Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([O:15][CH3:16])[CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N+:24]([C:27]1[CH:34]=[CH:33][C:30](CBr)=[CH:29][CH:28]=1)([O-:26])=[O:25].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:16][O:15][CH:13]([CH:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:6][C:30]1[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(C)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(C)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-methoxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.4 mmol) in CH2Cl2 (25 mL) is cooled to 0° C. and TFA (2.5 mL) is added dropwise. The mixture is allowed to stir at room temperature overnight. The volatiles were removed and CH3CN (20 mL) is added. After addition of 4-nitrobenzyl bromide (1.25 g, 5.78 mmol) and K2CO3 (2.0 g, 14.4 mmol) the mixture is stirred at room temperature for 5 hours. Aqueous workup followed by chromatography. (260 mg, 25%). 1H NMR (300 MHz, CDCl3) ∂8.17 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.4 Hz), 4.29 (1H, d, J=14.4 Hz), 3.48 (1H, d, J=14.4 Hz), 3.30-3.33 (1H, m), 3.32 (3H, s), 2.88-2.91 (1H, m), 2.73-2.78 (1H, m), 2.14-2.19 (1H, m), 1.61-1.85 (4H, m), 1.15 (3H, d, J=6.6 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:12][CH2:13]1
Reactant: Cc1nc(N)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(N2CCC(N)CC2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
3.2 g (7.6 mmol) of {1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester are dissolved in DCM (50 mL) and 26 mL TFA are added. The reaction mixture is stirred over night at RT. The reaction mixture is adjusted to neutral pH using concentrated aqueous Na2CO3 solution and the DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried. The crude product is used without further purification in the next step.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[H-].[Na+].[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21](I)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1.[Cu]Br>[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21]([O:3][C:2]2[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=2[O:8][CH3:9])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccccc1O
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccccc2OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A mixture of guaiacol (0.77 g, 6.2 mmol), copper (I) bromide (0.89 g, 6.2 mmol), and sodium hydride (0.3 g of a 60% dispersion, 7.5 mmol) in 100 mL pyridine was heated to reflux and stirred under nitrogen for 15 min. 3-Iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol) was added, and the resulting mixture was stirred at reflux for 20 h. The mixture was cooled to room temperature and quenched by the addition of saturated NH4Cl (15 mL). Volatiles were removed under reduced pressure. The residue was partitioned between dilute aqueous HCl (100 mL) and ethyl acetate (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with dilute aqueous HCl (2×100 mL), saturated Na2CO3 (2×100 mL), again with dilute aqueous HCl (2×100 mL) and finally with water (100 mL), and were evaporated. Chromatography in hexanes-ethyl acetate gradient provided 0.75 g of 3-(2-methoxy-phenoxy)-phthalic acid dimethyl ester, eluting at 25-30% ethyl acetate, in 38% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.86-6.91 (m, 1H), 6.93-7.01 (m, 2H), 7.05 (dd, J=7.9 Hz. J=1.6 Hz, 1H), 7.13-7.20 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.66-7.69 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>>[NH2:47][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCC(N)=O

Procedure:
5-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide (4.4 g, 14 mmol) was treated with mCPBA (4.28 g, 24.8 mmol), ammonium hydroxide (40 mL), and p-toluenesulfonyl chloride (5.24 g, 27.4 mmol) according to a modification of the method described in Part F of Example 34. At the completion of the amination reaction, a precipitate was present and was isolated by filtration. The precipitate was triturated and sonicated with acetone, isolated by filtration, and dried in a vacuum oven at 80° C. to provide 1.28 g of 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide as a tan powder, mp 