Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Product: CCOC(=O)C1(c2ccc(N3CCCC3)nc2)CC1
Temperature: 100 °C

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (69.8 mg, 0.309 mmol) and pyrrolidine (250.0 μL, 3.0 mmol) in a sealed tube was heated at 100° C. for 4 hours. Then the excess pyrrolidine in the mixture was removed under reduced pressure. The residue was purified by flash chromatography column to afford ethyl 1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([O:28]C)=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+]>CO.O>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]3)=[CH:19][CH:20]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OC)CC=CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)O)CC=CC2)cc1

Procedure:
A solution of the product of Step 5, above (5.76 g, 14.9 mmol) and lithium hydroxide monohydrate (6.23 g, 148 mmol) in 148 ml of methanol and 148 ml of water was heated at reflux for 2 hours. The reaction was then concentrated in vacuo, the residue was taken up in water and the pH was adjusted to 4 with concentrated HCl when the title compound precipitated as a colorless solid which was filtered off, dried in vacuo and recrystallized first from ethyl acetate/methanol, then from methanol to yield 1.9 g of title compound which was contaminated with 2.5% of 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]-2-vinylcyclopropane-1-carboxylic acid. Another recrystallization from methanol yielded 1.5 g of title compound, mp 232°-233° C., now about 98.3% pure, as determined by reverse-phase HPLC using a C-18 Beckman 25 cm long column and 30% pH 2.3 phosphate buffer in acetonitrile as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].C(NC(C)C)(C)C.[Li].[CH3:21][O:22][C:23](Cl)=[O:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:23]([O:22][CH3:21])=[O:24])[CH2:10][CH2:9][CH:8]([CH2:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC1CCC(C(=O)OC)CC1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC1CCC(C(=O)OC)(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A solution of 4-ethyl-cyclohexanecarboxylic acid methyl ester (10.4 g, 61.2 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamine (11.2 g, 92 mmol) in THF (90 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (8.7 g, 92 mmol) in THF (25 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL). THF was removed in vacuo and the aqueous residue was extracted with EtOAc (200 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a colorless liquid (14 g) with diisopropyl-carbamic acid methyl ester present. MH+229.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].Br[CH:16]([CH2:22][CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:16]([CH2:22][CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC)Oc1ccc(C2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 44.6 g of 4-(p-hydroxyphenyl)-tetrahydropyran in 50 ml of ethanol was added at 20° C to a mixture of 5.75 g of sodium in 250 ml of ethanol and the mixture was stirred for one hour and then was cooled to 0° C. 55.1 ml of ethyl 2-bromo-butyrate were added to the reaction mixture which was then allowed to return to 20° C and was refluxed overnight. The ethanol was evaporated and the residue was taken up in 50 ml of 1N sodium hydroxide and 250 ml of methylene chloride. The aqueous phase was decanted and was extracted again with methylene chloride. The organic phases were dried and evaporated to dryness to obtain 56.3 g of raw product which was rectified under reduced pressure to obtain 40 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-butanoate with a boiling point of 143° C. at 0.3 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12](N(OC)C)=[O:13])=[CH:11][C:6]=2[N:5]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:4]=1)[CH3:2].[CH3:23][Mg]Br>>[CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12](=[O:13])[CH3:23])=[CH:11][C:6]=2[N:5]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1cn(CCCOC)c2cc(C(=O)N(C)OC)ncc12
Product: CCc1cn(CCCOC)c2cc(C(C)=O)ncc12

Procedure:
