Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[CH:19]=3)=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[C:19]=3[CH:21]([OH:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=O
Reactant: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-imidazo[1,2-a]pyridine (19b) (50 mg, 0.2 mmol), ethyl glyoxylate 50% in toluene (0.20 mL, 1.0 mmol) and p-toluenesulfonic acid (6 mg, 0.03 mmol) in ethanol (1 mL) was heated at 80° C. for 1 hour. Ethyl glyoxylate 50% in toluene (0.10 mL, 0.5 mmol) was added and the heating was maintained for one supplementary hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogencarbonate (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired hydroxyl-ester (19c) (56 mg, 0.159 mmol, 80%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[CH2:23][CH3:24])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1CC
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a mixture of 10.0 g of (2S,4R)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride, 15.5 g of potassium carbonate and 50 ml of chloroform, 9.46 g of diethyl sulfate were dropwise added. At 40° C., the mixture was stirred for 4 hours and then allowed to cool, washed with water, added with an aqueous dilute HCl solution and the formed aqueous layer was separated. This aqueous layer was neutralized with potassium carbonate, extracted with chloroform and the extract was washed with water, dried and concentrated under reduced pressure to obtain (2S,4R)-2-ethoxycarbonyl-N-ethyl4-hydroxy pyrrolidine as an oily product. Yield 8.15 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 96 mg, 0.33 mmol), methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (85 mg, 0.3 mmol) and ytterbium trifluoromethanesulfonate (28 mg, 0.045 mmol) were stirred in acetonitrile (0.4 mL) with some molecular sieves. The resulting mixture was then heated to reflux (80° C.) overnight and then allowed to cool to room temperature. The mixture was poured into ethyl acetate (5 mL) and washed successively with saturated aqueous sodium bicarbonate and aqueous brine. The organic phase was separated, dried over anhydrous sodium sulphate and then concentrated and the residue purified by silica gel column chromatography (10% ethyl acetate in cyclohexane) to give the title compound as a white solid (75 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CC(C)=O>[CH2:33]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=2)[C:6]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:7]1)[CH:32]=[CH2:31]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCn1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21

Procedure:
2-(5-Trifluoromethyl-1H-indazol-3-yl)-isoindole-1,3-dione (500 mg, 1.51 mmol), K2CO3 (313 mg, 2.26 mmol) and allyl bromide (365 mg, 3.02 mmol) in acetone (10 mL) were heated to reflux overnight. The reaction was filtered, and the residue was concentrated and purified by silica gel column chromatography using hexanes:ethyl acetate 2:1 to give the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(Cl)(Cl)Cl.[C:15](Cl)(Cl)=[S:16].C(=O)(O)[O-].[Na+]>O>[N:1]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1ccsc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccsc1N=C=S
Reaction time: 1 h
Yield: 65.1 %

Procedure:
In a sulfonation flask, 50.2 g (0.32 mol) of methyl 2-aminothiophene-3-carboxylate are added to 480 ml of chloroform and 320 ml of water. Then 40.5 g (0.35 mol) of thiophosgene and 1000 ml of saturated aqueous sodium bicarbonate solution are added simultaneously in 40 minutes under stirring. The stirring continued for 1 h at room temperature and then the organic phase is separated. The water phase is extracted twice with chloroform and the organic phase dried over sodium sulfate. After removal of the chloroform in the water-jet vacuum 61.3 g of a dark oil is obtained, which is further purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5). 41.5 g of methyl 2-isothiocyanatothiophene-3-carboxylate are obtained in the form of a brown powder having a melting point of 63-65° C.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:42])P(N(C)C)(N(C)C)=O>O1CCCC1>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:33]([CH3:42])[CH3:32])=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1C(=O)N(C)C)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 0.1 ml of hexamethylphosphoramide was dissolved 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, and 0.2 ml of thionyl chloride was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 50% aqueous dimethylamine solution was added dropwise with stirring. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 0.49 g of N-acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH:12]2[CH2:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([O:18][C:16]1[CH2:17][CH:12]([CH2:11][CH2:10][S:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:8][CH:7]=2)[CH2:13][C:14](=[O:19])[CH:15]=1)(=[O:31])[CH3:30]
