Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:3]=1.[OH-].[Na+].Cl.C([N:24](CC)CC)C.[Cl-].[NH4+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.C(O)C.O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:24])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NCc1ccccn1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCO
Solvent: CO
Product: NC(=O)c1sc(Br)cc1NCc1ccccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a solution of methyl 5-bromo-3-[(pyridin-2-ylmethyl)amino]thiophene-2-carboxylate (336 mg, 1.03 mmol) in MeOH (3 mL) and ethanol (10 mL) was added a solution of sodium hydroxide (124 mg, 3.09 mmol) in water (1.5 mL). After stirring at 100° C. for 5 h, 6 M aqueous HCl (0.33 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was diluted with DMF (5 mL). Then, triethylamine (2.9 mL, 21 mmol) and ammonium chloride (1.1 g, 21 mmol) were added. After stirring at room temperature for 5 min, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 g, 6.2 mmol) and 1-hydroxybenzotriazole (835 mg, 6.2 mmol) were added to the mixture, and stirring was continued for 18 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give the title compound (160 mg, 50%) as a yellow solid:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(C)C

Procedure:
10.00 g of glycine ethyl ester hydrochloride (71.6 mmol) and 21.97 ml of NEt3 (2.2 eq.) were dissolved in 200 ml of CH2Cl2 and treated between 0° and 5° dropwise with 7.81 ml of isobutyryl chloride (1.05 eq.), dissolved in 50 ml of CH2Cl2. The reaction mixture was allowed to reach ambient temperature (2.5 h) and then quenched by carefully pouring onto crashed ice/HCl/AcOEt. Separation of the layers, additional extraction of the aqueous phase with AcOEt, washing with Na2CO3 and brine, drying of the combined organic phase over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) yielded 11.74 g of the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[Cl:41].[OH-].[Li+]>O1CCCC1.CO.ClCCl.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:23][CH2:24]3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:41]
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cnc(N)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)O)c(Oc4cnc(N)c(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 318G (12.5 g) in tetrahydrofuran (50 mL) and methanol (25 mL) was added lithium hydroxide (1.0 M, 52.5 mL) and the reaction heated to 55° C. The reaction was stirred for 4 hours, cooled, diluted with dichloromethane (300 mL) and water (50 mL) and quenched with 1N aqueous HCl (1.0M, 50 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:25])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:25])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(OCc3ccccc3)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(OCc3ccccc3)c(Br)cc21
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of N-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.38 (d, J=8 Hz, 2H), 7.30 (dd, J=7, 8 Hz, 2H), 7.23 (m, 2H), 6.61 (s, 1H), 5.03 (s, 2H), 2.94 (m, 3H), 2.81 (m, 3H), 2.62 (m, 1H), 2.30 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated for C18H20BrNO+H: 346, observed: 346.
Reaction SMILES: Br[CH2:2][CH2:3]Br.C([O-])([O-])=O.[K+].[K+].[SH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[OH:19]>CC(C)=O>[O:19]1[C:13]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=2[S:11][CH2:3][CH2:2]1
Reactant: Oc1ccc(O)c(S)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc2c(c1)SCCO2
Reaction time: 10 h
Yield: 55.2 %

Procedure:
1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K2CO3 (8.21 g, 59.4 mmol) were slurried in acetone (250 mL) and a solution of 2-sulfanyl-1,4-benzenediol (prepared according to J. Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) was added over 4 h to the stirred mixture. Once the addition was complete stirring was continued for a further 10 h before the solvent was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried (MgSO4) and evaporated. Purification of the residue by column chromatography [SiO2; 9:1 (pentane/EtOAc)] gave the title compound (2.48 g, 55%) as a pale orange oil; δH (CDCl3, 400 MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s), 6.66 (1H, d); MS m/z (ES−) 167 (M−H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[CH:20][CH:21]=3)[CH:26]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccccc4c3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting naphthalene-2-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The title compound is obtained as a white solid.
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:53])C=2)C1)=O)(C)(C)C>>[ClH:53].[Cl:1][C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[N:24]=2)[CH:22]=1)=[O:17]
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1Cl)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]2[CH2:16][N:15]([C:17]([C:19]3[N:20]=[C:21]([N:24]4[CH2:27][CH:26]([S:28][C:29]5[C@H:30]([CH3:53])[C@@H:31]6[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]6[C:33]=5[C:34]([O:36]CC5C=CC([N+]([O-])=O)=CC=5)=[O:35])[CH2:25]4)[O:22][CH:23]=3)=[O:18])[CH2:14]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH2:12][CH:13]1[CH2:14][N:15]([C:17]([C:19]2[N:20]=[C:21]([N:24]3[CH2:27][CH:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([OH:36])=[O:35])[CH2:25]3)[O:22][CH:23]=2)=[O:18])[CH2:16]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(NC(=O)OCc6ccc([N+](=O)[O-])cc6)C5)co4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N5CC(N)C5)co4)C3)[C@H](C)[C@H]12
Reaction time: 3.5 h
Yield: 45.7 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-{1-{4-[3-(p-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (250 mg, 0.321 mmol) (obtained as described in Example 79(1)) in a mixture of tetrahydrofuran (13 ml) and distilled water (13 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (250 mg) at room temperature for 3.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The resulting mixture was shaken in a separatory funnel and the aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→distilled water:acetonitrile (82:18)) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-(3-aminoazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (68 mg, yield 46%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[CH3:20])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].N1C=CC=CC=1>C(Cl)(Cl)Cl.O>[C:1]([O:4][C:5]1([CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[CH3:20])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc(N)cc2OC1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc2c(c1)OCC(CN(C(C)=O)C(C)C)(OC(C)=O)CO2