3-Ethyl-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide and methylmagnesium bromide were treated in the similar manner to Reference Example 6(5) to give 1-[3-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(106-4)] as a pale yellow oil
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:12]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)n1nc(N)c2c(=O)[nH]ccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)n1nc(NC(=O)c2ccccc2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-1-tert-butyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (20.0 mg) obtained in Example 264 and pyridine (0.016 ml) in THF (3 ml) was added benzoyl chloride (0.023 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (28.8 mg).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:19]O>C(Cl)Cl>[C:1]1([C:7]23[O:19][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: OO
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
In a 50 mL flask equipped with a magnetic stirrer, 7.9 g (50 mmol) of 1-phenylcyclohexene and 63 mg (0.25 mmol, 0.5 mol %) of MTO are dissolved in 1.5 Molar CH2Cl2 and to this solution is added 0.48 mL (6 mmol, 12 mol %) of pyridine followed by 7.6 mL (75 mmol; 1.5 equivalents) of 30% aqueous H2O2 added dropwise from a syringe (circa 5-10 minutes). During the H2O2 -addition the temperature is kept at 20-25° C. by applying an external cooling bath. The reaction is complete after 6 h and the aqueous phase is seperated and discarded. The remaining H2O2 in the yellow organic phase is decomposed to O2 and H2O by stirring with a catalytic amount of MnO2 (circa 10 mg). After the yellow color has completely disappeared the mixture is dried over Na2SO4, concentrated, and purified by filtration through a short column of silica gel which has been deactivated with NEt3. The column is washed with hexane/CH2Cl2 and concentration of the eluate affords 7.9 g (91%) of 1-phenyl-1,2-epoxycyclohexane as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.S([C:27]#[N:28])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([C:27]#[N:28])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: COc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C#N)sc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzothien-7-yl methyl ether (1 g, 6.1 mmol) in THF (12 mL) at −78° C. was added a solution of 2.5 M n-butyllithium in hexanes (2.9 mL, 7.3 mmol). After stirring for 1.5 hr this solution was added dropwise to a solution of tosyl cyanide (1.66 g, 9.1 mmol) in THF (8 mL), this was left stirring at −78° C. for 0.5 hr and then warmed to room temperature. After 16 h this was poured onto ice-water and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo to give an oil. This was purified by flash chromatography with a gradient of 0–30% ethyl acetate in hexane to give the title compound (0.31 g, 27%); δH (300 MHz, CDCl3) 7.79 (1H, s, 3-ArH), 7.46–7.38 (1H, m, 4-ArH), 7.37–7.31 (1H, m, 5-ArH), 6.88–6.82 (1H, m, 6-ArH) and 3.94 (3H, s, OCH3). Starting material 1-benzothien-7-yl methyl ether was recovered from the reaction (0.56 g, 56%); δH (300 MHz, CDCl3) 7.45–7.29 (4H, m, ArH), 6.75 (1H, m, ArH), 4.00 (3H, s, OCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 72.9 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoate (346 mg, 0.77 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 245 mg (73% yield) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoic acid. MS found: (M+H)+=389.
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[CH2:4].[CH3:16][O:17][CH2:18][CH2:19]Br>C(O)C.O>[CH3:16][O:17][CH2:18][CH2:19][C:5]([CH2:2][CH:3]=[CH2:4])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COCCBr
