Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[O:28])[N:14]=2)=[O:27])=[CH:21][CH:22]=1
Reactant: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CNCC3CCCCC3)CC2)cs1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
55.2 To a stirred mixture of 100 mg N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide in 5 ml THF at r.t. were added 0.04 ml (aminomethyl)cyclohexane and 0.09 ml triethylamine. After 48 hrs stirring at r.t. under argon atmosphere, the reaction mixture was concentrated. The crude product was purified by chromatography on silica using a gradient from CH2Cl2 to CH2Cl2/MeOH 95:5 in 20 min to give 19 mg 4-chloro-N-[4-(2-{4-[2-(cyclohexylmethyl-amino)-acetyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 518.5 ([M+H]+)
Reaction SMILES: C(N1CC[C@@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2S(NC2C(C(OC)=O)=C3C(C4CC4CO3)=CC=2)(=O)=O)=O)C1)C.[F:38][C:39]([F:44])([F:43])[C:40](O)=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([N:8]1[CH2:5][CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH2:9]1)=[O:41]
Reactant: CCN1CC[C@@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC(c2cccc(F)c2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (Intermediate 92, 2.51 g) in trifluoroacetic acid (15 mL) and DCM (15 mL) was left to stand at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was azeotroped with toluene. The residue was dissolved in DCM (15 mL) and pyridine (5 mL) and trifluoroacetic anhydride (3.15 g) was added. The mixture was left to stand at room temperature for 30 minutes, then washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give 2,2,2-trifluoro-1-[3-(3-fluorophenyl)azetidin-1-yl]ethanone (2.31 g) as a light brown oil.
Reaction SMILES: C([C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:10])[CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:16]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[C:3]1[C:4]([CH3:10])=[CH:5][CH:6]=[N:7][C:8]=1[Cl:16])[CH3:15]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)ccnc1Cl
Temperature: 50 °C

Procedure:
1-Cyano-4-(N,N-dimethylamino)-1-ethoxycarbonyl-2-methyl-1,3-butadiene (25.0 g, 0.12 mol) prepared in a manner analogous to that described in Example (i) above in toluene (250 ml) was heated to 50° C. for 3 hours with stirring whereupon a steady stream of hydrogen chloride was passed through the reaction mixture. After cooling, the mixture was washed with water (250 ml). The aqueous layer was then extracted with toluene (3×100 ml). The pooled organic layers were dried with sodium sulphate and evaporated. Distillation of the residue in high vacuo yielded 2-chloro-4-methylnicotinic acid ethyl ester as colourless oil (15.3 g, 64% of theoretical yield) with b.pt.0.04 Torr 97° C.-98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 547.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:11]([C:3]1[C:2]([NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:23])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[N:12]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1cc2c(cc1N)OCO2
Product: N#Cc1cc2c(cc1NC(=O)NC(=O)c1ccccc1)OCO2

Procedure:
Prepared as in Example 53a from 6-aminobenzo[d][1,3]dioxole-5-carbonitrile and benzoyl isocyanate as a yellow solid (157 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 6.19 (s, 2H), 7.42 (s, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.74 (s, 1H), 8.03 (d, J=9.2 Hz, 2H), 11.32 (d, J=12.8 Hz, 2H). MS 309 (MH+).
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].[OH-].[Na+].Cl>O.CO>[NH2:5][C:4]1[N:21]([C:22](=[O:23])[NH2:24])[N:20]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of α-formyl-4-benzylphenylacetonitrile (152.22 g), semicarbazide hydrochloride (72.24 g), methanol (400 ml) and water (80 ml) was stirred at room temperature, and after 18 hours, maintained pH to about 10 with 5N sodium hydroxide aqueous solution. When heat was generated, the reaction mixture was cooled with ice-water. After stirring at room temperature for 1 hour, the reaction mixure was neutralized with 10% hydrochloric acid, and water (1 l) was added. After stirring for 1 hour, the precipitate was separated by filtration, washed with water, and dried to give the title compound (165.52 g).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2[nH]cnc2cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc2c(cc1Br)ncn2C1CCCCO1
Yield: 106.3 %

