Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C.C1COCC1.CC(=O)OCC>[Br:28][C:4]1[N:3]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1ccn(S(=O)(=O)N2CCCCC2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)n(S(=O)(=O)N2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of compound 4a (4.77 g, 15.9 mmol) in dry DMF (20 mL) and dry THF (20 mL) was added NBS (3.12 g, 17.5 mmol) in portions at 0° C. The mixture was stirred at rt overnight, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=1/0 to 15/1) to give compound 4b (4.2 g, 63%).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].N1CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:28]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:29])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccncc1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCOCC
Product: COC1C(OC(=O)N2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 2 h

Procedure:
To a mixture of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (26 mg), pyridine (44 μl), and 4-dimethylaminopyridine (2 mg) in dichloromethane (0.8 ml) was added dropwise 4-nitrophenyl chloroformate (20 mg) at ambient temperature. After stirring for 2 hours, piperidine (40 μl) was added in one portion. The solution was stirred overnight at ambient temperature and then diluted with diethyl ether (20 ml). The mixture was washed with brine, aqueous saturated sodium bicarbonate solution, and brine successively. The mixture was dried and evaporated under reduced pressure to give a crude oil, which was purified by preparative thin layer chromatography to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-piperidinocarbonyloxy-1-oxaspiro[2,5]octane (34.3 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])C(Cl)=O.[CH3:7][C:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([C:21](O)=O)[CH:9]=1.[C:24](O)(=[O:26])C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:7][C:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([CH2:21][C:24]([O:5][CH3:1])=[O:26])[CH:9]=1
Reactant: Cc1cc(C(=O)O)cc2c1[nH]c1ccccc12
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Cc1cc(C)c2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73 mg of oxalyl chloride was added, with ice-cooling, to a solution of 92 mg of 1-methylcarbazole-3-carboxylic acid, as obtained in Example 27, in 5 ml of methylene chloride. One drop of N,N-dimethylformamide was then added to the reaction mixture, which was next warmed to room temperature, stirred for 2 hours, and then concentrated by evaporation under reduced pressure. 10 ml of diethyl ether and an excess of a solution of diazomethane in diethyl ether were added to the residue thus obtained, and the reaction mixture was stirred for one night at room temperature. Acetic acid and then a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 2 g of silica gel with a 1:1 v/v mixture of hexane and ethyl acetate as the eluent. Subsequently, 6 mg of silver oxide was added to a solution of the eluted residue in 5 ml of methanol. The reaction mixture was refluxed for 5 hours, filtered to remove inorganic materials, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 2 g of silica gel with a 2:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 90 mg of the title compound as an oil.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:31]4)=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC[C@@H]4CCNC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@@H](COc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 20 %

Procedure:
(R)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-((1-isopropylpyrrolidin-3-yl)methoxy)picolinamide (26 mg, 20%) was prepared using a procedure analogous to that described in Example 20, substituting (R)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-ylmethoxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9](=[O:12])[NH:10][CH:11]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:13]([N:10]1[C:9](=[O:12])[C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:2]([Br:1])=[CH:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]cc(Br)c2cccnc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2ncccc2c(Br)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a suspension of 5-bromo-1,7-naphthyridin-8(7H)-one (0.50 g, 2.22 mmol) in anhydrous DMF (60 mL) was added benzyl bromide (0.34 mL, 2.88 mmol) and Cs2CO3 (0.94 g, 2.88 mmol). The reaction was stirred at rt for 16 h. After that time the reaction was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.584 g, 83%) as a brown solid: 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J=4.4, 1.5 Hz, 1H), 8.16 (dd, J=8.2, 1.5 Hz, 1H), 7.66 (dd, J=8.2, 4.4 Hz, 1H), 7.42 (s, 1H), 7.28-7.41 (m, 5H), 5.28 (s, 2H); ESI MS m/z 314.9 [M+H]+ and 316.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][NH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:34]OC(OC)N(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:10][N:11]([S:14]([C:17]2[N:18]=[N:19][N:20]([CH3:34])[CH:21]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)=[O:5]
Reactant: COC(OC)N(C)C
Reactant: O=C(NCC1(c2ncccc2F)CCN(S(=O)(=O)c2c[nH]nn2)CC1)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: Cn1cc(S(=O)(=O)N2CCC(CNC(=O)c3ccc(Cl)cc3Cl)(c3ncccc3F)CC2)nn1