202-203° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=2)[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=2)[N:13]=[CH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCN(C)Cc3ccccc3)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccccc1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of methyl 2-(1-{2-[benzyl(methyl)amino]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (100 mg, 0.26 mmol) in MeOH (5 mL) was added 10 N NaOH solution (1 g). The mixture was stirred and refluxed for 1 hr and then cooled to r.t. The pH was carefully adjusted to 6.5 and the resulting mixture was concentrated to a residue. The residue was diluted with MeOH (10 mL) and filtered. The solids were washed with additional MeOH (10 mL). The filtrate was concentrated to an oily residue and chromatographed on silica gel (90% MeOH, 10% pH 7 buffer [potassium phosphate based] to give an amber oil. This oil was then chromatographed on reverse phase C18 silica gel [40-63 microns (mesh 230-400); 60 Å; 500 m2/g; pore volume 0.8 ml/g] using 80% MeOH/10% DI H2O to give the title compound (28 mg) as a beige solid: 1HNMR (400 MHz, DMSO): δ 2.18 (3H, s), 2.69 (2H, m), 3.51 (2H, m), 4.18 (2H, m), 7.17-7.23 (5H, m), 7.58 (1H, s), 7.73 (2H, m), 8.34 (1H, s), 8.54 (1H, s). [M+H] Calc'd for C19H20N4O2, 337. Found, 337.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC(OC)=CC=3)=[CH:20][CH:19]=2)[C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(COc2ccc(Nc3c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c3C(=O)O)cc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1c2cc(O)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 5.0 g of 2-chloro-6-[[4-[(4-methoxyphenyl)methoxy]phenyl]amino]-3,5-dinitrobenzoic acid, 10 ml of phosphorus oxychloride, 0.2 ml of N,N-dimethylaniline and 50 ml of 1,2-dichloroethane was heated at reflux for 15 minutes and the reaction mixture was filtered hot. The filter cake was washed with 1,2-dichloroethane to provide the title compound, mp 278°-281° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][OH:26])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[N:32]#[C:33]Br.N>CO>[NH2:32][C:33]1[O:26][CH2:25][C@H:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])=[CH:7][CH:6]=2)[N:1]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)CO1
Temperature: 25 °C
Reaction time: 36 h
Yield: 6.7 %

Procedure:
Isoquinoline-5-sulfonic acid [4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-amide (109 mg) was dissolved in methanol (3 ml) at room temperature before addition of sodium acetate (72.2 mg) and a solution of cyanogen bromide (40.4 mg) in methanol (1 ml) dropwise. The reaction mixture was stirred at room temperature for 36 hours, then aqueous ammonia 25% was added (55 μl) and stirring was continued for an another hour. The solvent was evaporated in vacuo and the residue purified by Isco chromatography (column: Silicycle Si-Amine, AcOEt) to give isoquinoline-5-sulfonic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide (7.8 mg) as a yellow solid. Description. MS (ISP): 397.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1ccc(C=O)cc1Br
Product: CCOc1ccc(Cc2ccc(OC)c(Br)c2)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 3-bromo-4-methoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:30])[C:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:30])[C:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:6]1[CH2:7][CH2:8][C:9]2[O:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: CCOC(=O)C(C)(C)CCCCC(Br)c1ccccc1Cl
Reactant: c1cc2c(o1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2occc2C1
Temperature: 65 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
4,5,6,7-Tetrahydrofuro[3,2-c]pyridine (0.16 g, 1.3 mmol), 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (0.49 g, 1.3 mmol) in DMF (13 mL), and potassium carbonate (0.27 g, 1.95 mmol) were combined under an argon atmosphere at room temperature. The mixture was heated to 65° C. overnight under an argon atmosphere. The reaction continued at 65° C. for 48 hours. After cooling to room temperature and concentration under reduced pressure, the crude product (0.28 g) was purified by column chromatography (silica gel, ethyl acetate/heptane=1/20 to 1/5) to afford 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (Compound Ij, 0.26 g, 48.1% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.42 (d, 1H, J=7.5 Hz), 7.29 (d, 1H, J=7.2 Hz), 7.17 (t, 1H, J=8.7 Hz), 7.14 (s, 1H), 7.09 (t, 1H, J=8.1 Hz), 6.08 (s, 1H), 4.12 (t, 1H, J=4.2 Hz), 4.01 (q, 2H, J=7.2 Hz), 3.98 (d, 1H, J=14.4 Hz), 3.26 (d, 1H, J=13.5 Hz), 2.79-2.53 (m, 4H), 1.90-1.73 (m, 2H), 1.35-1.32 (m, 2H), 1.20-1.06 (m, 7H), 1.04 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.91, 148.97, 140.89, 139.39, 134.93, 129.50, 129.00, 128.02, 126.84, 115.82, 108.84, 63.33, 60.54, 47.61, 47.51, 42.28, 40.78, 33.21, 26.23, 25.35, 24.65, 14.50.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Li+]>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH3:14])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncc1CO
