Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1I)[C:5]#[N:6].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccco2)c(O)c1
Temperature: 100 °C

Procedure:
3-Hydroxy-4-iodo-benzonitrile (120 mg, 0.49 mmol) and PdCl2(PPh3)2 (35 mg, 0.049 mmol) and 2-furyltributyltin (200 g, 0.56 mmol) in N,N-dimethylformamide (DMF) (5 mL) is degassed and heated at 100° C. for 30 minutes (min). After the mixture cooled to room temperature, an aqueous work up is performed and the product is isolated from chromatography (80 mg, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:21]([NH:20][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[O:10])=[O:22])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide (0.48 g, 0.96 mmol) in methanol (20 mL) was added sodium borohydride (36 mg, 0.96 mmol). The reaction was stirred at room temperature for 5 min, treated with water, and concentrated in vacuo. The residual mixture was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.47 g (98%) of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:32][CH:29]2[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)c(F)c2)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared as a white solid from 2-fluoro-4′-(methylsulfonyl)-4-biphenylol (0.25 g, 0.94 mmol), N-Boc-4-piperidinemethanol (0.21 g, 0.94 mmol) and Ph3P (0.25 g, 0.94 mmol) in THF (6 mL) followed by diisopropyl azodicarboxylate (0.20 g, 94%, 0.94 mmol) in THF (2 mL) in a manner similar to Example 1, Step 2. The crude product was triturated with hot hexane containing 1% of MeOH to give 20 mg of the title compound as a white solid. The filtrate was purified by chromatography on a silica gel column eluted with 3:4 EtOAc/hexane to give additional 0.34 g (overall 83%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.99 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=7.4 Hz), 7.50-7.40 (m, 1H), 6.90-6.80 (m, 2H), 4.20-4.10 (m, 2H), 3.91 (d, 2H, J=6.4 Hz), 3.14 (s, 3H), 2.90-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 486 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].Cl.[Br:21][C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>C(O)(=O)C>[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:10][C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
1-(2,4-Difluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (4.8 g, 16.9 mmol) prepared in Step 3 and 3-bromophenylhydrazine hydrochloride (4.2 g, 18.6 mmol) were added to acetic acid (50.0 mL). The reaction mixture was stirred at 95° C. for 5 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane) to give 2.7 g of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH3:28])([C:9]1[CH:14]=[CH:13][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11][CH:10]=1)[CH3:8])(=[O:3])[CH3:2].Br[C:30]1[N:31]=[C:32]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1(C)C(C)=CC=CC=1.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>[CH2:46]([N:43]1[CH2:42][CH2:41][N:40]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:39]=[C:30]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([CH3:8])([CH3:28])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=3)[N:31]=2)[CH2:45][CH2:44]1)[CH3:47]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)CCOC(C)=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCOC(C)=O)cc3)cc3ccccc23)CC1
Yield: 86.2 %

Procedure:
3-Methyl-3-(4-tributylstannylphenyl)butyl acetate (4.05 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.10 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.16 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.32 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-acetoxy-1,1-dimethylpropyl)phenyl]isoquinoline as a brown viscous oil and the starting material-The resulting mixture (1.32 g) was then dissolved in methanol (30 ml), to which was then added a 5N aqueous solution of sodium hydroxide (3.00 ml), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated, and water was added to the resulting residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 0.74 g of the free compound of the title compound as a pale yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([NH:14][C:3](=[O:5])[CH2:2][SH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CS
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=C(CS)NC1CCCCC1
Reaction time: 72 h

Procedure:
A solution of ethyl 2-mercaptoacetate (12 g) and cyclohexylamine (29.7 g) in ethanol (50 ml) was allowed to stand at ambient temperature for 72 hours, and was then refluxed for 6 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml). The solution was washed sequentially with 2M HCl (3×50 ml), water (2×50 ml) and brine (50 ml) and the solvent removed in vacuo. The crude product was purified by chromatography on silica (eluting with dichloromethane/methanol 99:1 v/v) to give N-cyclohexyl-2-mercaptoacetamide as low-melting tan crystals; NMR: 1.0-2.0(complex, 11H, cyclohexyl-CH2 and SH), 3.2(d, 2H, CH2), 3.6-3.9(m, 1H, cyclohexyl-CH), 6.4-6.9(broad d, 1H, NH); m/e 174 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:13]1CCOC[CH2:14]1>>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:13])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Reactant: C1COCCO1
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90 %

