Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[CH2:9][N:10]([CH:13]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[C:19]([CH3:21])[CH:20]=3)[CH3:14])[C:11](=[O:12])[C:7]=2[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>C1COCC1.CCOC(C)=O>[CH3:35][O:36][CH2:37][C:38]([NH:2][C:3]1[C:8]2[CH2:9][N:10]([CH:13]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:19]([CH3:21])[CH:20]=3)[CH3:14])[C:11](=[O:12])[C:7]=2[CH:6]=[CH:5][N:4]=1)=[O:39]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 38.8 %

Procedure:
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (20 mg, 0.050 mmol, Example-17, single enantiomer) and triethylamine (0.069 mL, 0.50 mmol) in THF (1.0 mL) is added 2-methoxyacetyl chloride (27 mg, 0.25 mmol) at rt. The reaction mixture is stirred for 21 hours at rt and diluted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated in vacuo. The residue is purified by preparative LC-MS to give 8.5 mg (39% yield) of the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]#[C:28][Si](C)(C)C>C1COCC1>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([C:33]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[O:34])=[CH:22][C:21]=1[O:20][CH3:19])#[CH:28]
Reactant: COc1cc(C(=O)N2CCN(C)CC2)ccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)N2CCN(C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
1M TBAF in THF (1.43 mL, 1.05 mmol) was added to a solution of {3-methoxy-4-[(trimethylsilyl)ethynyl]phenyl}(4-methylpiperazin-1-yl)methanone (0.450 g, 1.36 mmol) in dry THF (7 mL) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue taken up with EtOAc (30 mL), washed with brine, dried over sodium sulfate and evaporated to afford the title compound (0.263 g, 75%).
Reaction SMILES: NC1C=C2C(=CC=1N)N=CC(C#N)=C2NC1C=C(OC)C(OC)=C(OC)C=1.[N:28]([C:31]1[CH:40]=[C:39]2[C:34]([C:35]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:46][CH:45]=3)=[C:36]([C:41]#[N:42])[CH:37]=[N:38]2)=[CH:33][C:32]=1[N+:57]([O-])=O)=[N+]=[N-]>C1COCC1.C(O)C.[Pd]>[NH2:57][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:31]=1[NH2:28])[N:38]=[CH:37][C:36]([C:41]#[N:42])=[C:35]2[NH:43][C:44]1[CH:45]=[CH:46][C:47]([O:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[CH:48][CH:49]=1
Reactant: N#Cc1cnc2cc(N=[N+]=[N-])c([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Agent: COc1cc(Nc2c(C#N)cnc3cc(N)c(N)cc23)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cnc2cc(N)c(N)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 119.7 %

Procedure:
Following the procedure of 6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile (intermediate from Example 33), hydrogenation of a suspension of 736.0 mg (1.74 mmol) of 7-azido-6-nitro-4-(4-phenoxyanilino)-3-quinolinecarbonitrile and 147.2 mg of 10% palladium-on-carbon in 21 mL of THF and 6 mL of ethanol yields 765.1 mg of crude 6,7-diamino-4-(4-phenoxyanilino)-3-quinolinecarbonitrile.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[Mg][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]([OH:22])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: COc1c(C=O)c(C2CCCC2)cc2c1C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c2c(cc(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 3.7 g (12.24 mmol) of 7-cyclopentyl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 6A) are suspended in 150 ml of tetrahydrofuran and cooled to −78° C. 29.4 ml (14.68 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoro-methyl)phenyl]magnesium in tetrahydrofuran are added slowly. The mixture is then warmed to −20° C. and stirred at this temperature for 30 min. At −20° C., another 12.3 ml (6.15 mmol) of the above Grignard solution are added, and the mixture is stirred for a further 45 min. The mixture is then hydrolyzed using 5% strength sodium bicarbonate solution and then extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→2:1). This gives 2.35 g (43% of theory) of the title compound.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5].Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]>>[Cl:9][C:8]([Cl:11])([Cl:10])[CH2:7][O:6][C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:5]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1cccc(C(=O)O)c1)OCC(Cl)(Cl)Cl
Yield: 86.5 %

