Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:21]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(OCC(F)(F)C(F)F)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 52.8 parts of 2,2,3,3-tetrafluoro-1-propanol, 117.8 parts of 2-naphthalenesulfonyl chloride, 294 parts of pyridine and 2.0 parts of N,N-dimethyl-4-pyridinamine was stirred for 48 hours at room temperature. The reaction mixture was diluted with water and the whole was left to crystallize. The product was filtered off, washed with water and recrystallized from 2-propanol, yielding 98.2 parts (76.2%) of 2,2,3,3-tetrafluoropropyl 2-naphthalenesulfonate; mp. 89.6° C. (interm. 27).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 48 h

Procedure:
A solution of 14 g of 3,4-dichlorobenzaldehyde in 65 ml of acetone is diluted with 435 ml of water and treated with a solution of 5 g of sodium hydroxide in 50 ml of water. The mixture is stirred for 48 hr, extracted with benzene, dried and concentrated in vacuo to give 3,4-dichlorobenzalacetone as an oil which crystallizes on standing.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([OH:10])[C@H:8]([OH:11])[C@@H:7]([CH2:12][OH:13])[NH:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[C@@H:9]([OH:10])[C@H:8]([OH:11])[C@@H:7]([CH2:12][OH:13])[NH:6][CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CN[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CN[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 71.7 %

Procedure:
To a solution of 12 (465 mg, 3.14 mmol) in methanol (50 ml) in a Parr hydrogenation flask, 10% Pd on C (50 mg) was added. The system was sealed, purged with nitrogen (5 times) and hydrogen (5 times) and then pressurized to 5 psi hydrogen. After running the reaction on a shaker for 3.5 hr, the system was vented, purged with nitrogen and filtered. The filtrate was concentrated to give pure 20 (365 mg, 91%). DSC (mp) 184° C. Anal calcd. for C6H14N2O3 0.25H2O C, 43.23, H, 8.77, N, 16.81 Found C, 43.42, H, 8.43, N, 16.47.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.9 %

Procedure:
A 0° C. solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5 ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1 M solution in THF, 15.75 mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with 1N HCl, stirred for 20 minutes, then extracted with DCM. Concentration and silica gel chromatography (10-50% EtOAc/hexanes) yields the title compound 1.87 g (87% yield) as colorless needles. 1H NMR (500 MHz, CDCl3) δ 7.55 (m, 1H), 7.04 (d, J 9.4 Hz, 1H), 7.04 (d, J 8.3 Hz, 1H), 4.70 (d, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:31][CH2:32][CH3:33])[CH:5]1[CH2:30][C:8]2=[CH:9][C:10]3[C:11](=[O:29])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl>CC(O)=O.[Zn]>[CH2:31]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:30][C:8]2=[CH:9][C:10]3[C:11](=[O:29])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=4)[CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:32][CH3:33]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C3

Procedure:
Using procedure 47, 6-(dipropylamino)-6,7-dihydro-2-[[4-(trifluoromethoxy)phenyl]methyl]cyclopent[f]isoindole-1,3(2H,5H)-dione (107, 0.17 g, 0.37 mmol) was reduced with Zinc dust (0.24 g, 3.7 mmol) in glacial HOAc (10 mL). The resulting solid was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 128 as a white solid (m.p. 210-211° C.).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[C:3]=1[C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:21]([C:20]1[C:3]2[C:4](=[O:19])[N:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]3[N:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=3[C:2]=2[NH:31][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc2c(O)c(C(=O)Cc3ccccc3)c(=O)n(-c3ccccc3)c2n1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c3[nH]nc(Cc4ccccc4)c3c(=O)n(-c3ccccc3)c2n1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-7-methyl-1-phenyl-3-phenylacetyl-1,8-naphthyridin-2(1H)-one (370 mg, 1.0 mmol) produced in Synthesis Example 3 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 160 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-7-methyl-5-phenyl-1H-pyrazolo [4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (281 mg, yield 83%).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O.O1CCOCC1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1occc1-2
Yield: 44.6 %

