Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])I.I[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>[Zn].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.C1COCC1>[CH2:26]([CH:23]1[CH2:22][CH2:21][CH:20]([CH:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]([F:5])=[C:2]([F:6])[F:1])=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24]1)[CH2:27][CH3:28]
Reactant: CCCC1CCC(C2CCC(c3ccc(I)cc3)CC2)CC1
Reactant: FC(F)=C(F)I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(c3ccc(C(F)=C(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (77 mmol) of zinc powder, 50 ml of THF and 13.5 g (65 mmol) of trifluoroiodoethylene is stirred overnight, initially with ice cooling, later at room temperature. 20.5 g (50 mmol) of 1-iodo-4-[4-(4-propylcyclohexyl)cyclohexyl]benzene and 1.1 g-of tetrakis(triphenylphosphine)palladium are then added.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]2[CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cn2cnc(Cl)cc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
4-Amino-6-chloropyrimidine (100 mg, 0.772 mmol) was suspended in DMF (0.5 mL), and the suspension was stirred overnight at 50° C. after adding 1-bromo-3-methylbutan-2-one (153 mg, 0.920 mmol) and molecular sieve 4A (200 mg). The reaction mixture was allowed to cool to room temperature. After adding a sodium hydrogen carbonate aqueous solution, the mixture was filtered through Celite (registered trademark), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=98/2) to give 7-chloro-2-isopropylimidazo[1,2-c]pyrimidine (64.7 mg, yield 43%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl.O.O.Cl[Sn]Cl.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:15][C:10](=[O:11])[CH:9]([CH2:13][CH3:14])[NH:8]2
Reactant: CCC(Nc1cccc(Cl)c1[N+](=O)[O-])C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCC1Nc2cccc(Cl)c2NC1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2-((3-chloro-2-nitrophenyl)amino)butanoic acid (1.5 Kg, 5.8 mol), 4 N aq. HCl (4.35 L, 17.4 mol) and EtOH (5.3 L) was added SnCl2.2H2O (3.93 Kg, 17.4 mol). The reaction mixture was heated to reflux for 5 h. At this time LC-MS analysis showed that the reaction was complete. After cooling to rt the reaction mixture was evaporated under reduced pressure. The resulting residue was cooled to 0° C. using an ice-water bath and an aqueous solution of 10 N KOH (12 L, 180 mol) was carefully added with vigorous stirring. After filtration to remove insoluble solids, the filtrate was extracted with DCM (2×10 L) washed with water, brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 8-chloro-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one (1.1 Kg) as a yellow solid, which was used without further purification. 1H NMR (DMSO-d6) δ ppm 9.70 (s, 1H), 6.65-6.83 (m, 3H), 6.31-6.44 (m, 1H), 3.66-3.72 (m, 1H), 1.53-1.71 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). Mass Spectrum (ESI) m/z=211.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:26]>C1COCC1.O>[C:18]([O:17][C:15]([NH:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([OH:26])=[O:22])=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution (S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-3,3-dimethyl-2-oxopyrrolidine-1-carboxylate (2.7 g, 7.56 mmol) in THF (27 mL) and water (3 mL) was added LiOH (1 N, 15.2 mL, 15.2 mmol). The reaction mixture was stirred at RT overnight and concentrated. The residue was dissolved in water (20 mL), acidified with 10% citric acid to pH 6-7, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoic acid (2.6 g, 91.7%), which was used without further purification. LRMS (M−Boc+H+) m/z 276.2.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:3]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[O:2]
Reactant: COC=C1CCc2cc(C#N)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)CCC2C=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(Methoxymethylene)indane-5-carbonitrile (1.5 g, 8.1 mmol) in DCM (40 mL) was added BBr3 (6 g, 24 mmol) at −78° C. The mixture was stirred for 3 hours at −78° C. Then water was added. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude 1-Formylindane-5-carbonitrile, which was used for next step without further purification. MS m/z: 172 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>COCCOC>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:29]#[N:30])[CH:36]=2)=[C:16]([F:21])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCN(Cc1ccc(Br)c(F)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCN(Cc1ccc(-c2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 78.8 %