Reactant: O=C1CC(=O)CC(CCSc2ccc(C(F)(F)F)cc2)C1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC(=O)CC(CCSc2ccc(C(F)(F)F)cc2)C1

Procedure:
6.32 Grams of 5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 50 ml of tetrahydrofuran, and 2.12 g of triethylamine was added. Thereafter, 1.73 g of acetyl chloride was added dropwise with thorough stirring under ice-cooling. After continuing stirring for further 2 hours at room temperature, the precipitated solid was filtered off. The solvent was removed from the filtrate, and the residue was dissolved in ether. The ether layer was successively washed with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate. Ether was removed to obtain 7.13 g of 1-acetoxy-5-[2-(4-trifluoromethylphenylthio)ethyl]-1-cyclohexene-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[CH2:16]([O:18][C:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:35][CH2:34][C@H:33]([NH2:36])[C:32]1=[O:37])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:35][CH2:34][C@H:33]([NH:36][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[C:32]1=[O:37])=[O:20])[CH3:17]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CCOC(=O)n1c(CN2CC[C@H](N)C2=O)cc2ncccc21
Agent: Cl
Product: CCOC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)cc2ncccc21

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylic acid ethyl ester hydrochloride as starting material. The crude product is purified by column chromatography eluting with 60% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccc4)CC3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]piperidine (INTERMEDIATE 7, 4 g, 15.28 mmol) in 60 mL DMF was added K2CO3 (63 g, 45.8 mmol), and 2-(bromoethyl)benzene (2.3 mL, 16.8 mmol). The reaction mixture was stirred at ambient temperature overnight, diluted with EtOAc, and washed three times with water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. LC-MS m/z=366.17 [M+1]+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][CH2:45][NH:46]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH:28]C(OC(C)(C)C)=O)=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][CH2:45][NH2:46])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH2:28])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.8 ml.), methanol (30 ml.) and tetrahydrofuran (30 ml.) was stirred at room temperature for 3 hours. After evaporation, methanol was added to the residue. The solution was evaporated in vacuo again, and the residue was dissolved in water (30 ml.). The solution was adjusted to pH 3.5 with saturated aqueous sodium bicarbonate solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark: Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C@@H:19]([CH2:42][OH:43])[O:18][C@H:10]2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[N:46]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][C:50]=1[Cl:57])=[N+:47]=[N-:48].[H-].[Na+].O>CN(C=O)C>[N:46]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53][O:43][CH2:42][C@H:19]2[O:18][C@@H:10]([S:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:9]([O:8][CH2:7][C:6]3[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:20]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:51][C:50]=1[Cl:57])=[N+:47]=[N-:48]
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COCc3ccc(N=[N+]=[N-])c(Cl)c3)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (8) (1.25 g, 1.98 mmol) and 4-azido-3-chlorobenzyl bromide (584 mg, 2.37 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 95 mg, 2.37 mmol), and the resulting mixture was stirred at room temperature for 3 hr. Cold water was added and the mixture was extracted twice with ether. The combined ether layers were washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) as white crystals (1.25 g, yield 79%).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.O>[CH2:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1NC(=O)C2CC12
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCN1C(=O)C2CC2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.48 g, 60% in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (4.0 g) and 1-iodooctane (8.88 g) in dry dimethylformamide (70 ml) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for a further 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water (100 ml) and then extracted with ether (150 ml). The organic extract was washed with water (2×70 ml), dried (MgSO4) and evaporated in vacuo to leave a brown oil. The oil was purified by distillation in vacuo (boiling point 146-147° C. @ 0.1 mmHg) to give the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2=[O:15].[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([C:6]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:14])=[C:11]([O:12][CH3:13])[C:2]=2[Cl:1])[C:7]1=[O:15])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C1CCc2c(cc(F)c(OC)c2Cl)C1=O