Procedure:
To a suspension of 2,4-dichloro-N-{[4-(3-fluoropyridin-2-yl)-1-[(1H-1,2,3-triazol-4-yl)sulfonyl]piperidin-4-yl]methyl}benzamide (0.15 g; 0.29 mmol) in toluene (5 ml) was added N,N-dimethylformamide dimethyl acetal (0.35 g; 0.4 ml; 2.92 mmol) and the mixture heated at reflux for 1 hour. The solvent was removed under vacuum and the residue azeotroped twice with toluene. The crude product was purified by preparative TLC on silica gel eluted with 3% methanol in DCM to give the title compound as the most polar isomer.(30 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH:14]=[CH:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[CH:15]([OH:16])[CH:14]2[CH:13]([O:25]2)[CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@H]1O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)[Si](C)(C)OCC1OCC2OC2C1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C., stirred solution of trans-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.110 g, 0.45 mmol) in CH2Cl2 (10 ml) was added m-CPBA (75%, 0.108 g, 1.08 mmol) and the mixture was stirred for 1 h at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na2CO3 (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (2540% EtOAc in hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[N:16]1[CH:17]=[CH:18][C:13]([CH2:11][CH2:12][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Fc1ccc2[nH]cc(CCc3ccncc3)c2c1
Temperature: 0 °C
Yield: 71 %

Procedure:
The starting product was prepared according to the same procedure as that described in the last paragraph of Example 2. 9.5 g of 5-fluoro-indole (U.S. Pat. No. 879,619) and 11 g 4-vinyl-pyridine were refluxed for 6 hours in 50 ml acetic acid. The mixture was then poured onto 300 g of crushed ice and alkalinized with a 20% potassium carbonate solution. A precipitate formed which was squeezed and washed in water several times. After drying under vacuum, 12 g of 3-[2-(4-pyridyl)-ethyl]-5-fluoro-indole were obtained which melted at 128° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([OH:24])[CH2:7][NH:8][CH:9]([CH3:23])[CH2:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]([OH:20])[C:16](OC)=[O:17])=[CH:13][CH:12]=1.Cl.[NH2:31][C:32]([NH2:34])=N.[Na]>CO>[NH2:31][C:32]1[O:20][CH:15]([C:14]2[CH:21]=[CH:22][C:11]([CH2:10][CH:9]([NH:8][CH2:7][CH:6]([OH:24])[C:5]3[CH:25]=[CH:26][CH:27]=[C:3]([C:2]([F:1])([F:28])[F:29])[CH:4]=3)[CH3:23])=[CH:12][CH:13]=2)[C:16](=[O:17])[N:34]=1
Reactant: COC(=O)C(O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(Cc1ccc(C2OC(N)=NC2=O)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 29.3 %

Procedure:
To a solution of methyl 4-[2-[(3-trifloromethyl-β-hydroxyphenethyl)amino]propyl]mandelate (1.5 g) and guanidine hydrochloride (0.35 g) in methanol at room temperature was added a solution of sodium (0.084 g) in methanol. The solution was heated under reflux for 2 h., cooled, filtered and the solvent removed in vacuo. The residue was partitioned between ethyl acetate, and water, the organic layer separated, dried (magnesium sulphate), and evaporated to an oil which was chromatographed on silica. Elution with chloroform:methanol (95:5) gave 2-amino 5-[4-[2[(3-trifluoromethyl-β-hydroxyphenethyl)amino]propyl]phenyl]oxazol-4-one (0.45 g) as a 40:60 mixture of diastereoisomers, m.p. 152°-164° C. (acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].C([Li])CCC.[N+:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([O-:37])=[O:36].O>O1CCCC1>[N+:35]([C:38]1[CH:39]=[CH:40][C:41]([C:42]([N:20]2[C:21]3[C:16](=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:13][CH2:12]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18][C:19]2=[O:24])=[O:43])=[CH:45][CH:46]=1)([O-:37])=[O:36]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Yield: 18.9 %

