Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([N:30]1[CH2:31][CH2:32][S:28][CH2:29]1)=[O:14])=[O:9]
Reactant: C1CSCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCSC1
Temperature: -25 °C
Reaction time: 12 h

Procedure:
N-[(2-Oxo-1-pyrrolidinyl)acetyl]-L-proline as prepared in Example 1-B) (623 mg) was suspended in a mixture of methylene chloride (3 ml) and DMF (5 ml), to which were added HOBt (530 mg) and thiazolidine (0.21 ml). The mixture was cooled to -25° C. and DCC (588 mg) was added thereto. The mixture was stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 12 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 468 mg of 3-{N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl}thiazolidine.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OC1C=CCCC1
Solvent: c1ccncc1
Product: CC(=O)OC1C=CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 2-cyclohexen-1-ol (16) (45.5 mmol, 5.02 mL) in pyridine (0.27 mol, 22 mL) at 0° C., acetic anhydride was added dropwise and the reaction mixture was stirred at 0° C. for ½ h. The ice bath was removed, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with HCl (1N), saturated NaHCO3, brine, and concentrated in vacuo to give 6 g (94%) of the crude product 17 which was used in the next step without further purification. TLC with 20% EtOAc/Hexane, stained with 5% H2SO4/EtOH, Rf for (16): 0.4, Rf for (17): 0.8.
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C)nc(O)c1CN
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
2-Hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 0.43 mmol) was dissolved in ethanol (10 mL) and warmed to 60° C. before it was treated with raney nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resultant mixture was allowed to stir at 60° C. for 2 hours. The cooled reaction mixture was filtered through celite and rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 56%) as a white solid. LRMS (M+H+) m/z: calcd 168.09. found 168. HPLC purity (214 nm): 73%. 1H NMR (300 MHz, d6-DMSO): δ 6.04 (s, 1H), 3.77 (s, 3H), 3.42 (s, 2H), 2.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(F)c(N)c1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Reaction time: 8 h

Procedure:
TEA (1.92 mL, 13.8 mmol) was added to a mixture of 3-amino-2,4-difluoro-benzylamine (0.58 g, 2.5 mmol) in THF (40 ml) followed by pivaloyl chloride (0.31 mL, 2.5 mmol) and it was stirred overnight. The mixture was diluted with EtOAc, washed successively with satd. NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][OH:30])[C:21]=1[CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]=1[CH3:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C/CO)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-1-methyl-1-propenyl)benzene (120 mg) and triethylamine (32.8 mg) in dichloromethane (1.2 ml) was dropwise added methanesulfonyl chloride (34 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacua to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) as colorless oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[F:18])/[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(N)s1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
A mixture of 5-tert-butylthiazol-2-amine (1.93 g, 12.3 mmol) and triethylamine (3.44 mL, 2.46 mmol) in dichloromethane (50 mL) was treated with 2-fluoro-5-(trifluoromethyl)benzoyl chloride (Alfa, 1.87 mL, 12.3 mmol) and stirred at room temperature for 6 hours. The reaction mixture was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to give the title compound (3 g, 71% yield). MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: I[C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C@@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: I[C@H]1CCOC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(S[C@@H]2CCOC2)cc1
Reaction time: 8 h

Procedure:
To a suspension of (3S)-3-iodotetrahydrofuran [prepared according to the method outline in US2006004018] (1.2 g, 6.061 mmol) and K2CO3 (1.675 g, 12.12 mmol) in DMF (12.00 mL) at ambient temperature was added 4-bromobenzenethiol (1.146 g, 6.061 mmol). The resulting suspension was stirred at this temperature overnight. Water was added and then the aqueous layer extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a clear oil which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[NH:22][C:21]2=[O:31])=[C:4]([F:32])[CH:3]=1.N(OC(C)(C)C)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]([F:17])([F:18])[F:19])=[CH:6][C:5]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[NH:22][C:21]2=[O:31])=[C:4]([F:32])[CH:3]=1
Reactant: Nc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2C(F)(F)F)c(Cl)cc1F
Reaction time: 0.5 h