Procedure:
To an aqueous solution (200 ml) of 8.22 g of m-aminobenzoic acid and 4.8 g of sodium hydroxide was dropwise added 25.0 g of 2,2,2-trichloroethyl chloroformate at room temperature. During the dropwise addition, the reaction solution was controlled to pH 10 or more by appropriately adding a 1N sodium hydroxide aqueous solution. After the reaction, the solution was controlled to pH 1 by adding 1N hydrochloric acid, and the precipitates were collected by filtration. The resultant crude crystals were dried and then washed with a ethyl acetate/n-hexane mixed solvent to obtain 16.2 g (yield 87%) of the title compound as a solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([S:45]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)(=[O:47])=[O:46])=[CH:43][CH:44]=1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.40 g, 3.53 mmol) and triethylamine (1.48 mL, 10.59 mmol) in methylene chloride (35 mL) was added 4-methoxy-benzenesulfonyl chloride (1.46 g, 7.06 mmol) in three portions over 15 minutes. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with saturated sodium bicarbonate and the aqueous solution was washed with methylene chloride. The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (4% to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 483.1 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:30]=[CH:29][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40])[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCNc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
6-[[1,2-Diphenyl-1H-benzimidazol-5-yl]amino]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:60]=[N+:61]=[N-:62])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C1
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To a stirring solution of cis-(3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester (850 mg, 4.22 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in THF (25 mL) cooled to 2° C. was added DEAD reagent (0.92 mL, 5.84 mol) over 5 minutes. The mixture was stirred for 5 minutes and DPPA (1.26 mL, 5.84 mmol) was added over 5 minutes. Stirring was continued for 17 hours at room temperature. The mixture was evaporated to dryness. The residue was stirred in ethyl ether briefly and the white solid triphenylphosphine oxide was removed by filtration (1 g). The filtrate was again reduced in volume and purified by silica gel chromatography eluting with ethyl acetate and hexanes to afford trans-(3-azido-cyclopentyl)-carbamic acid tert-butyl ester (950 mg).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([O:15][C:16]([NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:11]([O:15][C:16](=[O:17])[NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](=[O:23])[N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: OCCNC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C1CCCCC1
Agent: CCN=C=NC(CCNC)NC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of N-cyclohexylethanolamine (0.55 g, 3.9 mmol) and 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (1.0 g, 3.5 mol), in DCM (200 mL), HOBT (0.62 g, 4.5 mmol) and TEA (1.0 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 0.87 g, 4.5 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added to the reaction mixture. The reaction mixture was then washed with aqueous citric acid solution, saturated NaHCO3 solution, and NaCl solution. The organic layer was collected, dried with MgSO4, and then evaporated to yield {1-cyclohexyl-3-[cyclohexyl-(2-hydroxy-ethyl)-carbamoyl]-propyl}-carbamic acid tert-butyl ester as an oil, which was used in the next step without further purification.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([NH2:28])=O>C1(C)C=CC=CC=1>[NH2:28][C:26](=[S:10])[CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCC(N)=S
Yield: 42.3 %

Procedure:
Lawesson's reagent (2.6 g) was added to a toluene (10 ml) solution of methyl succinamate (1.7 g). The reaction mixture was heated under reflux for 4 hours, cooled, and then concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the entitled compound (400 mg) as an oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)Cc1ncccn1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ncccn3)c21

Procedure:
Prepared as in Example 15 from (R-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyrimidin-2-yl)acetic acid (Example 31a) (36% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.25 (m, 1H), 1.47-1.67 (m, 4H), 1.76 (m, 1H), 3.16 (t, 1H, J=12.6 Hz), 2.77-4.20 (m, 3H), 4.27-4.72 (m, 2H), 5.13 (m, 1H), 6.57 (d, 1H, J=8.2 Hz), 6.78 (br d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=5.0 Hz), 7.40 (br t, 1H, J=8.2 Hz), 7.71 (br s, 1H), 7.91 (br s, 1H), 8.71 (m, 2H), 10.90 (br s, 1H). MS 431 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]([CH2:10][C:11]([CH3:35])([CH3:34])[C:12](=[O:33])[CH:13]([N:27]1[CH:30](Cl)[CH2:29][C:28]1=[O:32])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])=[N+:8]=[N-:9]>C(O)(C)(C)C.O1CCCC1.C(OCC)(=O)C>[N:7]([CH2:10][C:11]([C:12]1[O:33][CH:30]2[N:27]([C:28](=[O:32])[CH2:29]2)[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])([CH3:35])[CH3:34])=[N+:8]=[N-:9]
Reactant: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(CN=[N+]=[N-])C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2O1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 117.9 %

Procedure:
313 μl of a 0.75 M solution of potassium tert-butoxide in tert-butanol are added at -30° C. to a solution of 107 mg (0.23 mmol) of p-nitrobenzyl 5-azido-2-(4-chloro-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 4.5 ml of dry tetrahydrofuran and the solution is stirred at -30° C. during the course of 30 minutes. The reaction mixture is then diluted with 20 ml of ethyl acetate, and the mixture is washed with 10 ml of water and 10 ml of NaCl solution. The aqueous phases are extracted using 10 ml of ethyl acetate and the combined organic phases are dried over MgSO4, filtered and then evaporated in vacuo. In this way, 105 mg of a yellow residue are obtained which is crystallized from methylene chloride/ diisopropyl ether. Yield 61 mg of melting point 81°-82° C. IR spectrum in CH2 --Cl2 : 2950, 2860, 2110, 1810, 1720, 1590, 1530, 1370, 1320, 1085, 1020 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:27].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(F)c(Cl)cc21
Yield: 80.9 %

