Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(O)(=O)C>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[Cl:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCOC(=O)c1c(Cl)cccc1OC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OC)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 6-chloro-2-methoxybenzoate (1.8 g, 8.4 mmol), bromine (1.41 g, 8.8 mmol) and acetic acid (5 ml) is stirred at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated and the residue is purified by column chromatography (petrol ether: ethyl acetate, 95:5 v/v) yielding the pure product as a yellow oil, 1.7 g, (69%).
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[N:14]=[C:13]([CH2:15]Cl)[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:21][OH:22]>>[N:3]1([C:9]2[N:14]=[C:13]([CH2:15][O:22][CH3:21])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: COC(=O)c1cnc(N2CCCCC2)nc1CCl
Agent: [H-]
Agent: [Na+]
Product: COCc1nc(N2CCCCC2)ncc1C(=O)OC
Reaction time: 3 h
Yield: 44 %

Procedure:
Sodium hydride (0.19 g; 7.8 mmoles) was added to 50 ml of methanol, and 2.1 g (7.8 mmoles) of 2-piperidino-4-chloromethyl-5-methoxycarbonylpyrimidine was added at room temperature. The mixture was stirred for 3 hours. After the solvent was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.90 g (yield 44%) of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Yield: 57.1 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (864 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (913 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (948 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:14]([NH:21][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CCC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of 5-methoxy-2-tetralone (30 g, 170.24 mmol) dissolved in CH2Cl2 (250 mL) were added benzylamine (23 mL, 212.80 mmol) and AcOH (0.97 mL, 17.02 mmol), and the mixture was stirred for 4 h at room temperature. It was then cooled to 0° C. and NaB(OAc)3H (0.38 eq, 13.71 g, 64.69 mmol) was added over a period of 20 min. After 1 h stirring at 0° C., NaB(OAc)3H (1.07 eq, 38.61 g, 182.16 mmol) was added over a period of 30 min. It was added CH2Cl2 (100 mL), the reaction mixture warmed to room temperature and stirred for 15 h. The mixture was cooled again to 0° C., and H2O (200 mL) was added slowly. The pH of the solution was adjusted to 8.0 by adding NaHCO3 saturated aqueous solution (300 mL), and the mixture was stirred at 0° C. for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2×150 mL). All organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (58.7 g) was purified by flash chromatography on silica gel (40:60:1-100:0:1 AcOEt/Hexane/Et3N), followed by trituration with hexane, affording 33.87 g of the title compound (Rf=0.5 (10% MeOH/CH2Cl2), yellow solid, 74% yield).
Reaction SMILES: [Br-:1].[CH:2]1([C@@:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N+:14]([CH3:26])([CH2:17][CH2:18]CC3C=CC=CC=3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].OC1CC[N+](C)(CCCC2C=CC=CC=2)CC1.[Br-].OC1CC[N+](C)(CC[O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)CC1>>[Br-:1].[CH:2]1([C@@:7]([OH:33])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N+:14]([CH3:26])([CH2:17][CH2:18][O:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:15][CH2:16]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(CCCc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Reactant: C[N+]1(CCOc2ccccc2)CCC(O)CC1
Agent: C[N+]1(CCCc2ccccc2)CCC(O)CC1
Agent: [Br-]
Product: C[N+]1(CCOc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1

Procedure:
This compound is prepared by an analogous method to 4-((R)-2-Cyclopentyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Example 9) by replacing 4-Hydroxy-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Intermediate K) with 4-hydroxy-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (Intermediate L).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (3.80 g, 0.00834 mol) in 67 mL of THF was added 13 mL of water followed by 13 mL of 1 N HCl. The mixture was stirred at rt for 1 h. After diluted with ethyl acetate, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue after concentration was purified on column, eluting with 0 to 50% EtOAc in hexane, to generate the corresponding alcohol compound (2.90 g, 90.6%). MS (ESI): (M+H)+=384.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]12([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH:25]=O)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>ClCCl>[C:12]12([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH:25]=[N:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(N=Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
3 g of basic alumina and 1.94 g (12.9 mmoles) of methyl 4-aminobenzoate are mixed in a mortar, then introduced into a round bottom flask. 3 g (11.1 mmoles) of 3-(1-adamantyl)-4-methoxybenzaldehyde in 50 ml of anhydrous dichloromethane are added with stirring. After heating at reflux for 24 hours, the reaction medium is extracted with dichloromethane and evaporated to dryness. The crude product is recrystallized in a mixture of ethyl acetate and acetone. After filtration, 3.4 g (75%) of the expected product whose melting point is 180°-182° C. are obtained.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.O([CH3:21])[Na]>C1COCC1>[C:13]1([CH:17]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:14]=[CH:15][CH:16]=[CH:21][CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: CO[Na]
Reactant: O=C(CO)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 57 %