Procedure:
A mixture of 100 (550 mg, 2.57 mmol), TsOH.H2O (50 mg, 0.26 mmol), and 3,4-dihydro-2H-pyran (1.08 g, 12.85 mmol) in THF (10 mL) was heated at reflux overnight. After the solvent was removed in vacuo, the residue was partitioned between DCM (300 mL) and water (100 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0.5 to 1% MeOH) to afford 817 mg (100%) of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (102) as yellow oil: MS (ESI) m/z=299 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2ccc(N)cc2c(O)c1C(=O)OCC
Yield: 75.1 %

Procedure:
A stirred mixture of diethyl 4-hydroxy-6-nitroquinoline-2,3-dicarboxylate (4.4 g, 13 mM), powdered iron (6.6 g, 118 mM) and glacial acetic acid (18.5 g, 307 mM) in ethanol (80 mL) was refluxed for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled and filtered and the filtrate was concentrated. The dark residue was chromatographed (eluant: methylene chloride/methanol; 98/2) over silical gel to provide (3.01 g, 75.3%) the title compound as light orange crystals, mp 219°-221° C.; MS(CI): 305 (M+H).
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([O:14][C:15](=[O:35])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29](C(=O)C)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29]([O:10][C:8](=[O:9])[CH3:4])=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)=[O:35])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)NCCc1ccc(Oc2ccc(C(C)=O)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1ccc(Oc2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
Metachloroperbenzoic Acid (1.2 g, 4.1 mmol) was added to a solution of {2-[4-(4-acetyl-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (1.0 g, 3.1 mmol) in chloroform (75 mL). Stirred at room temperature for 72 hours, quenched with saturated aqueous Na2S2O3, then extracted with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (2 g). The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield Acetic acid 4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenyl ester (430 mg). 1H NMR (CDCl3, 300.00 MHz): 7.19-6.92 (m, 8H), 4.98 (s, 1H), 4.17-4.07 (m, 2H), 3.42 (q, 2H, J=6.6 Hz), 2.79 (t, 2H, J=7.2 Hz), 2.29 (s, 3H), 1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][O:23][C:24](=[O:26])[CH3:25])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1CCC(CO)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Solvent: c1ccncc1
Product: CCN1CCC(COC(C)=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.98 g) in pyridine (5 ml), acetic anhydride was added dropwise with stirring under ice-cooling and the mixture was stirred for 2 hours at room temperature. Pyridine was distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane. After washing with a saturated aqueous solution of copper sulfate and with water in this order, the mixture was dried and the solvent was distilled off under reduced pressure to give 8-t-butyldimethylsilyloxymethyl-4-acetyloxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (2.23 g).
Reaction SMILES: [CH:1](=[C:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Cl:14])[C:7]=1[Cl:15])=[O:5])[CH3:2]>S(=O)(=O)(O)O>[CH3:16][CH:3]1[CH:1]([CH3:2])[C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:4]1=[O:5]
Reactant: CC=C(C)C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2C