Procedure:
3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.0 g) dissolved in anhydrous N,N-dimethylformamide (10 ml) was added to a solution of t-butyl nitrite (1.28 g) in anhydrous N,N-dimethylformamide (40 ml) kept at 60-5° C. under nitrogen. The resulting mixture was stirred for 30 minutes at this temperature. The solution was poured into water and extracted with ethyl acetate: hexane, 1:1, (300 ml). The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2. 3-[4-Chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimid-ine-2,4-dione (Intermediate 11-28) was isolated as an amorphous solid (1.64 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1>[OH-].[Na+].O1CCOCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2 g methyl 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate in 30 ml 1N sodium hydroxide and 5 ml dioxane is stirred at 60° C. for 5 hours. This is then diluted with water, filtered, acidified with acetic acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness to obtain an oily product which crystallizes on standing. This is recrystallyzed to obtain 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. (M.P. 132°-4° C.)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15]Br>>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: CC(C)CCBr
Reactant: OCCCCCCCCCBr
Product: CC(C)CCCCCCCCCCCO
Yield: 51 %

Procedure:
12-methyltridecan-1-ol was prepared from 9-bromononan-1-ol and 3-methylbutylbromide in 51% yield. The 1H NMR and MS-ESI data matched those reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour and Fragrance Journal 19:199-204).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][N:14]2[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[C@H:18]([CH3:36])[N:17]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]2=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>Cl.O1CCOCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][N:14]2[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[C@H:18]([CH3:36])[N:17]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:40])=[O:41])[C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]2=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(Cl)nc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)c(Cl)nc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Reaction time: 2 h
Yield: 158.1 %

Procedure:
A rt suspension of tert-butyl(S)-1-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (61.6 mg, 89.8 μmol) in 4 M HCl in dioxane (449 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (44.2 mg, 79%) as a white solid. MS m/z 586 (MH)+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][C:23]([OH:25])=[O:24]>C1(C)C=CC=CC=1>[C:23]([O:25][C@@H:11]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]1=[CH:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21])(=[O:24])[CH3:22]
Reactant: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of androst-5-ene-3,17-dione (2.00 g) in toluene (10 ml) at 15° C., AcOH (10 ml) and LTA (3.40 g) were added. After stirring for 2 h, the mixture was warmed to RT and stirred for 24 h. The reaction was quenched by addition of H2O and extracted three times with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by triturating with a 1:1 mixture of n-hexane:EtOAc (3 ml) to give 4α-acetoxyandrost-5-ene-3,17-dione (600 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH:19](C#N)[C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1.Br.O>C(O)(=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1
Reactant: N#CC1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Yield: 26.6 %

Procedure:
1'-(4-bromo-2-fluorobenzyl)-4-cyano-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.0 g.) was heated under reflux in 48% w/w hydrogen bromide in acetic acid (30 ml.) for 90 minutes. The solution was poured into water (120 ml.). The precipitate was collected, washed with water (100 ml.), air dried and recrystallised twice from 2-propanol to give 1'-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.25 g.), m.p. 218°-220° C.
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.[C:25]1([S:31]([N:34]([CH2:41][C:42](O)=[O:43])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([S:31]([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:41][C:42]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([N:9]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=4[C:12]4=[N:20][O:21][C:22]([CH3:23])=[C:11]4[C:10]3=[O:24])[CH2:4]2)=[O:43])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CN(c1ccccn1)S(=O)(=O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Agent: I
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CN(c3ccccn3)S(=O)(=O)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 144 h
Yield: 47 %