Procedure:
2.36 g (17.3 mmol) of 2-hydroxyacetophenone, 1.7 g of 3-pyridine-carboxaldehyde (15.9 mmol), and 9 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 2.05 g (57%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.66 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.67 (d, d, J=1.5, 4.8 Hz, 1H), 8.03-8.00 (m, 1H), 7.92 (d, J=15.7 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.76 (d, J=15.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.43 (d, d, J=5.1, 8.1 Hz, 1H), 7.07 (d, d, J=0.9, 8.1 Hz, 1H, 6.99 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][C@H:25]1[O:30][C@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:27]3[CH2:26][C@@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Temperature: 85 °C

Procedure:
To an ice cooled solution of 3-chloro-6,7-difluoro-1,2-benzoxazole-5-carbaldehyde (prepared according to the procedure described in International Application Publication No. WO 2010/043893, 10.0 g, 46.0 mmol) in anhydrous acetonitrile (50 mL) was added diisopropylethylamine (11.9 g, 91.9 mmol) followed by (2R,6R)-2,6-dimethylmorpholine (5.2 g, 46.0 mmol) and the mixture was heated at 85° C. for 12 hours in a sealed tube. After cooling to room temperature, the volatiles were removed under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (2×15 mL) followed by brine and then dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product that was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give title compound as solid. Yield: 11.0 g (76%). 1H NMR (400 MHz, DMSO-d6) δ: 1.2 (d, 6H), 3.0 (m, 2H), 3.4 (m, 2H), 4.1 (m, 2H), 8.0 (s, 1H), 10.3 (s, 1H). ES MH+: 313.3 for C14H14ClFN2O3.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:13])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]=[C:3]1[S-:14].[K+].NC1SC(C)=C(C)C=1C(OCC)=O.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1.C(O)C>C(Cl)(Cl)Cl>[NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:13])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]=[C:3]1[S:14][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1
Reactant: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: Cc1sc2nc([S-])n(N)c(=O)c2c1C
Agent: CCOC(=O)c1c(N)sc(C)c1C
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1sc2nc(SCCCN3CCN(c4ccc5ccccc5n4)CC3)n(N)c(=O)c2c1C
Yield: 49.7 %

Procedure:
A mixture of 80 mg of potassium 3-amino-5,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-thiolate, which was prepared from ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate; 104 mg of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline as prepared in the Step 1-1-B; and 5 ml of ethanol, was heated under reflux for 4.5 hours. After cooling off the reaction mixture, chloroform was added, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=100: 1) to provide 72 mg (50%) of 3-amino-5,6-dimethyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3H-thieno[2,3-d]pyrimidin-4-one.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][C@@H:9]3[CH3:24])[CH2:6][CH2:5]1)[CH3:3].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:24][C@H:9]1[CH2:10][C@@H:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:23])[NH:12]2)[C@@H:18]2[C@@H:8]1[C@H:7]1[C@:21]([CH3:22])([CH2:20][CH2:19]2)[C@@H:4]([C:2](=[O:1])[CH3:3])[CH2:5][CH2:6]1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 20-hydroxy-7β-methyl-5α-4-azapregnan-3-one (22.3 gms, 67 mmol, product of Step 10) in dry methylene chloride under nitrogen (110 mL) was added 4-methyl morpholine N-oxide (11.8 gms, 100 mmol) followed by 4Å molecular sieves (33 gm). To this mixture was added tetrapropylammonium perruthenate (1.2 gm). After stirring at room temperature for 4 h, the reaction mixture was poured through pad of silica gel in a 300 mL sintered glass funnel which was subsequently eluted with 4:1 ethyl acetate/methylene chloride (5 L). The solvent was removed by rotoevaporation and the title compound recrystallized.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 95° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[O:17][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)=[CH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:38]>>[ClH:38].[C:1]([C:9]1[CH:10]=[C:11]2[O:17][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)=[CH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2ncc(C(=O)c3ccccc3)cc2o1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(c1ccccc1)c1cnc2cc([C@H]3CCCN3)oc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
6-(benzoyl)-2-(1-Boc-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine is dissolved in CH2Cl2 (10 mL). The mixture is cooled to 0° C., TFA (10 mL) is added and the reaction is stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture is basified with 15% NaOH and extracted with CH2Cl2 (200 mL), which is dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et2O, cooled to 0° C., and treated with HCl in EtOH to afford the hydrochloride salt.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:11]([CH2:15][CH3:16])[C:12](Cl)=[O:13])[CH3:10].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:9]([N:11]([CH2:15][CH3:16])[C:12]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:13])[CH3:10]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylthio-1,2,4-triazole, 7.5 g. diethylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 7.75 ml. dry triethylamine was refluxed under anhydrous conditions for 22 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 110° - 111°C./0.2 mm. (93.6% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1(C)[CH:28]=[CH:27][C:17]([CH2:18]SC(=S)N(CC)CC)=[CH:16][CH:15]1[CH3:29].[OH-].[Na+].[CH:33](O)(C)C>O>[CH3:33][C:28]1[CH:27]=[C:17]([CH:16]=[C:15]([CH3:29])[C:14]=1[OH:13])[CH2:18][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[O:12]
Reactant: CCN(CC)C(=S)SCC1=CC(C)C(C)(O)C=C1
Reactant: O=c1[nH]nc(-c2ccccc2)o1
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cn2nc(-c3ccccc3)oc2=O)cc(C)c1O
Temperature: 60 °C
Reaction time: 9 h