Procedure:
(4-Bromo-3-fluoro-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5c: 1.5 g, 4.00 mmol) was dissolved in 1,2-dimethoxyethane (15 ml) under nitrogen. Palladium tetrakis(triphenylphospine) (5 mol %) was added followed by an aqueous 2 M sodium carbonate solution (7 ml) and 3-cyano-phenyl boronic acid (0.883 g, 6.01 mmol) was added. The reaction mixture was heated at reflux for 24 hours before being cooled to room temperature and filtered through Celite, rinsing with dimethoxyethane. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford 1.25 g (78%) of title product (I-5d).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[N:16]12[CH2:17][CH2:18][CH:19]([CH2:20][CH2:21]1)[CH:14]([O:13][C:12]1[CH:22]=[CH:23][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:15]2
Reactant: c1ccc(COc2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(OC2CN3CCC2CC3)cc1
Yield: 84 %

Procedure:
The product of Example 15A (1.20 g, 3.9 mmol) in ethanol (20 mL) was treated with Pd/C (Aldrich, 10% wt., 0.2 g) under H2 at ambient temperature for 10 hours. The mixture filtered through a short column of diatomaceous earth and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless oil (0.72, yield, 84%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.75 (m, 1H), 1.80–1.92 (m, 1H), 2.00–2.30 (m, 2H), 2.76–3.02 (m, 5H), 3.25–3.35 (m, 1H), 4.40 (m, 1H), 6.60–6.80 (m, 4H) ppm. MS (DCl/NH3) m/z 220 (M+H) +.
Reaction SMILES: [CH3:1][O:2][C:3]1=[C:4]([CH3:45])[C:5](=[O:44])[O:6]/[C:7]/1=[CH:8]/[C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33]C(=O)CC3C=CC=CC=3)[C:31](=[O:43])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:13]2[C:14]([C:15]([O:17][CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:9](/[CH:8]=[C:7]3\[C:3]([O:2][CH3:1])=[C:4]([CH3:45])[C:5](=[O:44])[O:6]\3)[CH2:10][S:11][C@H:12]12
Reactant: COC1=C(C)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC1=C(C)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Diphenylmethyl 3-(E-2,5-dihydro-4-methoxy-3-methyl-2-oxofuran-5-ylidenemethyl)-7β-phenylacetamidoceph-3-em-4-carboxylate (0.47 g), in dry dichloromethane (5 mls) was cooled to -20° C. under argon. This was treated with N-methylmorpholine (0.183 mls) and then a solution of phosphorous pentachloride in dichloromethane (5.13 mls, 40 mgs/ml). The solution was maintained at -20° C. for 30 mins and then methanol (5 mls) was added quickly, in one portion. The solution was allowed to warm to room temperature for a further 30 mins and water (10 mls) added. The reaction was vigorously stirred for 30 mins and then the dichloromethane removed in vacuo. The pH was adjusted to 7-8 with aqueous saturated sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. `Flash` chromatography on silica gel, eluting with 80% ethyl acetate/hexane afforded the title compound as a yellow foam, (0.221 g, 58%), νmax (CH2Cl2) 3400(vw), 1760, 1720, 1625, 1490(w) and 1450(w) cm-1 ; δH (CDCl3) 1.94 (3H, s), 3.47 (2H, ABq, J18.2Hz), 3.87 (3H, s), 4.83 (1H, d, J5.1Hz), 4.98 (1H, d, J5.1Hz), 6.25 (1H, s), 7.00 (1H, s) and 7.2-7.5 (10H, m); [mass spectrum: +ve ion (3NOBA, Na+) MNa+, 527].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6](=[CH:9][C:10]([CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH3:11])[CH2:7][OH:8].C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:8][CH2:7][C:6]([F:5])=[CH:9][C:10]([CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][CH:13]=1)[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C=C(F)CO)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (0.41 ml), 2-fluoro-4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enol (Example 10) (0.2 g), benzene (10 ml) and pyridine (0.081 ml) to yield the title compound (0.23 g, 99%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=O)C>[OH-].[Na+].O.CC(C)=O>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(=O)OC1NC(=O)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SC1NC(=O)C1C