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1(C(=O)OCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Ethyl 5-chloro-7-fluoro-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (651 mg, 2.17 mmol) was dissolved in dimethylformamide (DMF, 2.2 mL) with gentle heating. After cooling to room temperature, sodium hydride (160 mg, 61% dispersion in mineral oil, 4.0 mmol) was added to give a black solution which was placed under N2. Iodobutane (1.15 mL, 10 mmol) was added and the reaction stirred at room temperature for 19 hours. The reaction mixture was then partitioned between EtOAc/H2O and the organic portion was washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7.5 cm) silica gel column, eluting with 1000 mL of 2% EtOAc in hexane. The product-containing fractions were concentrated to give ethyl 2-butyl-5-chloro-7-fluoro-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([C:20](=[O:25])N(OC)C)=[C:15]2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:8]>O1CCCC1>[C:20]([C:16]1[CH:17]=[N:18][C:19]2[C:14]([C:15]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:7](=[O:8])[C:6]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:5]=1[Cl:4])(=[O:25])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1N1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 0.9M solution of methylmagnesium bromide in tetrahydrofuran (1.3 ml) was added dropwise a solution of 8-(2,6-dichlorobenzoylamino)-3-(N-methoxy-N-methylcarbamoyl)-4-morpholinoquinoline (107 mg) in dry tetrahydrofuran (1 ml) with cooling in an ice bath. The mixture was stirred at the same temperature for 1 hour, at ambient temperature for 1 hour, at 50° C. for 2 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel. The obtained oil was crystallized from ethanol to give 3-acetyl-8-(2,6-dichlorobenzoylamino)-4-morpholinoquinoline (19 mg) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[Cl:32][C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[C:38]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:22])([F:20])[F:21])(=[O:17])=[O:18])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 26, step (c)) under the conditions described in Example 26, step (d-f)) using 4-chloro-5-trifluoromethylphenylboronic acid in step (d).
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH:24]=[CH2:25].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:25]([CH:3]1[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[C:11]=2[CH2:1][CH2:2]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
A mixture of 3.3 g. of the product of Example 1, 1.45 g. of freshly distilled 3-bromopropene and 1.7 g. of sodium bicarbonate is stirred at room temperature, for 24 hours, in 50 ml. dimethylformamide. At the end of this period, the mixture is poured into water, extracted with ether, and the combined extracts are dried and stripped down. The residue is dissolved in benzene, and the resulting solution chromatographed through a column of neutral alumina. The oily residue obtained on stripping down the eluate is recrystallized from isopropyl alcohol to yield 3-allyl-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine m.p. 112°-113°.
Reaction SMILES: C[Si](C)(C)[N:3]([C@H:8]([B:13]1[O:17][C@@H:16]2[CH2:18][C@@H:19]3[CH2:22][C@H:21]([C@:15]2([CH3:25])[O:14]1)[C:20]3([CH3:24])[CH3:23])[CH2:9][CH:10]([CH3:12])[CH3:11])[Si](C)(C)C.[ClH:28]>O1CCOCC1.C(OCC)C>[ClH:28].[CH3:25][C@:15]12[C@H:21]3[CH2:22][C@H:19]([C:20]3([CH3:23])[CH3:24])[CH2:18][C@H:16]1[O:17][B:13]([C@@H:8]([NH2:3])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:14]2
Reactant: CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1)N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of crude N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine of Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and diethyl ether (200 ml), a 4 N solution of hydrogen chloride in dioxane (193 ml, 0.772 mol) was added, while cooling at 0° C. The mixture was then stirred at room temperature for 4 hours and concentrated. The residue was taken up with anhydrous hexane (500 ml) and a 2 M solution of hydrogen chloride in diethyl ether (48 ml, 0.096 mol) was added. The mixture was stirred at 0° C. for 1 hour, then concentrated. The residue was taken up with anhydrous hexane and the resulting suspension was stirred at room temperature overnight. The solid was collected by filtration and dried under vacuum affording 38.1 g of product (66% yield). A second crop (4.13 g, 7% yield) was obtained from the mother liquors.