Temperature: 55 °C
Yield: 111.1 %

Procedure:
To a solution of ethyl 6-chloro-4-(methylamino)nicotinate (4.7 g, 21.9 mmol) in THF (30 mL) and methanol (30 mL) was added lithium borohydride (2.4 g, 109.8 mmol), and the reaction mixture was heated at 55° C. overnight. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (1 mL) and filtered. The filtrate was concentrated to afford the title compound (4.2 g, crude) as a white solid, which was directly used in the next step without further purification. MS (ES+) C7H9ClN2O requires: 172, 174. Found: 173, 175 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH3:13][N:14](CCO)[CH3:15].[Na]>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH2:10][N:14]([CH3:15])[CH3:13])=[O:7])=[CH2:2]
Reactant: C=CC1CC1(C#N)C(=O)OCC
Reactant: CN(C)CCO
Agent: [Na]
Product: C=CC1CC1(C#N)C(=O)OCCN(C)C
Reaction time: 0.58 h

Procedure:
2-(N,N-dimethylamino)ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was prepared by reacting essentially equimolar amounts of ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate and N,N-dimethylaminoethanol. For the reaction, a small amount of sodium metal (1.13 wt. %) was reacted with the N,N-dimethylaminoethanol prior to the addition of the ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate. The reaction mixture was stirred for 35 minutes after which time gas chromatographic analysis indicated the reaction to be 70% complete. After workup of the reaction mixture, the crude product was vacuum distilled to obtain the 2-(N,N-dimethylamino)ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate (B.p. 97° C. at 0.015 mm Hg). The infrared spectrum was consistent with the structure. nmr (CDCl3)τ 3.97-4.85(3 vinyl H, mult.); 5.75(2H, tr.); 7.15-7.60(1H(2 ring position, hidden), mult); 7.37(2H, tr.); 7.74(6H,s); 7.85-8.55(2H(3 ring position), mult.).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.C(N)C.CO[C:17]1[C:21]([NH:22][CH2:23][CH3:24])=[N:20][S:19](=[O:26])(=[O:25])[N:18]=1.[CH3:27][N:28]([CH2:30][C:31]1[O:35][C:34]([CH2:36][S:37][CH2:38][CH2:39][NH2:40])=[CH:33][CH:32]=1)[CH3:29]>>[CH3:29][N:28]([CH2:30][C:31]1[O:35][C:34]([CH2:36][S:37][CH2:38][CH2:39][NH:40][C:17]2[C:21]([NH:22][CH2:23][CH3:24])=[N:20][S:19](=[O:26])(=[O:25])[N:18]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCNC1=NS(=O)(=O)N=C1OC
Agent: CCN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of ethylamine and treatment of the resultant 3-methoxy-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the title compound, which is identical to the product prepared in Example 12.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>CCCCCC.O.O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[C:20]([OH:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[C:17]([F:16])([F:27])[F:28])[C:12]#[N:13])=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture comprising 5.8 g of 63% sodium hydride, 25 ml of tetrahydrofuran and 10 ml of liquid paraffin, was heated, and a mixture comprising 13.5 g of 4-tert-butylbenzyl cyanide and 15.0 g of 2-trifluoromethylbenzoyl chloride, was dropwise added thereto over a period of 2 hours at a temperature of from 65 to 70° C. After completion of the dropwise addition, the reaction was carried out for 2 hours at the same temperature. The reaction mixture was left to cool to room temperature, and 250 ml of water was poured into the solution. Then, 80 ml of n-hexane was poured, followed by stirring and washing for 10 minutes, and the mixture was left to stand still for 30 minutes, whereupon the aqueous layer was separated and obtained. To the aqueous layer, 8.3 g of concentrated hydrochloric acid was gradually dropwise added with stirring, followed by further stirring for 30 minutes. Precipitated crystals were collected by filtration and washed with 100 ml of water, and then dried at 55° C. for 24 hours to obtain 23.8 g of the desired product. The NMR spectrum data of this product were the same as in Reference Preparation Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:5]1[CH2:10][CH:9](O)[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[CH2:6]1.I[Si](C)(C)C.