Procedure:
3-Acetoxy-3-N-acetylisopropylaminomethyl-7-amino-3,4-dihydro-2H-1,5-benzodioxepin (0.1 mole) from Example 86, Step B, in chloroform is treated with 0.11 mole of ethyl chloroformate and pyridine in chloroform. The mixture after stirring and heating in a water bath for several hours is diluted with water, extracted with ether, the combined ethereal extracts washed, dried and evaporated to give 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]1.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:11]1[CH2:12][CH:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: Cc1ccsc1C1CC(=O)CC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccsc1C1CC(=O)C=C(N)C1
Yield: 90.4 %

Procedure:
A solution of 5-(3-methyl-2-thienyl)-1,3-cyclohexanedione (3.0 g) and ammonium acetate (3.3 g) in ethanol (60 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate and water to precipitate crystals, which were filtered, washed with water and dried to give pale yellow crystals of 1-amino-5-(3-methyl-2-thienyl)cyclohexen-3-one (2.7 g).
Reaction SMILES: C[Si]([CH2:5][C:6]([O-:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>>[C:6]([O:8][Si:10]1([O:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: C[Si](C)(C)CC(=O)[O-]
Reactant: Cl[Si]1(Cl)CCC1
Product: CC(=O)O[Si]1(OC(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30.0 g trimethylsilylacetate was added 16.0 g 1,1-dichlorosilacyclobutane. The reactants were stirred for one hour at 25 ° C. and fractional distillation performed on the reaction mixture. The title compound was isolated as a clear, colorless fluid. The yield was 14.6 g (81.4%). The structure of the product was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[N:11]/[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A mixture of (E)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)ethylidene)hydrazinecarboxylate (5.1 g, 17.71 mmol) and Pd/C (0.5 g, 10%) in MeOH (100 mL) was stirred under 1 atm H2 at room temperature for 1 h. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (5:1) to give tert-butyl 2-(2-(tert-butyldimethylsilyloxy)ethyl)hydrazinecarboxylate (2.8 g, 55% yield) as colorless oil. LCMS (ESI) m/z: 235.3 [M-56+H+].
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]([NH:11][C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:27][CH:26]=1)[CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:10])[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[CH2:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]([NH:11][C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:27][CH:26]=1)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
A suspension of (R)-benzyl 3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoate (178.9 mg, 0.334 mmol) and Pd/C (71.0 mg, 0.033 mmol) in EtOAc (3 ml) is allowed to stir under hydrogen at room temperature for 1.5 hours. The reaction mixture is filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (90.7 mg) as a white solid; HPLC retention time=1.27 minutes (condition B); MS (m+1)=446.24; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J=7.5 Hz, 3H) 1.31-1.40 (m, 2H) 1.55-1.62 (m, 2H) 2.43-2.47 (m, 2H) 2.52-2.69 (m, 4H) 2.93 (A of ABX, Jab=3.7 Hz, Jax=7.7 Hz, 1H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.8 Hz, 1H) 4.07 (t, J=6.7 Hz, 2H) 4.49-4.57 (m, 1H) 6.31 (br d, J=8.6 Hz, 1H) 7.26-7.37 (m, 4H) 7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55 (br t, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:22][C:21]1[C:2]([Cl:1])=[C:3]([CH:18]=[CH:19][CH:20]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Yield: 98.5 %