Procedure:
To a suspension of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (10 g) in anhydrous tetrahydrofuran (250 ml) was added slowly n-butyllithium (20 ml, 1.5N hexane solution) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at room temperature for 2 hours. Then, to the mixture was added slowly a solution of p-nitrobenzoyl chloride (6.1 g) in anhydrous tetrahydrofuran (25 ml) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at the same temperature for 30 minutes. After completion of reaction, the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed successively with water and saturated saline solution and dried over magnesium sulfate. The choloroform extract was evaporated under reduced pressure and the resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:1) to give 1-(4-nitrobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]3,4-dihydrocarbostyril (2.6 g).
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=C.[CH:11]1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH3:11][C:7]([CH2:6][CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH3:10])=[CH2:8]
Reactant: C=CCCC=CC=C(C)C
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Product: C=C(C)CC=CC=C(C)C
Yield: 80.3 %

Procedure:
10 g of dimethyl-1,3,7-octatriene are kept under argon atmosphere for 36 hours with 0,303 g palladium acetylacetonate, 1,4 g of tricyclohexylphosphine and 0,1 g of H3Po4. After this period, 80.3% of 2,7-dimethyl-1,4,6-octatriene have been formed (GC-analysis).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][NH2:7])[O:13]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (2-benzyl-isoxazolidin-5-ylmethyl)-carbamic acid tert-butyl ester (Step A, 0.5 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1.95 g). The solution was stirred at room temperature for 4 hours then concentrated in vacuo to afford the crude title product, which was used directly for the next step. LCMS (Method F) 0.20 min, M+H 194.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][CH:9]=1)(C)(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)C(O)=O.O[CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH:29]=1)[C:6]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])=[CH:10][CH:9]=1)=[O:19]
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=C1CCCN1CCCO
Product: O=C(Nc1ccc(OCCCN2CCCC2=O)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from tert-butyl(4-hydroxy-1-naphthyl)carbamate, 3-fluoro-5-piperidin-1-yl-benzoic acid and 1-(3-hydroxy-propyl)-pyrrolidin-2-one according to conditions described in general procedure D. A pink solid is produced (42 mg). Mp: 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 1.69(s, 6H), 1.95-2.04(m, 2H), 2.10-2.18(m, 2H), 2.34-2.39(m, 2H), 3.26(s, 4H), 3.37-3.45(m, 2H), 3.50-3.55(m, 2H), 4.09-4.13(m, 2H), 6.72-6.77(m, 2H), 7.03(d, J=8.4 Hz, 1H), 7.33(s, 1H), 7.46-7.55(m, 2H), 7.63(d, J=7.8 Hz, 1H), 7.82(d, J=7.5 Hz, 1H), 8.23(s, 1H), 8.27-8.30 (m, 1H); MS 490 (M+1).
Reaction SMILES: NO.[CH3:3][C:4]([CH3:10])([CH2:7][CH:8]=[CH2:9])[CH:5]=[O:6].C([Zn][CH2:14][CH3:15])C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CCCCCC.CCOCC.C1(C)C=CC=CC=1>[C:16]([O:6][CH:5]([C:4]([CH3:10])([CH3:3])[CH2:7][CH2:8][CH3:9])[CH:14]=[CH2:15])(=[O:18])[CH3:17]
Reactant: CC[Zn]CC
Reactant: C=CCC(C)(C)C=O
Reactant: CC(=O)OC(C)=O
Agent: NO
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC(OC(C)=O)C(C)(C)CCC
Reaction time: 72 h
Yield: 78 %