Procedure:
Anhydrous dioxane (0.5 litres), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchlorofornate (97.4 grams, 492 mmoles) were added to a one litre one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one litre of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 litres of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:21])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:21])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2ncccc2OCC2CC2)cc1
Solvent: O
Product: [O-][n+]1cccc(OCC2CC2)c1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 65.19 %

Procedure:
To a solution of 5 g 2-(4-chloro-phenyl)-3-cyclopropylmethoxy-pyridine in 15 mL acetic acid, 3 mL hydrogenperoxyde (30% in water) was added. The reaction mixture was then stirred at 70° C. for 15 h. The reaction mixture was diluted with water and quenched with sodium carbonate. The mixture was washed with methylene chloride. The organic phase was washed with water; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of ethyl acetate to ethyl acetate:methanol 4:1 to yield 3.46 g (65.19%) of the title compound as white solid, MS 276.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Yield: 95.4 %

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (15.00 g; 71.8 mmol; 1 eq) and diisopropylethylamine (12.5 mL; 71.8 mmol; 1 eq) in anhydrous acetonitrile (650 mL), imidazole (4.88 g; 71.8 mmol; 1 eq) is added under argon. The reaction mixture is allowed to stir under reflux for 20 hours until 1-fluoro-2-nitro-4-(trifluoromethyl)benzene has completely reacted. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (250 mL). The organic phase is then washed with water (100 mL), brine (100 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 5:5) afforded the title compound (17.7 g; 68.5 mmol; 96%) as a brown powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Cl:3])=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(CO)ccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1cc(CCl)ccc1OCc1ccccc1
Yield: 75.4 %

Procedure:
Thionyl chloride (5.95 g, 50.0 mmol) was added to a mixture of 4-benzyloxy-3-methoxybenzylalcohol (10.0 g, 40.9 mmol) in 50 ml ether at room temperature. The reaction turned into a clear solution and was monitored by TLC. The reaction was quenched with H2O. The product was extracted with ether. The aqueous layer was extracted with ether. The combined organic layer washed with 5% NaHCO3, brine and dried with Na2SO4. Ether was evaporated and the residue was purified by chromatography (on silica gel, ethyl acetate/hexane=2/8) to give a white solid 8.10 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5](Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:16]([NH:3][CH2:2][CH2:1][NH2:4])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: NCCN
Reactant: CCCCCCCCCCCCCl
Solvent: CCO
Product: CCCCCCCCCCCCNCCN
Reaction time: 1.5 h

Procedure:
N-propylol-N'-lauryl ethylenediamine is prepared by dissolving 2 kmol ethylenediamine in 500 liters absolute ethanol and then, while constantly stirring, 2 kmol laurylchloride is added while the temperature is maintained not to exceed 100°C and then the reaction mixture is held for 1.5 hours at that temperature. N'-lauryl-ethylenediamine is formed. Subsequently the reaction mixture is cooled to 30°C, the chloride is precipitated with ammonia and the precipitate is filtered off. The pH value of the pure solution is adjusted to 8.5 and 2 kmol propionaldehyde ia added. The temperature is maintained at 40°C during a subsequent 3 hour period while stirring. Then the alcohol is driven off under vacuum and the unreacted products are washed out with water. The end product has a molecular weight of about 300 and the formula ##EQU12##
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[H][H]>C1COCC1.CO.[Ni]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(N)cc1