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]([C@@H:4]([N:5]1[CH2:6][C:7]2[CH:14]=[CH:13][S:12][C:8]=2[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:22]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (9) (59.79 g, 177.0 mmol) in toluene and acetonitrile is added to a solution of iodotrimethylsilane in acetonitrile at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 2 hours. Water is then added to the mixture at 0–5° C. The mixture is then warmed again to room temperature and stirred for an additional 4 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oil product (55.8 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:11]([CH3:24])[CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[C:20]([O:19][C:17]([NH:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:48](=[O:49])[CH2:47][O:46][C:45]3[CH:44]=[CH:43][C:42]([CH2:41][CH:37]4[S:36][C:35](=[O:34])[NH:39][C:38]4=[O:40])=[CH:52][CH:51]=3)=[C:3]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:4]=2)=[CH:10][C:11]=1[CH3:24])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of t-butyl N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate (1.56 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.05 g), diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and anhydrous tetrahydrofuran (30 ml) was stirred at room temperature for 19 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1 as the eluant to afford the desired compound (1.89 g, Rf=0.19: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:3 as the eluant).
Reaction SMILES: [S:1]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[OH-].[K+]>CN(C=O)C>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)cc1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2cc3ccccc3n2CCCCBr)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-tosyl-1H-indole (199 mg, 0.73 mmol) in 3 mL DMF was added 1,4-dibromobutane (263 μL, 2.20 mmol) in 1 mL DMF and KOH (41 mg, 0.73 mmol), and the reaction stirred at room temperature 1.75 h. The reaction mixture was then partitioned between water and ether, and the aqueous layer extracted twice with ether. The combined organic extract was washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 15% ethyl acetate in hexanes to give a final yield of 178 mg (0.44 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.66-1.81 (m, 2H), 1.81-1.94 (m, 2H), 2.44 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 4.35 (t, J=7.6 Hz, 2H), 7.21 (t, J=7.0 Hz, 1H), 7.30-7.44 (m, 5H), 7.73 (d, J=7.9 Hz, 1H), 7.87 (d, J=8.1 Hz, 2H). 13C NMR (500 MHz, CDCl3, δ): 22.07, 29.04, 30.26, 33.26, 44.41, 111.08, 111.49, 121.67, 123.42, 125.83, 126.19, 128.09, 130.44, 135.22, 138.78, 139.12, 145.08. MS m/z 406.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3]1.[CH2:13](O)[CH2:14][OH:15].[OH-].[Na+]>C1C=CC=CC=1.C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:1]1[C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]2)[O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)C1CCCC2(C1)OCCO2

Procedure:
A mixture of ethyl 3-oxocyclohexanecarboxylate (Nallet, J- P., et al, Bull. Soc. Chem. Fr., Part II, No. 3-4, pages 153-156 (1979)) (101.7 g) ethylene glycol (38.9 g) and para-toluenesulfonic acid (5.5 g) in 1000 mL of benzene is refluxed with a Dean-Stark trap for 4 hours. The solution is cooled, washed with 1N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo to give 113.1 g of a light oil which is dissolved in 1000 mL of ethanol, treated with sodium hydroxide (25.3 g) in 250 mL of water, and refluxed for 2.5 hours. The mixture is concentrated in vacuo, cooled in an ice bath, and acidified with ice-cold 1N aqueous hydrochloric acid solution to a pH of 2. The title compound is extracted with chloroform (2×500 mL), dried over magnesium sulfate, and concentrated in vacuo. The title compound (99.3 g) is obtained as a yellowish oil, which is determined to be 98% pure by gas chromatography and is carried on without further purification.