Procedure:
By following the procedure described in Example 5, Step D, using as the reactants 2-ethylidene-2',3'-dichloro-4'-methoxypropiophenone (30 g.) and sulfuric acid (120 ml.), there is obtained 2,3-dimethyl-5-methoxy-6,7-dichloro-1-indanone.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[C:15]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2cc(CO)c(-c3ccccc3-c3ccccc3)nc12
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of (2-chloro-8-methylquinolin-3-yl)methanol (342 mg, 1.65 mmol), 2-biphenylboronic acid (392 mg, 1.98 mmol) and K3PO4 (399 mg, 1.88 mmol) in DME (4 mL) and water (1 mL) was degassed. Pd(PPh3)4 (95 mg, 0.08 mmol) was added, the mixture was degassed and heated in the microwave at 120° C. for 1 h. The reaction mixture was allowed to cool and extracted with EtOAc (150 mL). The organic layer was washed with water (50 mL), separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc in heptane) gave the title compound (145 mg, 27%) as a white crystalline solid. δH (MeOD-d4) 8.19 (s, 1H), 7.71 (d, J 8.1 Hz, 1H), 7.40-7.66 (m, 6H), 7.15-7.20 (m, 2H), 7.08-7.12 (m, 3H), 4.30-4.40 (br m, 1H), 4.11-4.22 (br m, 1H), 2.70 (s, 3H). LCMS (ES+) 326.3 (M+H)+, RT 3.98 minutes (Method 3).
Reaction SMILES: [CH3:1]I.[Mg].[Cl-].[C:5]1([CH2:11][N+:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC>[C:5]1([CH2:11][N:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]2[CH3:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: Cc1cc[n+](Cc2ccccc2)cc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1=C(C)C(C)N(Cc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of methyl iodide (112 mL, 1.8 mole) in ether (225 mL) was added dropwise to a suspension of magnesium turnings (44 g, 1.8 mole) in ether (225 ml) under nitrogen over a period of 1 hour. The mixture was stirred at room temperature for 1 hour, transferred into a 1000 mL addition funnel and then was added to a suspension of N-(phenylmethyl)-3,4-dimethylpyridinium chloride (350.7 g, 1.5 mole) in ether (1500 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and was then poured into a solution of saturated ammonium chloride (3 L). The organic layer was separated and the aqueous layer was extracted with ether (1000 mL). The combined ether layers were washed with water (500 mL), then brine (500 mL) and were dried over sodium sulfate and potassium carbonate-. The solvent was removed in vacuo to afford 284.1 g (76%) of 1,2-dihydro-N-(phenylmethyl)-2,3,4-trimethylpyridine, as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([CH3:17])([CH3:16])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.CO.C[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH2:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=1
Reactant: COC(=O)C1C(Cc2ccc(Cl)cc2)=CCC1(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C