Procedure:
2-Methyl-2-(4-nitrophenyl)propanenitrile (Compound of step 1, 16 g, 84.1 mmol) and Raney-Ni (4.16 g) were shaken in THF-MeOH [(1:1), 160 mL] under 40 psi of hydrogen for 10 hours at RT, After completion of reaction, the catalyst was filtered-off and the solvent was evaporated to dryness. The crude product was purified by column chromatography (silica gel, ethyl acetate in hexane) to obtain the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([F:17])=[C:15]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:14]=[CH:13][N:12]=1)=O.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[C:11]1[C:16]([F:17])=[C:15]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:14]=[CH:13][N:12]=1)=[N:25]/[OH:26]
Reactant: NO
Reactant: O=C(c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C(/c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of (2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone (0.030 g, 0.090 mmol) and hydroxylamine hydrochloride (0.043 g, 0.615 mmol) in pyridine (Volume: 0.452 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-100% EtOAc in hexanes over 11 min, tr=0.4, 2 min) gave the title compound (29 mg, 0.079 mmol, 88% yield) as a yellow residue. ESI MS (M+H)+=347.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]1([CH:26]2[CH2:31][NH:30][CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N12CCN(CC1)CC2>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:31]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccccc4)C3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 31.9 %

Procedure:
A mixture of 2.8 g (0.01 mols) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.8 g (0.011 mole) of 2-phenylpiperazine and 2.2 g (0.02 mole) of 1,4-diazabicyclo[2.2.2]octane in 6 ml of dimethyl sulphoxide is heated at 140° C. for 4 hours. The solution is concentrated under high vacuum, and the residue is stirred with 20 ml of water and the pH is adjusted to 7 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, and boiled in 30 ml of methanol. 1.3 g (32% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 218°-220° (with decomposition) is obtained (recrystallized from glycol monomethyl ether).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:19]C#N)=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[S:3][C:4]([SH:19])=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1SC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1S
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a stirred solution of 2-amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-5-thiocyanato-1,3-thiazole (2.83 g, 8.19 mmol) in methanol (30 mL) at room temperature was added sodium borohydride under nitrogen (0.93 g, 24.6 mol) and stirring was continued for 1 hour. After addition of water, stirring was continued until gas evolution subsided and the aqueous solution was washed with methylene chloride to remove impurities. Aqueous thiolate solution was neutralized with dilute hydrochloric acid and the product was extracted with ethyl acetate (all manipulations were performed under nitrogen to prevent formation of disulfide). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford pale orange foam of title product (1.72 g) which was used f6r further steps without further purification. 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.60 (m, 2H), 3.20 (m, 2H), 3.65 (s, 2H), 5.40 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[C:2]1([CH:1]([OH:8])[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(O)c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 3.0 g of 6-benzoyl-3,4-dihydrocarbostyril in 120 ml of methanol was treated at 0° C. with 1.2 g of sodium borohydride. The mixture was stirred at 25° C. for 18 hours during which time the suspended solid dissolved. The solvent was removed under reduced pressure and the residue partitioned between 10% methanol in methylene chloride and water. The extract was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give 6-(phenylhydroxymethyl)-3,4-dihydrocarbostyril, m.p. 166°-169° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:20][OH:21])[N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:20]([C:16]1[N:17]=[C:18]([CH3:19])[N:13]2[CH:12]=[C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:35](=[O:36])[N:6]4[C:7]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[S:15][C:14]=12)=[O:21]
Reactant: Cc1nc(CO)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 32 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-5-methylimidazo-[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (279 mg) was dissolved in 30 ml of dichloromethane. Manganese dioxide (500 mg) was added to the solution. The mixture was stirred at room temperature for 14 hr. The reaction solution was filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel to give 89 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-formyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[CH:16]1([C:13]2[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CC2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(C2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A solution of (S)-tert-butyl-1-(5-cyclopropylpyridin-2-yl)ethylcarbamate (Method 31; 2.04 g, 7.78 mmol) in DCM (10 ml) was treated with HCl/dioxane (9.72 ml, 4 N, 38.8 mmol) and stirred at room temperature for 2 hours. The solvent was removed to give the title compound (1.73 g, 93%) as white solid. 1H NMR (400 MHz) δ 8.60 (br, 3H), 8.50 (s, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 4.52 (m, 1h), 2.03 (m, 1H), 1.50 (d, J=6.8 Hz, 1H), 1.04 (m, 2H), 0.79 (m, 2H). MS: Calcd.: 162. Found: [M+H]+ 163.