Procedure:
Methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 9, 0.129 g) was added to a solution of lithium hydroxide monohydrate (0.42 g) in water (2 mL) and dioxane (8 mL), and the mixture was irradiated in the microwave at 130° C. for 1 hour. After cooling, the mixture was acidified with formic acid, and evaporated to dryness. The residue was triturated with 10% methanol in DCM, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%. The isolated product was triturated with ethyl acetate and the solid was collected by filtration and dried in vacuo to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylic acid (0.056 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][C:13]([CH2:17][N:18]([CH3:32])[C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=3)([OH:16])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][C:13]([CH2:17][N:18]([CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:30][CH:31]=3)([OH:16])[CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)C1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)C1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
The compound (1.00 g) obtained in Example 8 was dissolved in 6 N hydrochloric acid (2.5 mL), followed by stirring at room temperature overnight. The mixture was treated with sodium carbonate to be adjusted to pH 7, the precipitate was collected by filtration, was washed with water, and was dried to yield the titled compound (0.355 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=2)O1>>[F:17][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:32]4[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=4)[CH:3]=3)[N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 56 %

Procedure:
Following the Suzuki coupling procedure of Example 10, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate, were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 100 mg (56%) of Ethyl 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate. ESI MS m/z 451.1 (M+1).
Reaction SMILES: [N+](C1C=C(S(O[C:14]2[NH:15][S:16](=[O:25])(=[O:24])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)(=O)=O)C=CC=1)([O-])=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CC(C)=O>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:14]2[NH:15][S:16](=[O:24])(=[O:25])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC2=Nc3ccccc3S(=O)(=O)N2)c1
Solvent: CC(C)=O
Product: CN1CCN(C2=Nc3ccccc3S(=O)(=O)N2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a stirred suspension of 1.0 g of 3-(m-nitrobenzenesulfonyloxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide in 10 ml of acetone is added dropwise 0.53 g of 1-methylpiperazine, while the mixture is cooled in an ice bath. After the addition, the mixture is stirred at room temperature for 1 hour. After removal of acetone by distillation under reduced pressure, 30 ml of water is added to the residue. The crystalline precipitate is collected by suction filtration and treated with 2 ml of a 10% aqueous sodium hydroxide solution. After removal of the insoluble materials by suction filtration, the filtrate is adjusted to a pH 8.0 with dilute hydrochloric acid. The crystalline precipitate is collected by suction filtration and recrystallized from a mixture of dimethylformamide and water to give 0.2 g of the desired product, m.p. 265°-267° C.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[N:33]=[C:32]5[C:34](=[O:38])[NH:35][C:36](=[O:37])[C:31]5=[CH:30][CH:29]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[N:33]=[C:32]5[CH:34]([OH:38])[NH:35][C:36](=[O:37])[C:31]5=[CH:30][CH:29]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:13][CH2:14][CH2:15]1
Reactant: O=C1NC(=O)c2nc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NC(O)c2nc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)ccc21
Reaction time: 0.5 h

Procedure:
Magnesium perchlorate (0.89 g) was added to a solution of 2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (E233) (0.72 g, 1.98 mmol) in a mixture of chloroform:methanol (1:1; 20 ml) at 0° C. under argon. Sodium borohydride (113 mg) was added and the mixture stirred at for 0.5 h. The mixture was adjusted to pH 2 with HCl (2M), stirred for an additional 0.5 h, then taken to pH11 with sodium hydroxide (2N). The mixture was then extracted with dichloromethane and the combined organic extracts dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E234); MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][S:23][C:22]=1[C:30](Cl)=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][S:23][C:22]=1[C:30]([NH:19][CH2:18][C:12]1[CH2:13][C@@H:14]([N+:15]([O-:17])=[O:16])[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH:11]=1)=[O:31]
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1Cl
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 3-chloro-4-methanesulfonyl-thiophene-2-carbonyl chloride (43 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (48 mg, 84%). 1H NMR (300 MHz, CDCl3) δ ppm 8.39 (s, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 7.17-7.25 (m, 2H), 5.82 (m, 1H), 5.04-5.17 (m, 1H), 3.98-4.19 (m, 3H), 3.18-3.21 (m, 3H), 2.51-2.95 (m, 3H), 2.16-2.35 (m, 1H). MS (ESI) m/z 523 (M+H)+.
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:9][CH2:10][CH2:11][CH:4]2[CH2:3]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[O:23]([C:21]([N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:9][CH2:10][CH2:11][CH:4]2[CH2:3]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cccc(C23CCCC2CN(C)CCC3)c1
Solvent: ClCCl
Product: COc1cccc(C23CCCC2CN(C(=O)Oc2ccccc2)CCC3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.4 g. of 2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine in 200 ml. of dichloromethane was added dropwise over thirty minutes to a stirred solution of 11.2 g. of phenyl chloroformate. The reaction mixture was then heated to reflux and stirred for four hours. The reaction mixture was then cooled to 25° C., and the solvent was removed therefrom by evaporation under reduced pressure to provide 2-phenoxycarbonyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine as a solid. The solid thus formed was dissolved in 600 ml. of ethyl alcohol containing 140 ml. of 50 percent aqueous sodium hydroxide solution. The reaction mixture was heated at reflux and stirred for sixty hours. After cooling to 25° C., the reaction mixture was added to 500 ml. of water, and the aqueous solution was acidified to pH 2 by the addition of 12 N hydrochloric acid. The aqueous acidic solution was washed with diethyl ether to remove any unreacted carbamate, and the aqueous acidic solution was then made alkaline by the addition of 50 percent aqueous sodium hydroxide solution. The aqueous alkaline solution was extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 7 g. of 5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. B.P. 136°-140° C. at 0.05 torr.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)OCC[O:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>C1COCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:13])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C2(CCCOCCc3ccccc3)OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)CCCOCCc2ccccc2)cc1
Yield: 101 %