Procedure:
To a vial containing aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added a solution containing 2,2-dimethyl-4-pentenal (0.34 g, 90% pure, 2.7 mmol), toluene (3.0 mL), and 1 M diethylzinc in hexane (6.0 mL). After 3 days at room temperature, acetic anhydride (1.2 mL, 13 mmol) was added. After 2 additional days, the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 95% hexane and 5% ether as eluant. The product (+)-3-acetoxy-4,4-dimethylhept-1-ene (0.39 g, 78%) was isolated as a colorless liquid by distillation of the solvent at reduced pressure. Anal. for C11H20O2. Calcd: C, 71.70; H, 10.94; found: C, 71.75; H, 10.66. 1H NMR (CDCl3/TMS): δ0.84 (s+t, 6 H total), 0.87 (s, 3 H), 1.46 (m, 1 H), 1.62 (m, 1 H), 1.89-2.06 (m, 2 H), 2.07 (s, 3 H), 4.71 (dd, 1 H), 4.96-5.05 (m, 2 H), 5.81 (m, 1 H). 13C NMR (CDCl3/TMS): δ10.96, 21.02, 22.33, 23.12, 37.41, 43.46, 81.41, 117.37, 134.74, 171.11. [α]D25=+14.2, c=2.02 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 100° C. on Cyclodex B stationary phase (J & W Scientific) indicated that the enantiomeric excess of the product was 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:24])=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
3.04 g (10.0 mmol) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 15 ml of N,N-dimethylformamide and treated portionwise at room temperature with 1.78 g (11.0 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution had finished the clear brown solution was stirred at 50° for 30 min., cooled and treated dropwise at a temperature below 25° within about 10 min. with 2.5 ml of conc. ammonia. After stirring for 30 minutes the suspension obtained was evaporated and the residue was triturated with 30 ml of water. The white crystals were filtered off under suction and dried in a vacuum. There were obtained 2.8 g (92%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 251°-253°.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:7]1[CH3:32])C.[OH-].[K+].Cl>C1COCC1.O>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]([CH3:32])=[C:8]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)(=[O:24])=[O:25]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester (1.23 g, 2.60 mmol) in THF (50 mL), was added a solution of potassium hydroxide (0.73 g, 13.0 mmol) in water (50 mL), and the resulting solution stirred at room temperature for 2 hours. Aqueous HCl (2N, 15 mL) was then added and the aqueous layer extracted with ethyl acetate (100 mL). The organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid was triturated with diethyl ether and dried in vacuo to afford 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid (1.09 g, 2.45 mmol, 94%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=1)=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the manner as in Example 1, 2.75 grams (0.009 mole) of 2(3-trifluoromethyphenoxy)nicotinoyl chloride, 1.5 grams (0.009 mole) 3,4-dichloroaniline, 0.9 grams (0.009 mole) triethylamine and 125 milliliters toluene were combined to yield 2.3 grams (59.8% of theoretical yield) of the desired product, a waxy solid. The structure was confirmed by mass spectrometry.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:15].[NH+]1C=CC=CC=1.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:15][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[NH2:9]
Reactant: Br
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A suspension of 4-tert-butyl-2-nitroaniline (1.033 g, 5.32 mmol) in glacial acetic acid (7.8 mL) was warmed with a heat gun until all solids had dissolved. The solution was then cooled and treated portion wise with pyridinium hydrobromide perbromide (1.96 g, 6.12 mmol). After addition, the solution was stirred at room temperature for 1 h. The mixture was added to water (50 mL) and treated with a small amount of sodium sulfite. After stirring for 30 min, the precipitate was collected by filtration. The solid obtained was washed with water and dissolved in EtOAc. Washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow-orange solid (1.36 g, 94%).