Procedure:
A solution of the nitro compound from Example 52 (0.50 g) and ammonium chloride (0.5 g) were dissolved in 50% aqueous ethanol. Iron powder (0.5 g) was added and the mixture stirred at reflux temperature for 3 hr before being cooled and solids removed by filtration. The filtrate was treated with 10% sodium hydroxide solution and the product extracted into ethyl acetate. The organic solution was washed with brine, dried over sodium sulphate (Na2SO4) and concentrated to give a residue which was purified by silica gel chromatography to give the title compound as a white powder (0.45 g).
Reaction SMILES: OC(C)CC(OCC)=O.[Br:10][CH2:11][CH:12]([OH:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Br:10][CH2:11][C@H:12]([OH:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(O)CBr
Agent: CCOC(=O)CC(C)O
Product: CCOC(=O)C[C@@H](O)CBr
Yield: 99 %

Procedure:
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-bromo-3-hydroxybutyrate (1%, w/v) was used as a reactant and novozyme 435 lipase was used as a biocatalyst. After reaction for 1 hour 40 minutes, ethyl (R)-4-bromo-3-hydroxybutyrate (99% e.e) was obtained at 88.3% conversion.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[O:1]([C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (360 mg, 2 mmol) in anhydrous tetrahydrofuran (20 mL) was added phenol (188 mg, 2 mmol) and triphenylphosphine (524 mg, 2 mmol) at 0° C., then stirred for 1 hour, (E)-diisopropyl diazene-1,2-dicarboxylate (404 mg, 2 mmol) was added, then stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=4:1) to give (S)-methyl 4-(1-phenoxyethyl)benzoate (410 mg, 80%). LRMS (M+H+) m/z: calcd 256.11. found 256.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:7][CH:6]=1)#[N:4].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>O>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([CH2:29][N:21]([CH2:20][CH2:19][N:14]2[CH2:15][CH:16]3[O:18][CH:12]([CH2:11][N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=4)[CH2:17]3)[CH2:13]2)[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CS(=O)(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a suspension of sodium hydride (0.013 g of a 60% suspension in mineral oil, washed with pentane) in anhydrous N,N-dimethylformamide (4 mL) was added N-{2-[7-(4-Cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-methanesulfonamide (0.109 g, 0.30 mmol) at 0° C. The mixture was stirred for 2 hours while the temperature was allowed to warm to room temperature. At 0° C., 4-bromomethyl-benzonitrile (0.065 g, 0.33 mmol) was added. The mixture was stirred for 2 hours at room temperature, whereupon water (5 mL) was added. The aqueous layer was extracted with dichloromethane (3×5 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia dichloromethane as eluent, which afforded 79 mg (54.9%) of the title compound.
Reaction SMILES: [C:1]1([CH2:6][SH:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N1C(=O)C2=CC=C[CH:20]=[C:13]2[C:12]1=[S:21])CC>>[CH2:12]([S:21][S:7][CH2:6][C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH3:20]
Reactant: CCCN1C(=O)c2ccccc2C1=S
Reactant: SCc1cccs1
Product: CCCSSCc1cccs1

Procedure:
Starting from thenylmercaptan and N-propylthiophthalimide there is obtained propyl-thenyl-disulphide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 5-bromo-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[C:7]([F:8])=[C:2]([O:28][C:22]2[C:21]([F:20])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(Oc2c(F)cccc2F)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.1 g of 4-chloro-6-(2-butynyloxy)-5-fluoropyrimidine, 0.1 g of potassium carbonate, and 0.08 g of 2,6-difluorophenol, followed by stirring at 60° C. for 4 hours. The reaction mixture was left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.1 g of 4-(2-butynyloxy)-6-(2,6-difluorophenoxy)-5-fluoropyrimidine (the present compound (190)).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]12([OH:17])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[C:18]([O:21][CH:22]=[CH2:23])(=[O:20])[CH3:19].C(OC12CC3CC(CC(C3)C1)C2)=C>C1(C)C=CC=CC=1>[C:18]([O:21][CH:22]([O:17][C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2)[CH3:23])(=[O:20])[CH3:19]
Reactant: C=COC(C)=O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: C=COC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)OC12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and sodium carbonate (64 mg, 0.6 mmol) in toluene (1.0 ml), 1-adamantanol (152 mg, 1 mmol) and vinyl acetate (258 mg, 3 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 5 hours. The reaction mixture was analyzed by gas chromatography to find that 1-adamantyl vinyl ether and 1-(adamant-1-yloxy)ethyl acetate were produced in yields of 91% and 1%, respectively, with a conversion from 1-adamantanol of 93%.