Procedure:
This compound was synthesized as described under 5.c) with 2 ml of HCl (1N) and 2.00 g (5.4 mmol) of 2-(4-tert-butylphenyl)-2-[3-(2-phenylethoxy)propyl]-1,3-dioxolane obtained under b) in 50 ml of THF to give 1.77 g (99%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[S:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.I[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([S:22][CH2:31][CH3:32])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:28])([F:27])[F:29])[CH:3]=1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CCI
Product: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodoethane following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[S:10](Cl)(Cl)=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][S:10][N:9]=[C:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(Cl)cc1N
Agent: O=S(=O)(O)O
Product: Clc1ccc2nsnc2c1

Procedure:
A mixture was prepared by mixing 4.0 g (28 mmol) of 4-chloro-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resultant precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.6 g of 5-chloro-2,1,3-benzothiadiazole as a crude product (melting point, 50 to 54° C.; yield, 96%). This crude product was vacuum-distilled to yield a pure product of 5-chloro-2,1,3-benzothiadiazole (melting point, 54° C.; yield, 85%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12.CN(C)C=O.P(Cl)(Cl)(Cl)=O>O.CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:21][CH:22]2[C:42](=[O:43])[N:24]3[C:25]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 90.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.35 g.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.54 g.), N,N-dimethylformamide (393 mg.), phosphoryl chloride (825 mg.), tetrahydrofuran (21.2 ml.), acetone (3.9 ml.) and water (3.9 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer 2.52 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:15][C@H:14]([C:16](O)=[O:17])[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:16]([C@H:14]1[CH2:15][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]1([CH3:20])[CH3:19])(=[O:17])[NH2:30]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)[C@@H](C(=O)O)C[C@H]1NC(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H](C(N)=O)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A mixture of (1S,3R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxylic acid (2.6 g, 9.38 mmol), ammonium chloride (2.0 g, 37.5 mmol), TEA (2.84 g, 28.2 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.35 g, 14.1 mmol) in dry DMF (52 mL) was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the crude product, which was purified by HPLC (10-50% acetonitrile in water) to afford the title compound (1.86 g, 6.71 mnmol, 66% yield for two steps). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.40-7.30 (m, 5H), 5.51-5.37 (m, 1H), 5.27-5.17 (m, 1H), 5.15-4.96 (m, 3H), 3.96-3.87 (m, 1H), 2.48-2.39 (m, 1H), 2.37-2.27 (m, 1H), 2.15-2.05 (m, 1H), 1.31 (s, 3H), 0.96 (s, 3H). MS (ESI) m/z 277.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:9]=1)[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:27][C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=2)[CH:9]=1)([CH3:6])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid ethyl ester (0.24 g, 0.608 mmol) in THF (15 ml) was added a solution of LiOH (0.127 g, 3.03 mmol) in water (3.4 ml) and stirred at r.t. for 18 h. After evaporation of the solvent, the residue was diluted with ethyl acetate (100 ml); cool to 0° C., acidified with 1N HCl (pH˜3-4). The organic phase were washed with, brine (20 ml) and dried over Na2SO4 and concentrated to get 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid (0.075 g, 33%). 1H NMR (400 MHz, CDCl3): δ 1.588 (s, 6H), 2.97 (t, J=6.8 Hz, 2H), 3.41 (t, J=6.8 Hz, 2H), 6.22 (s, 1H), 6.30 (d, J=8.4 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.32 (d, J=8 Hz, 2H), 7.57 (d, J=7.6 Hz, 2H).