Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[O:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc(Br)co1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc(Br)co2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-bromofuran-2-carbaldehyde (2.10 g, 12.0 mmol) and THF (10 mL) that was cooled in an ice bath was added 1-methylpiperazine (1.60 ml, 14.4 mmol) dropwise, followed by sodium triacetoxyborohydride (3.81 g, 18.0 mmol) in 3 portions as solid. Acetic acid (0.343 ml, 6.00 mmol) was added, and the reaction was stirred for 18 hours at ambient temperature. The dark mixture was diluted with water (10 mL) and basified to pH>12 by addition of 5N NaOH. The mixture was extracted with diethyl ether (3×50 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting black oil (2.10 g, 66%) was carried forward without purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])[C:4]([NH2:6])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C1COCC1.C(N(CC)CC)C>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:2][C@H:3]([CH2:7][CH2:8][C:9]([F:10])([F:11])[F:12])[C:4]([NH2:6])=[O:5])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NC(=O)[C@H](N)CCC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a suitable dry vessel was added (R)-2-amino-5,5,5-trifluoropentanamide hydrochloride (199.52 g 0.966 mol, 1.0 equiv) followed by 4-chlorobenzenesulfonyl chloride (215.22 g 0.989 mol, 1.02 equiv, 97% w/w %) and 1.6 L of THF at room temperature. Triethylamine (206.5 g, 2.04 mol, 2.1 equiv.) was added over 20 min, maintaining the pot temperature at 15-25° C., and the resulting white slurry was stirred at 15-25° C. for 30 min. Water (1.4 L, 7 vol) of was added to the reaction mixture at 20-25° C. and then THF (1.4 L, 7 vol) was removed by distillation under vacuum (the pot temperature was maintained at 40-60° C. under 250-400 mmHg during distillation process). When the distillation process was complete, 1.4 L (7 vol) of water was added over 30 min while maintaining the pot temperature at 50-60° C., and the resulting slurry was stirred at 50-60° C. for 30 min and then cooled to 10° C. The slurry was agitated for not less than 1 hour, and the product was filtered. The filter cake was washed with water (600 mL each wash) until the pH of the cake wash measured ≧5. The cake was dried under vacuum at not more than 70° C. (jacket temp.) until the loss on drying is <0.5 w/w %, giving the title compound as a white solid (300 g, 91% yield.) 1H NMR (DMSO-d6) (400 MHz) δ 160-1.90 (two m, 1H each of CH2), 2.10-2.35 (m, 2H of CH2—CF3), 3.85-3.88 (m,1H, —(CONH2)CH(NH), 7.13 & 7.37 (br s, 1H, each of CONH2), 7.61 (m, 2H, Ar—Ha), 7.64 (m, 2H, Ar—Hb), 8.18 (d, 1H, J=8.0 Hz, NH—SO2). 13C NMR (DMSO-d6) (100.0 MHz) δ 171.75, 140.27, 137.77, 131.71, 129.56, 128.95, 126.22, 55.12, 30.1, 29.82, 29.53, 29.25, 25.82, 25.79.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][CH3:49])/[C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:42]([OH:44])=[O:43])=[C:15]([CH2:18][NH:19][C:20]4[N:21](C)[N:22]=[C:23](OC(C5C=CC=CC=5)C5C=CC=CC=5)[C:24](=[O:26])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:50]1([O:56]C)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][CH3:49])/[C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:42]([OH:44])=[O:43])=[C:15]([CH2:18][NH:19][C:20]4[NH:21][N:22]=[C:23]([CH2:50][OH:56])[C:24](=[O:26])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COc1ccccc1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(CO)n[nH]3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 25 %

Procedure:
A solution of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid (400 mg.) in anisole/TFA (1:1 v/v; 10 ml.) was allowed to stand at ambient temperature for 20 minutes. The solvent was evaporated and the residue was dissolved in an aqueous ammonium carbonate buffer, pH6, and purified by HPLC using ammonium carbonate buffer/MeOH 92:8 v/v as eluant to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-hydroxymethyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid (yield 25%) having the following nmr in solvent B:--3.52(s,3 H); 3.6(s, 2 H); 4.04(s, 3 H); 4.4(s, 2 H); 5.18(d,1 H); 5.84(d, 1 H); 7.1(s, 1 H).
Reaction SMILES: [Br:1][C:2]([Br:16])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>O1CCCC1.C(OCC)C>[Br:16][C:2]([Br:1])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
To a stirred mixture of 2-(2,2-dibromoethenyl)-5-(4-hydroxyphenyl)thiophene (1.0 g, 0.003 mole) and triethylamine (1.2 g, 0.08 mole) in tetrahydrofuran (20 mL) was added acetyl chloride (0.44 g, 0.0056 mole). The reaction mixture was stirred at room temperature for approximately 18 hours. The mixture was diluted with diethyl ether and washed in succession with an aqueous 5% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The washed mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, yielding 0.5 g of 2-(2,2-dibromoethenyl)-5-(4-acetyloxyphenyl)thiophene as a solid (mp 115°-115.5° C.).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:34][O:35][NH2:36]>CO>[CH3:34][O:35][NH:36][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CON
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 7 h
Yield: 495.6 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic acid (320 mg) in methanol (3 ml) are added triethylamine (0.33 ml) and N,N'-dicyclohexylcarbodiimide (495 mg), and th mixture is stirred for 7 hours. To this solution is added a solution of methoxyamine hydrochloride (33.4 mg) and triethylamine (56 μl) in methanol (0.3 ml). After the addition of a further amount of N,N'-dicyclohexylcarbodiimide (124 mg), the mixture is left stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure to about 1 ml and then diluted with ethyl acetate (8 ml) and 5% sodium hydrogen carbonate (7 ml). After the separated solid (461 mg) is removed by filtration, the filtrate is saturated with sodium chloride and diluted with ethyl acetate-methyl ethyl ketone mixture (1:1). The mixture is acidified to pH 1 with hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (375 mg), identical with the product prepared with N,N'-carbonyldiimidazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCO.CO>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Solvent: CO
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 84.9 %