Procedure:
The crude 2-(4-chlorobenzyl)-4,4-dimethyl-3- methoxycarbonylcyclopent-1-ene obtained in Example 7 was refluxed for 15 hours in methanol containing one equivalent of sodium methoxide to give 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonyl- cyclopent-1-ene as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)CCl>[Cl:9][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCc1ccccn1
Solvent: ClCCCl
Product: CC(Cl)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of 107.16 g (1 mole) of 2-ethyl-pyridine in 400 ml of ethylene chloride was heated at reflux while adding in portions 150 g (0.65 mole) of trichloroisocyanuric acid (min. 90% available chlorine) over 5 hours and the mixture was stirred for another 2 hours and then cooled and vacuum filtered. The filtrate was washed with 50 ml of 5% of potassium hydroxide, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13].CC[O-].[Na+]>CCOCC>[CH2:10]([O:11][C:12]([C@H:13]1[C@H:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7]1)=[O:14])[CH3:9]
Reactant: CC(=O)OCCCl
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1O[C@H]1c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized using a literature method (Alcaide, B.; Biurrun, C.; Martinez, A.; Plumet, J. Tetrahedron Lett. 1995, 36, 5417). To a solution of thiophene-2-carboxaldehyde (6.33 ml, 69 mmol) and chloroethylacetate (7.35 ml, 69 mmol) in 130 ml of ether was added freshly made NaOEt (4.7 g, 69 mmol) over a period of one hour. The solution was allowed to stir overnight at room temperature. The reaction mixture was then filtered and the filtrate was partitioned between water and ether. The ether layer was extracted and washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% EtOAc in hexanes containing 1% NEt3, Rf=0.55). The title compound was isolated as a red oil in 64% yield. 1H NMR (CDCl3, 200 MHz) δ:7.30 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.4 Hz, 1H), 6.99 (dd, J=5.0 Hz, 3.4 Hz, 1H), 4.33 (s, 1H), 4.28 (qd, J=7.0 Hz, 2.0 Hz, 2H), 3.68 (d, J=2.0 Hz, 1H), 1.33 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 168.0, 138.6, 127.5, 127.4, 126.3, 69.1, 57.5, 54.9, 14.3 ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C(COC)OC>[C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: COCCOC
Product: COc1cc(C(=O)Cl)cc(OC)c1OC(C)=O
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
4-Acetoxy-3,5-dimethoxy-benzoic acid (1.45 g) was heated with thionyl chloride (0.86 g) in 3 mL of dimethoxyethane. After 1.5 hours the mixture was stripped under vacuum leaving 1.60 g of 4-acetoxy-3,5-dimethoxy-benzoyl chloride as an oil. 1H NMR (CDCl3, 300 MHz) δ (ppm): 2.26 (s, 3H), 3.89 (s, 9H), 7.34 (s, 2H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C3OCCO3)cc2)CCCCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Magnesium turnings (14.6 g, 600 mmol) was placed in a dry 4-necked flask. Dry THF (50 mL) and a crystal of iodine were added. A mixture of 2-(4-bromophenyl)-[1,3]-dioxolane (Tetrahedron, 57, No.28, (2001), 5991-6002) (135 g, 589 mmol) in dry THF (200 mL) was slowly added to initiate the reaction. After the reaction had started, the addition of 2-(4-bromophenyl)-[1,3]-dioxolane was continued at such a rate that the temperature was maintained between 35 and 40° C. After the addition was complete the mixture was stirred for 2 hours and then cooled to 5° C. on an ice bath. Cyclohexanone (57.8 g, 580 mmol) was added dropwise while maintaining the temperature below 10° C. The mixture was stirred for 18 hours at room temperature and two third of the THF was removed in vacuo. The residue was poured into a mixture of ammonium chloride (65 g) in ice water (1 liter) and extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulphate), filtered and evaporated in vacuo. The residual oil was slurred in petroleum ether to afford 48 g of 1-(4-[1,3]dioxolan-2yl-phenyl)cyclohexanol as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:13]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 92.4 %

Procedure:
5-Bromo-2-tert-butylphenol (1.08 g, 4.71 mmol), benzyl bromide (0.69 mL, 5.7 mmol) and Cs2CO3(2.3 g, 7.1 mmol) were added to 23.6 mL of acetonitrile and stirred at room temperature for 64 hours. The reaction mixture was filtered and concentrated to dryness. Purification by FCC resulted in title compound (1.39 g, 92%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1)=[O:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]([NH:19][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Benzoyl chloride (0.44 g, 0.37 mL) was added to a mixture of 2-aminothiazole-5-carboxylic acid methyl ester (0.50 g, 3.16 mmol), 4-dimethylaminopyridine (0.050 g, 0.41 mmol) and pyridine (2.5 mL, 31.60 mmol) in N,N-dimethylformamide (20 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 12 h, and concentrated in vacuo. The residue was purified by column chromatography to yield 2-benzoylaminothiazole-5-carboxylic acid methyl ester in 78% yield (0.654 g); MS (ES+) m/z 263.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].CO.C([BH3-])#[N:22].[Na+]>>[NH2:22][CH:16]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:2]([Br:1])[CH:3]=1)[CH3:17]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(C(=O)N2CCOCC2)c(Br)c1
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(C(=O)N2CCOCC2)c(Br)c1

Procedure:
To a solution of the compound yielded from step 4 (160 mg, 0.51 mmol) in MeOH (3 mL) ammonium acetate (395 mg, 5.13 mmol) and sodium cyanoborohydride (32 mg, 0.513 mmol) were added. The reaction mixture was refluxed for 3 h. Then the mixture was quenched by addition of trifluoroacetic acid (pH=2) and evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions leads to the desired product.