Procedure:
40.5 g of 5-phenyl-1,3,4-oxadiazol-2-one (.25 mol) and 71 g of N,N-diethyl-dithiocarbamic acid (4-hydroxy-3,4-dimethylbenzyl) ester (0.25 mol) are dissolved in 500 ml of isopropanol at 60°C. After dropwise addition of 10 g of sodium hydroxide in 100 ml of water, the mixture is stirred for 9 hours at 60°C. The solvent is then largely evaporated off, the yellow residue is dissolved in acetonitrile, insoluble matter is filtered off and the mother liquor is again evaporated. The residue, which crystallises slowly, is recrystallised from methanol. 3-(3,5-Dimethyl-4-hydroxybenzyl)5-phenyl-1,3,4-oxadiazol-2-one (stabiliser No. 16) of melting point 135°C is thus obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.CN(C=O)C.CCN(CC)CC>[CH2:1]([N:3]([CH2:6][C:7]#[C:8][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2)[CH2:4][CH3:5])[CH3:2]
Reactant: C#CCN(CC)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N,N-diethyl propargylamine (38 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-[3-(N,N-diethylamino)-1-propynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 42%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:18]([C:36]([O:38]CC)=[O:37])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+]>C(O)C.O1CCCC1.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:18]([C:36]([OH:38])=[O:37])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
In a mixed solvent of ethanol (1 ml), tetrahydrofuran (1 ml) and water (1 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride (152 mg) obtained in Example 2 was dissolved under ice cooling, followed by the dropwise addition of a 1N aqueous solution of sodium hydroxide. The reaction mixture was stirred at room temperature for 90 minutes. After concentration under reduced pressure, 1N hydrochloric acid was added to the reaction mixture to make it weakly acidic. The colorless solid so precipitated was collected by filtration, followed by drying, whereby the title compound (62 mg, 42%) was obtained as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC.CCOC(C)=O>[OH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CCC/C=C\CO

Procedure:
Lindlar catalyst (palladium on calcium carbonate, poisoned with lead; 60 mg) was added to a solution of alkyne 38 (1.26 g, 8.07 mmol) in 2:1 hexane/EtOAc at 0° C. Hydrogen was bubbled through the reaction mixture until TLC analysis indicated the disappearance of 38 (2-3 h). The mixture was filtered and concentrated to yield 39 was a colorless liquid (1.277 g, 100%): IR (neat) 3410 (br), 3015 (w), 2940 (s), 2860, 1740 (s), 1435,, 1365, 1245, 1205, 1155, 1025, 1000 cm-1 ; 1H NMR (CDCl3) δ 5.66 (ddt, J1 =10.9 Hz, J2 -6.8 Hz, J3 =1.4 Hz, 1H), 5.44 (dtt, J1 =10.9 Hz, J2 =7.5 Hz, J3 =1.3 Hz, 1H), 4.15 (dd, J1 =6.7 Hz, J2 =1.1 Hz, 2H), 3.66 (s, 3H), 2.32 (t, J=7.3 Hz, 2H), 2.12 (dq, J1 =7.5 Hz, J2 =1.1 Hz, 2H), 1.99 (br, 1H), 1.71 (p, J=7.3 Hz, 2H9. A minor amount (ca. 3%) of methyl trans-7-hydroxy-5-heptenoate could be seen in the 1H NMR spectrum at δ 4.09. The longer the reaction proceeded beyond completion, the greater the amount of this product was produced.
Reaction SMILES: [CH:1]([P:3](=[O:6])([OH:5])[OH:4])=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+].[H][H]>O.[Pd]>[P:3]([CH2:1][NH:7][CH2:8][C:9]([OH:11])=[O:10])([OH:5])([OH:4])=[O:6]
Reactant: O=CP(=O)(O)O
Reactant: [H][H]
Reactant: NCC(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Yield: 90.1 %

Procedure:
To a 59% aqueous formylphosphonic acid solution (5.0 g; 0.23 mol) in deionized water (25 ml) was added glycine (1.56 g; 0.021 mol). The pH of the resultant mixture was adjusted to 7.0 by addition of 2.5N sodium hydroxide. The reaction mixture was then transferred to a 300 ml autoclave, a 10% palladium on carbon catalyst (1.0 g) added, and the reactor sealed and pressurized with hydrogen to 6.89×106N/m2 gauge. After 60 minutes of reaction at room temperature, 3.2 g of N-phosphonomethylglycine was obtained representing a 91% yield on glycine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[N:12]=1.C(OCC)(=O)C>C1COCC1.O>[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:12]=1)#[N:18]
Reactant: N#Cc1cccc(Cl)n1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Sc2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Mercaptopyridine (0.88 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were dissolved in THF (30 ml), and the mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.54 g, ca. 100%) as an oil.