Procedure:
To a solution of 5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28 mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46 mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) of EDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixture was stirred six days at rt. and was concentrated to dryness. The residue was dissolved in 20% isopropanol/chloroform, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using a MeOH/chloroform gradient and concentrated to dryness. The residue was slurried in ether/hexanes and concentrated to dryness to yield 79 mg (47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][C:30]#[N:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:29][C:30]#[N:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CC#N)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (104 mg, 0.28 mmol), chloroacetonitrile (25 μL, 0.39 mmol), K2CO3 (88 mg, 0.64 mmol), and DMF (2 mL). The reaction mixture was heated at 60° C. for 8 h then cooled to room temperature. The reaction mixture was concentrated and adsorbed onto silica gel then purified by silica gel flash chromatography with a 0-10% MeOH/CH2Cl2 gradient to afford product as a light green solid (65 mg, 57%). LC/MS (Method B) 3.84 min, [M+1]+ 406.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[C@H:51]([NH2:54])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])=[O:44]>C(Cl)Cl>[C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[CH:51]([NH:54][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])(=[O:44])[CH3:42]
Reactant: NC(=S)CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of dicyclohexyldicarbodiimide in 5 ml of methylene chloride was added to a solution of 1.01 g of the product of Step A, 2 ml of pyridine and 0.656 g of 7-amino-cephalosporanic acid and the mixture was stirred at room temperature to effect precipitation and was vacuum filtered. The product was rinsed with methylene chloride and dried to remove about 0.5 g of dicyclohexylurea. The filtrate was poured into 25 ml of hydrochloric acid and the mixture was stirred for 5 minutes. The decanted organic phase was washed with 25 ml of water and was dried and vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in isopropyl ether. Efflorescence occured and the mixture was vacuum filtered. The recovered product was rinsed and was dissolved in 4 ml of ethyl acetate 0.18 g of activated carbon were added thereto and the mixture was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was stirred while 20 ml of isopropyl ether were added over 5 minutes. The mixture was stirred another 5 minutes and was vacuum filtered. The recovered product was rinsed with isopropyl ether and was dried to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-amino-2-thioxoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:14][C:12]([CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])=[O:13]
Reactant: NC(=O)CCl
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a mixture of 12.21 g of 3-hydroxybenzaldehyde, 14.00 g of 2-chloroacetamide and 60 ml of dimethylformamide was added 20.70 g of potassium carbonate, and this was heated to stir at 90° C. for 2 hours. After cooled to room temperature, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran by heating. Insolubles were filtered and the filtrate was concentration under reduced pressure. The resulting crude crystals were washed with a mixed solution of tetrahydrofuran and t-butyl methyl ether and dried to obtain 13.05 g of 3-(aminocarbonylmethoxy)benzaldehyde [Compound No. (n)] as a crystal.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(S([C:19]1[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=1[C:24]#[N:25])=O)C>C(#N)C>[C:1]1([S:7][C:19]2[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=2[C:24]#[N:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(=O)c1sc(C#N)cc1C#N
Reactant: Sc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#N)c(Sc2ccccc2)s1
Reaction time: 8 h

Procedure:
4.4 ml of thiophenol and 5.0 ml of triethylamine are added, while stirring, to a solution of 8.9 g of 2-ethylsulphinyl-3,5-dicyanothiophene, obtained according to Example I, in 100 ml of acetonitrile. After leaving to stand overnight, the reaction mixture is refluxed for 8 hours. After evaporating the solvent, the residue is taken up in methylene chloride and chromatographed over a 1 l dry silica gel column. The desired product is obtained in a yield of 9.07 g; melting-point 68°-71° C. Optionally, any 2-alkylsulphinyl compound may be used as the starting substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 3-(4-fluorophenyl)propionyl chloride (287.6 g, 1.5 mol) in dichloromethane (1.4 L) was added dropwise during 3 h to an ice-cold, mechanically stirred suspension of aluminum chloride (226.0 g, 1.7 mol, Aldrich) in dichloromethane (2.2 L) under nitrogen. The resulting yellowish-black solution was refluxed for 5 h and allowed to cool to room temperature. The solution was washed successively with water (2 L), 1N sodium hydroxide (2 L), water (2 L) and brine (2 L). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a tan solid (229.1 g, 99%). The solid was recrystallized from dichloromethane-hexane to give 215.7 g (93%) of 6-fluoro-1-indanone as off-white crystals, m.p., 57-59° C.;