Procedure:
A solution of 0.33 ml of thioacetic acid in 4.5 ml of 1N sodium hydroxide solution is added dropwise at room temperature under a nitrogen atmosphere to a solution of 438 mg (3.06 mmoles) of 4-acetoxy-3-methylazetidin-2-one (produced according to K. Clauss et al., Lieb, Ann. Chem., 1974, 539; racemic mixture of cis- and trans-isomer in a ratio of 3:1; Mp 53°-65°) in 1.13 ml of water and 0.27 ml of acetone, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (4:1 to 3:2) and yields first of all the pure trans-compound, then a mixture of the cis- and trans-isomers of the title compound and subsequently the pure cis-compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[H-].[CH3:21]I>CN(C)C=O.CI>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:21])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide (3.77 kg) is suspended in dimethylformamide (20 L; Van Waters) and the mixture chilled in an ice bath. Sodium hydride (808 g, 60% dispersion; Aldrich) is added to the suspension under a nitrogen atmosphere. The temperature of the reaction mixture is maintained below 10?C. during the addition of the hydride. After the addition is complete the mixture is stirred for 1 hour, then methyl iodide (2.46 kg) is added slowly while maintaining the temperature below 10?C. The reaction mixture is stirred overnight and allowed to come to room temperature. HPLC analysis of the reaction mixture shows 97.7% product and ˜2.3% of the starting material. The addition of methyl iodide (53 g; Aldrich) and continued stirring (5 hours) does not change this ratio. The reaction mixture is quenched by the addition of 1 L of water. The mixture is triturated with hexanes (2×4 L) which are discarded. Most of the DMF is removed under reduced pressure. The residue is diluted with water (6 L) and product is extracted with methylene chloride (20 L; Barton). The solution is dried over sodium sulfate, filtered and the solvent evaporated to give a solid. This material is triturated with hexanes (15 L) and ethyl acetate (15 L). The slurry was cooled to room temperature, filtered and washed with hexanes (0.5 L). This material is found to be only ˜91% product by HPLC (area %). The material is purified by column chromatography. The material is dissolved in methylene chloride and passed through a pad of silica (˜18 kg). The polarity of the eluant is gradually increased by adding ethyl acetate (Barton). Eventually the column is flushed with ethyl acetate. In this manner 2.4 kg of N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide is obtained with a purity of 98.05% by HPLC (area %).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([OH:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH2:20][C:21](=[O:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.817 g (8.00 mmol) acetic anhydride is mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.086 g (0.200 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate in 10 ml absolute DMSO. Having stirred for 19 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a brown oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a yellowish oil.
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][CH:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CC#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(O)CCN)cc1

Procedure:
To a solution of (RS)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.0 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (RS)-3-hydroxy-4-(p-toluenesulfonyloxy)butylamine hydrochloride (18.1 g). Yield, 92 %.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][NH:17][C:12]3=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl[CH:19]([C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[O:23][N:22]=1)[CH3:20].[NH4+].[Cl-]>CN(C=O)C.O>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([C@@H:19]([N:17]3[CH2:16][CH2:15][CH2:14][N:13]4[C:9]([C:6]5[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=5)=[N:10][N:11]=[C:12]34)[CH3:20])[N:25]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Reactant: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](c1noc(-c2cccc(Cl)c2)n1)N1CCCn2c(-c3ccncc3)nnc21
Yield: 22.1 %