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C=CCC(CCOC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Metallic sodium (15 g, 230 mmol) was dissolved in dry ethanol (250 mL) with cooling in an ice bath, under nitrogen, and diethyl allylmalonate (Lancaster Synthesis, Windham, Mass.) (105 g, 525 mmol) in absolute ethanol (50 mL) was added dropwise under nitrogen. The mixture was stirred at room temperature for 1 h. and 2-bromoethyl methyl ether (87.57 g, 630 mmol) in absolute ethanol (50 mL) was then added dropwise. The mixture was heated at reflux for 3 h and then cooled to room temperature. The precipitate solid was filtered and washed with ethanol (2×100 mL). The residue obtained upon concentration of the filtrate was diluted with water (1 L). The mixture was extracted with ether (2×150 mL), dried over MgSO4 and concentrated to give the diester ether 2 (118 g, 87%) as a viscous liquid. IR (KBr) υmax 3069, 2971, 2927, 1734, 1640, 1459, 1443, 1382, 1361, 1284, 1223, 1196, 1119, 1077, 1031, 922, 856 cm−1: 1HNMR (CDCl3) δ1.24 t, J=7.0 Hz, 6 H), 2.17 (t, J=6.4 Hz, 2 H), 2.68 (d, J=7.1 Hz, 2 H), 3.2 (s, 3 H), 3.41 (t, J=6.5 Hz, 2 H), 4.17 (dis q, 4 H), 5.04-5.12 (m, 2 H), 5.63-5.79 (m, 1 H); 13CNMR (CDCl3) δ13.98, 32.05, 37.31, 55.08, 58.52, 61.13, 68.34, 118.93, 132.49, 170.17; mass spectrum (EI), m/z (rel itensity) 259 (M++1.16), 227 (20), 213 (19), 200 (37), 185 (13), 167 (17), 154 (25), 153 (65), 139 (38), 125 (25), 108 (100), 81 (30), 79 (31), 67 (23), 59 (23), 53 (23).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21](=[O:22])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 75.6 %

Procedure:
A solution of 20.0 g (266.3 mmol) of 2-(methylamino)ethanol was dissolved in 100 mL of CH2Cl2 and treated first with 74.23 mL (532.54 mmol, 2 eq) of Et3N then with 33.8 mL (239.64 mmol, 0.9 eq) of benzylchloroformate within a period of 1.5 h at RT. The reaction was partitioned between Et2O (×3)/aqueous 10% KHSO4 (×2), dried over Na2SO4 and evaporated to yield 37.93 g (68%) of (2-hydroxy-ethyl)-methyl-carbamic acid benzyl ester, MS: 210 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:23](OC([O-])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O>[CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11][CH2:10]2)[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCCCN1C(=O)NC(=O)C12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCN1C(=O)NC(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of the compound prepared in Example 5 (326 mg) in water (3 mL) were added potassium carbonate and t-butyl dicarbonate (348 mg) subsequently, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, dried over an anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1→1:2) to give the title compound (419 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[C:12](N(OC)C)=[O:13])=[CH:4][CH:3]=1.[Li]C.[CH3:28]COCC>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[S:10][C:11]=2[C:12](=[O:13])[CH3:28])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide (1.79 g, 4.79 mmol) in THF (97 mL) at −20° C. was added a 1.60 M solution of MeLi in ether (4.19 mL, 6.70 mmol). The reaction was stirred for 30 minutes at −20° C. An additional portion of a 1.60 M solution of MeLi in ether (0.838 mL, 1.34 mmol) was added and the reaction was stirred for 30 more minutes at −20° C. The reaction was quenched by adding saturated ammonium chloride (25 mL) followed by water (35 mL). The mixture was extracted with ethyl acetate (2×150 mL) and the combined organic layers were dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100-40/20) to give 1.27 g (81% yield) of the title compound as a light yellow solid. LC/MS (FA) ES+ 329, 331. 1H NMR (300 MHz, CDCl3) δ: 8.75-8.73 (m, 2H), 7.83-7.81 (m, 2H), 7.34-7.31 (m, 2H). 7.26-7.23 (m, 2H), 4.53 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11]O)[N:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:32][C:33]1[N:37]([CH3:38])[N:36]=[N:35][N:34]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][S:32][C:33]2[N:37]([CH3:38])[N:36]=[N:35][N:34]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: Cn1nnnc1S
Reactant: CC(=O)c1cc(C)n(CCO)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)n(CCSc2nnnn2C)n1
Temperature: 5 °C
Reaction time: 4 h
Yield: 45.4 %

Procedure:
