 mole) was added over a period of 2-5 minutes to a solution of 94.5 g. of thioanisole in 600 ml. of tetrahydrofuran, stirred under nitrogen. The mixture was stirred at room temperature for about 16 hours, then cooled to -70° C. (solid CO2), and 141 g. of 6-(4-methoxyphenyl)hexyl iodide in 210 ml. of tetrahydrofuran was added slowly. The reaction mixture was stirred at -65° C. for two hours and then allowed to warm to room temperature. Water was added and the mixture extracted with pentane. The pentane extracts were washed with water, dried and concentrated to remove the solvent. The residue was distilled in vacuo, b.p. 171°-174° C. (0.15 mm.). The distillate crystallized and was recrystallized from pentane, to give 7-(4-methoxyphenyl)heptyl phenyl sulfide, m.p. 58°-59° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: CC(C)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 4-isopropoxy-phenylamine as a mixture of cis and trans diastereomers. White solid. MS (m/e): 304.190 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14](C(N[C@@H](C3C=CC=CC=3)C)=O)[C:13]([O:26][CH3:27])=[N:12][C:11]([CH2:28][CH3:29])=[C:10]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].N12CCCN=C1CCCCC2>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13]([O:26][CH3:27])=[N:12][C:11]([CH2:28][CH3:29])=[C:10]2[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)N[C@H](C)c2ccccc2)C(OC)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
Into a stirred solution of (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH2Cl2 was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 5.27 g of the (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate was obtained (77% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:14](O)[CH:15]=[CH2:16].C(B(CC)CC)C>C1COCC1.C(OCC)(=O)C.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>[CH2:16]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)[CH:15]=[CH2:14]
Reactant: C=CCO
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCB(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCc1c[nH]c2cccc(C(=O)OC)c12
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a stirring mixture of methyl indole-4-carboxylate (5.20 g, 29.68 mmol), allyl alcohol (2.02 mL, 29.68 mmol), and triethyl borane (1.0M solution in THF, 8.90 mL, 8.90 mmol) in THF (120 mL) at room temperature under an atmosphere of nitrogen was added Pd(PPh3)4 (1.71 g, 1.48 mmol). The mixture was heated at 70° C. for 16 h then cooled to room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution (200 mL), brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) afforded methyl 3-allyl-1H-indole-4-carboxylate (5.61 g, 88%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.44 (bs, 1H), 7.59 (m, 1H), 7.44 (m, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.05 (m, 1H), 5.00 (m, 2H), 3.96 (s, 3H), 3.64 (m, 2H); MS (ESI+) m/z 150 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3-fluorophenylboronic acid (39 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([OH:11])=O.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[CH3:2])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1CCCN1CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC1CCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 47 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methylpyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 63, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methylpyrrolidin-1-yl)acetamido)propanamide (19 mg, 47%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.93 (t, 1H), 7.60 (d, 2H), 7.29 (m, 5H), 7.19 (m, 2H), 7.00 (m, 4H), 4.73 (s, 1H), 4.52 (s, 2H), 3.69 (m, 2H), 3.05 (m, 1H), 2.82 (m, 1H), 2.46 (m, 1H), 2.23 (m, 1H), 1.91 (m, 1H), 1.67 (m, 2H), 1.33 (m, 1H), 1.03 (d, 3H). MS (EI) for C29H32FN3O4: 506.5 (MH+).
Reaction SMILES: [C:1]1([SnH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:14]1([Sn:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:22][CH2:21][C:20]#[N:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Reactant: C=CC#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: N#CCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 100 %

Procedure:
9.1 g of the triphenyltin hydride (0.026 mol), prepared in the aforementioned example (1), 2.8 g of acrylonitrile (0.052 mol), 85 mg of 2,2'-azobisisobutyronitrile, and 25 ml of toluene were mixed together in a 100 ml four-neck flask equipped with a stirrer and reflux condenser, and stirred while heating for 6 hours at 60° C. After it was confirmed by means of an IR spectrum that the absorption of Sn-H bonds had completely disappeared, a crystal precipitate was separated by filtration. The filtrate was then concentrated under reduced pressure to yield 10.5 g of the final product of 3-(triphenylstannyl)propionitrile (yield=100%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a12) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][C:51]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][N:53]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:52][C:51]=12
Reactant: c1nc2n(n1)CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2ncnc2C1
Reaction time: 20 h
Yield: 21 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by “patent application WO2009090055”) and N,N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:13]=[S:14].Cl.[NH2:16][NH:17][C:18](N)=[NH:19].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:19][C:18]1[N:12]([C:3]2[C:4]([CH3:11])=[CH:5][C:6]([CH:8]3[CH2:9][CH2:10]3)=[CH:7][C:2]=2[Cl:1])[C:13]([SH:14])=[N:16][N:17]=1
Reactant: Cc1cc(C2CC2)cc(Cl)c1N=C=S
Reactant: N=C(N)NN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CC2)cc(Cl)c1-n1c(N)nnc1S
Temperature: 50 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Compound 3 (935 mg, 4.2 mmol) was dissolved in 5 mL of dimethylformamide, aminoguanidine hydrochloride salt (695 mg, 6.3 mmol) and diisopropyl ethylamine (1.1 mL, 6.3 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (20 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(2-chloro-4-cyclopropyl-6-methylphenyl)-4H-1,2,4-triazole-3-thiol (4). (780 mg, 66% yield)