Procedure:
A solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (1) (0.25 g, 1.1 mmol) and aniline (2) (0.16 g, 1.7 mmol) in n-BuOH (25 mL) was heated at 120° C. for 12 h in a pressure tube. The reaction mixture was cooled, was dissolved in methanol (10 mL) and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35 mL) and was washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The ethyl acetate extract was dried over Na2SO4 and was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give (260 mg, 83%) N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (3) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24].Cl[C:31]1C=C(Cl)[N:34]=[CH:33][N:32]=1>C1COCC1.N1CCCC1>[CH3:1][C:2]1([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:31]3[CH:24]=[C:23]([N:25]4[CH2:28][CH2:29][CH2:27][CH2:26]4)[N:34]=[CH:33][N:32]=3)[CH2:19][CH2:18]2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCN(CC)CC
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCNCC1)O2
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCN(c3cc(N4CCCC4)ncn3)CC1)O2
Reaction time: 18 h

Procedure:
To a stirred suspension of 3,4-dihydro-2,5,7,8-tetramethyl-2-(1-piperazinylmethyl)-2H-1-benzopyran-6-ol (EXAMPLE 126, 0.7 g), triethylamine (0.23 g, 2.3 mmol) and THF (10 ml), cooled to 0° in an ice-water bath, is added in a steady stream 4,6-dichloropyrimidine in THF (5 ml). The cooling bath is removed and the mixture stirred at 20°-25° for 18 hr. Ethyl acetate (50 ml) is added and the mixture is washed with water (50 ml), saline, dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue that is dissolved in pyrrolidine (5 ml). The mixture is heated at reflux for 2 hr and concentrated at reduced pressure. The residue is flashed chromatographed on silica gel (50 g) eluting with ammonia, methanol and ethyl acetate (0.5/4.5/95) to give the product which is crystallized from hexane-ethyl acetate to give the title compound.
Reaction SMILES: [N:1]([C@H:4]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:21][C:22](=[O:24])[CH3:23])[C@H:14]([CH3:25])[O:13][CH:5]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].C([O-])(O)=[O:27].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[N:1]([C@H:4]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:21][C:22](=[O:24])[CH3:23])[C@H:14]([CH3:25])[O:13][CH:5]1[S:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:27])=[N+:2]=[N-:3]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(Sc2ccccc2)[C@H]1N=[N+]=[N-]
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(S(=O)c2ccccc2)[C@H]1N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 2-azido-3,4-di-O-acetyl-2,6-dideoxy-1-thio-L-galactopyranoside (22) (1.02 g, 2.80 mmol) in 50 mL of CH2Cl2 is added NaHCO3 at room temperature. The reaction mixture is cooled to -78° C., and mCPBA (0.878 g, 2.80 mmol, 50-60%) is added. The reaction mixture is stirred at -78° C. for 30 minutes and then allowed to warm to -40° C. over 1 h. The reaction is quenched with dimethyl sulfide (1 mL) at -40° C. and then poured into a solution of saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×30 mL) The organic layers are combined, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (EtOAc/petroleum ether) to afford the title compound 26 as a mixture of diastereomers.
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].O[CH:8]([CH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12].[CH:19](=C1CCCC1=O)CCCC>>[O:18]=[C:14]1[CH2:15][CH2:16][CH:17]([CH2:1][C:2]([O:4][CH3:19])=[O:3])[CH:13]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(O)C1CCCC1=O
Reactant: O=C(O)C(=O)O
Reactant: CCCCC=C1CCCC1=O
Product: CCCCCC1C(=O)CCC1CC(=O)OC