3-Acetyl-5-methyl-1-(2-hydroxyethyl)pyrazole (1.74 g), triphenyl-phosphine (4.071 g) and 5-mercapto-1-methyltetrazole (3.605 g) were dissolved in dry THF (125 ml) and cooled to 5° C. under an atmosphere of argon. A solution of diethylazodicarboxylate (2.70 g) in THF (25 ml) was added dropwise to the stirred, cooled solution. Stirring was continued at 5° C. for 4 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic solution was washed with NaHCO3 solution, brine, dried (MgSO4) and evaporated. Silica gel column chromatography provided the title compound (1.25 g), umax (CH2Cl2) 1683 cm−1; dH (CDCl3) 2.30 (3H, s), 2.55 (3H, s), 3.80 (2H, t), 3.92 (3H, s), 4.59 (2H, t), 6.51 (1H, s); m/z 266.0953 (M+), calculated for C10H14N6OS 266.0950.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10][C:11]1[S:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.Cl[Pd]Cl>[Br:10][C:11]1[S:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Br)s1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2ccc(Br)s2)n1

Procedure:
4-Iodo-2-methylsulfanyl-pyrimidine (2.5 g, 10 mmol), (5-Bromo-thiophen-2-yl)-tributyl-stannane (4.9 g, 11 mmol) and PdCl2 (702 mg, 1 mmol) were heated to 105° C. in toluene (30 ml) for 2 hours. The reaction mixture was poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via chromatography on silicagel (acetone/hexanes:0/100 to 3/97) to give the title compound as colourless foam. Yield: 1.6 g (55%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:36]1([C@H:42]([CH2:44][OH:45])[NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[OH:45][CH2:44][C@H:42]([NH:43][C:4](=[O:6])[CH:3]=[CH:2][C:1]([O:8][CH3:9])=[O:7])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=CC(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of monomethyl fumarate (3.0 g, 23 mmol) in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added (R)-α-phenylglycinol (3.0 g, 22 mmol) and stirring continued for 20 minutes. The volatiles were removed in vacuo (40° C.) and the residue purified by flash chromatography on normal phase silica gel using hexane:ethyl acetate (1:1) as eluant. Recovered 2.5 g (46%) of (18) as a white solid, m.p. 75°-77° C.; IR (neat) 3250 (OH), 1729 (C=O ester), 1666 (C=O amide), 1640 (C=C)cm-1 ; NMR (CDCl3) δ 7.3-7.4 (5H, m, Ph), 7.0 (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, br d, NH), 5.2 (1H, m, CH), 3.9 (2H, t, J 3 Hz, CH2), 3.8 (3H, s, CH3), 2.3 (1H, t, J 5 Hz, OH); [α]D -53° (CHCl3, 24° C., c=1); anal C13H15NO4 ; requires C 62.64% H 6.07% N 5.62%; found C 62.72% H 5.92% N 5.48%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.O.[NH2:23][NH2:24]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:24][NH:23]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 28.4 g of 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester [obtainable by dehydrating 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester employing p-toluenesulfonic acid] and 25 g of hydrazine hydrate (100% strength) in 400 ml of ethanol is boiled for 18 hours. The mixture is cooled, poured onto ice water and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH:27]=O)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[C:35]([O:39][C:40](=[O:45])[NH:41][CH2:42][CH2:43][NH2:44])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:35]([O:39][C:40]([NH:41][CH2:42][CH2:43][NH:44][CH2:27][CH2:26][CH2:25][CH:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=1[Cl:1])=[O:29])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:45])([CH3:38])([CH3:36])[CH3:37]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(CCC=O)COC(=O)Nc1cc2ccccc2cn1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(CCCNCCNC(=O)OC(C)(C)C)COC(=O)Nc1cc2ccccc2cn1
Temperature: 24 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-oxo-pentyl ester (0.8 g crude mixture, 1.64 mmol) in anhydrous DCE (3 mL) and AcOH (0.1 mL) was added (2-Amino-ethyl)-carbamic acid tert-butyl ester at 24° C. After 10 h of stirring at 24° C., sodium triacetoxyborohydride (1.05 g, 4.92 mmol) was added in one portion. The slurry was stirred for 2 h at 24° C., quenched with methanol and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 5-(2-tert-butoxycarbonylamino-ethylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (0.25 g, 25%) LRMS (M+H+) m/z 631.2.