Procedure:
NaH (716 mg, 29.8 mmol) was added slowly to a solution of 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (5.0 g, 24.8 mmol) in DMF (250 ml) under nitrogen. After 10 min a solution of 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (6.0 g, 24.8 mmol) in DMF (200 ml) was added, followed by stirring o.n. at r.t. A sat NH4Cl solution was added followed by water. The mixture was extracted with EA and DCM. The combined organic extracts were washed with water and brine, dried and concentrated. Recrystallization from EA gave 2.24 g (22%) of the racemic product 8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine. Separation on a Chiralpak AD column (100% 2-propanol) gave the title compound which eluted as second enantiomer. 1H NMR: 1.74 (d, 3 H) 2.17 (m, 2 H) 3.45 (m, 2 H) 4.10 (m, 2 H) 5.96 (m, 1 H) 7.44 (t, 1 H) 7.53 (m, 1 H) 7.59 (m, 2 H) 7.97 (m, 1 H) 8.08 (m, 1 H) 8.67 (d, 2 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c(Cl)c1
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(C)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 94.3 %

Procedure:
Using 7-(2-chloro-4-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.092 mmol) obtained in step 5 as a starting material and propionic acid (0.034 mL, 0.460 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.052 g, 93%) was obtained.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([CH3:30])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:33]N>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:33][N:2]=[CH:3][C:4]=2[CH3:30])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 40 above using compound B, 6-(3-dimethylamino-2-methylacryloyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6](#[N:8])[CH3:7].O1P2[O:15][P:16]3[O:18]P(O2)OP1[O:17]3>C(O)C.O.C(O)(=O)C.C(#N)C.C(O)(=O)C>[NH2:8][C:6]([P:16]([OH:15])(=[O:17])[OH:18])([P:16]([OH:18])(=[O:15])[OH:17])[CH3:7]
Reactant: O1P2OP3OP1OP(O2)O3
Reactant: CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 66 %

Procedure:
48.8 g (0.63 mol) ammonium acetate was suspended in 68 g (1.66 mols) acetonitrile in a flask which was scavenged with nitrogen, provided with an agitator and had a fractionating column mounted thereon, and the suspension was heated to about 80° C. under reflux. Next, 46.4 g (0.21 mol) molten P4O6 was added dropwise to the boiling mixture, the temperature being maintained at 80°-90° C. While the temperature was gradually increased to 160° C., 85.1 g distillate containing 91.5% acetonitrile and 8.2% acetic acid, corresponding to 77.9 g (0.190 mol)acetonitrile and 7.0 g (0.24 mol) acetic acid, was removed through a short column at a head temperature of 84°-89° C. After deduction of the acetonitrile feed material, 11.9 g (0.24 mol) acetonitrile was found to have been obtained as by-product. The acetonitrile/acetic acid mixture was recycled, after conversion of the acetic acid to ammonium acetate. The colorless residue retained in the flask was boiled for a short while in an ethanol/water-mixture (4:1) and 57.1 g 1-aminoethane-1,1-diphosphonic acid was obtained in a yield of 66%.
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:15])[CH:9]=[C:10]([N+:12]([O-])=O)[N:11]=1)=[O:6])[CH3:3]>CO.[Pd]>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:15])[CH:9]=[C:10]([NH2:12])[N:11]=1)=[O:6])[CH3:1]
Reactant: CN(C)NC(=O)c1nc([N+](=O)[O-])cn1C
Agent: [Pd]
Solvent: CO
Product: CN(C)NC(=O)c1nc(N)cn1C
Reaction time: 4 h

Procedure:
A suspension of N-(N',N'-dimethylamino)-1-methyl-4-nitroimidazole-2-carboxamide (2.01 g, 9.4 mmol) and 5% Pd on charcoal (0.8 g) in chilled methanol (100 mL) was purged of air and hydrogenated at room temperature and atmospheric pressure for 4 hours. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give N-(N',N'-dimethylamino)-1-methyl-4-aminoimidazole-2-carboxamide as a glassy solid which is unstable and used directly in the next step.