Procedure:
The reaction in Comparative Example 1 was carried out 3 times, the product was distilled to recover cyclopentanone and water, then 0.0206 mol oxalic acid was added to 1.11 mol 2-(1-hydroxy-n-pentyl)cyclopentanone and 0.012 mol 2-pentylidene cyclopentanone from the product, and the mixture was reacted at 120° C. Thereafter, the reaction was carried out in the same manner as in Example 7, to give methyl 3-oxo-2-pentylcyclopentylacetate. As a result, the yield in the whole process was 28%.
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17]C2CCCCO2)[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si](C(C)(C)C)(C)C.F>C(#N)C>[F:46][C:39]([F:47])([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@H:9]([OH:1])[CH2:10][CH2:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Product: CCCCCCC(F)(F)[C@H](O)CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1O

Procedure:
The compound (12-11)(0.93 g) was hydrolyzed in acetonitrile (30 ml) with 46% hydrofluoric acid(1.55 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=7/3-1/1), and the compound obtained was further fractionated by HPLC to give isopropyl 9-{2(R)-[4,4-difluoro-3(R)-hydroxydecyl]-3(R)-hydroxy-5-oxocyclopentyl}nonanoate (12-12).
Reaction SMILES: [C:1]1(=O)CCCC1.P([O-])([O-])([O-])=O.[BH4-].[Na+].[C:14]([O:17][CH:18]1[CH:22]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]([C:27]([O:29][CH3:30])=[O:28])[CH:20]([OH:31])[CH2:19]1)(=[O:16])[CH3:15]>O.CO>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH:22]1[CH:18]([O:17][C:14](=[O:16])[CH3:15])[CH2:19][CH:20]([OH:31])[CH:21]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C1CCCC1
Reactant: COC(=O)C1C(O)CC(OC(C)=O)C1CC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC1C(OC(C)=O)CC(O)C1C(=O)OC
Reaction time: 2 h

Procedure:
The cyclopentanone VI (8.6 g.), obtained according to the previous example, is dissolved in 50 ml. of methanol and added to 500 ml. of a phosphate buffer adjusted to a pH of 5.3. Then 20 ml. of an aqueous solution containing an excess of sodium borohydride (1.25 g.) is added at 5° C. After two hours at room temperature, 200 ml. of water is added to the reaction mixture which is then extracted several times with ethyl acetate. The combined organic layers are dried on MgSO4 and then evaporated to dryness giving 8.4 g. (98%) of crude methylester of 5-acetoxy-2-carbomethoxy-3-hydroxycyclopentaneacetic acid. This product examined by gas chromatography exhibits an 80% purity. The product which may be further purified by column chromatography has all the substituent groups with the desired orientation. The compound may not be distilled without decomposition. The principal absorption peaks in the N.M.R. spectrum in CDCl3 occur at the following frequencies expressed in δ units: 2.05 (3H, singlet), 3.65 (3H, singlet), 3.72 (3H, singlet), 4.30-4.70 (1H, multiplet, 5.18-5.43 (1H, multiplet).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[C:15]=[O:16]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]([NH:14][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[CH:22]4)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
1-(4-Chlorophenyl)piperazine (197 mg, 1.01 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 1H), 8.49 (d, 1H, 6.1 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.77 (m, 1H), 7.61-7.72 (m, 2H), 7.26-7.29 (m, 2H), 7.01-7.04 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESI+) m/z 367 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[O:32][C:33]=1[CH3:34]>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[O:32][C:33]=2[CH3:34])=[C:3]([O:14][CH3:15])[CH:4]=1)[CH3:13]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl (4-hydroxy-3-methoxyphenyl)acetate (7.00 g), potassium carbonate (5.43 g) and N,N-dimethylformamide (100 mL) was added 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.77 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)acetate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave white crystal (8.22 g, yield 56%) melting point: 106-107° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: COc1nc2ccc(Cl)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
3-Amino-6-chloro-2-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 803 mg of the titled compound (yield, 95%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=S)[CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:31][N:30]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: S=C=Nc1cccc(Br)c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Brc1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Bromo-3-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (3-Bromo-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 34% yield.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17]C1C=C(C)C=CC=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:17][C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][CH:2]=1)[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1cccc(C)c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 3-bromomethyltoluene (15 g), a 2M ethanolic solution of sodium ethylate (44.5 cc) and ethyl 2-mercaptoacetate (9.7 g) in ethanol (100 cc). Ethyl (3-methylbenzylthio)acetate (14.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.C[N:50]1CCO[CH2:52][CH2:51]1.CN(C=O)C>C1COCC1>[CH:35]1([CH:51]([NH:50][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])[CH3:52])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CN1CCOCC1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2)C1CCCCC1

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.050 g, 0.127 mmol), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.081 g, 0.254 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and R-(−)-1-cyclohexyl ethyl amine (0.032 g, 0.254 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.09 (d, J=6.3 Hz, 3H), 1.14-1.23 (m, 4H), 1.40 (s, 3H), 1.48 (s, 3H), 1.52-1.63 (m, 7H), 2.72 (s, 2H), 3.84 (m, 1H), 7.21 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 8.40 (s, 2H), 11.00 (s, 2H); MS [M+H]+: 502.45.