Procedure:
1,1-Dimethylethyl N-((7-chloro-6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (200 mg, 503 μmol) was reacted with TFA (2 mL) at ambient temperature for 30 minutes. The mixture was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (139 mg) as a white solid. MS m/e=342 (M+H)+. Calculated for C15H13NO5 341.05.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10](NC(CC3SC=CC=3)=O)[C:11](=O)[N:8]2[C:7]=1C([O-])=O)=O.[Na+].C(=O)(O)[O-:29].[Na+].[N-]=[N+]=[N-].[Na+]>O>[N:8]12[CH2:11][CH2:10][CH:9]1[S:22][CH2:23][C:6]([C:5]([OH:4])=[O:29])=[CH:7]2
Reactant: O=C([O-])O
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=CN2CCC2SC1
Temperature: 2.7777777777777777 °C

Procedure:
A solution of commercial cephalothin sodium salt (5.0 g), sodium bicarbonate (1.06 g), sodium azide (0.82 g) and water (75 ml) is heated at approximately 50° C. (122° F.) until TLC (thin layer chromatography) shows the starting material is consumed. The reaction is cooled to approximately 3° C. (37° F.), covered with ethyl acetate and acidified with 1N HCl. The ethyl acetate extract is dried over Na2SO4, filtered and the filtrate is concentrated to dryness to give [6R[6a,7B]]-3-(azidomethyl)-8-oxo-7-](2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-carboxylic acid. A mixture of this azido intermediate (1.0 g), 10% Pd/C (1.0 g), NaHCO3 (1.54 g) and 75% methanol/H2O is subjected to hydrogenation at room temperature until TLC shows the disappearance of starting azide. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is dissolved in water, acidified with 1N HCl and the solution is washed with CHCl3. The aqueous phase is concentrated to dryness and the crude product is purified using 50W-X4 cation exchange resin to give product (II).
Reaction SMILES: C[C@@]1(CO)[C@H](CCC)O1.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.[Si:34]([O:41][C@H:42]([CH2:47][CH2:48][CH3:49])[C@@H:43]([CH3:46])[CH:44]=[O:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[Si:34]([O:41][C@@H:42]([CH2:47][CH2:48][CH3:49])[C@H:43]([CH3:46])[CH:44]=[O:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CCC[C@@H]1O[C@]1(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=O

Procedure:
Epoxy alcohol 13, 1.25 eq TBSOTf, and 1.30 eq DIPEA were reacted as in the preparation of 16 to give the crude aldehyde 14 in 95% +yield. 1H NMR, 13C NMR, IR, and high resolution MS are identical to 16. [δ]D=+19.3° (c=1.10, CH2Cl2). 1H NMR integration of δ 9.67 and the contaminating diastereromer at δ 9.71 indicated a >50:1 ratio.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2].C(O)C.C(=O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:17]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C@H:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2]
Reactant: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Agent: O=C=O
Solvent: CCO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CC[C@H]3[C@H]2C2CCCC2)ccc1C#N

Procedure:
The title compound was prepared from the 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid prepared in Example 21 using chiral resolution (e.g., Method G (Chiralcel OJ-H 30×250 mm; 50% ethanol/carbon dioxide). Second eluting peak: chiral HPLC tR=3.49 minutes (Chiralcel OJ-H 4.6×250 mm; 50% ethanol/carbon dioxide)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCBr)cc2)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCN3CCCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1280 mg (2.2 mmol) of [2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(8-bromo-octyloxy)phenyl]methanone and 470 mg (6.6 mmol) of pyrrolidine were dissolve in 20 mL of dimethylformamide (DMF). The reaction mixture was heated to 100° C. and stirred under a nitrogen atmosphere. After 30 minutes, the reaction was allowed to cool and evaporated to dryness in vacuo. The crude product was chromatographed on a silica gel column eluted with a linear gradient begining with CHCl3 and ending with CHCl3—MeOH (19:1) (v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 890 mg (72%) of the title compound as a tan, amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>O1CCOCC1>[CH:12]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:14])[CH3:13]
Reactant: CC(C)Br
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Sc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirring suspension of 25 grams (0.2 mole) of 3-aminothiophenol in 200 ml. of 5N NaOH was added drop-wise a solution of 24.6 grams of 2-bromopropane (0.20 mole; M.W. 123.00) dissolved in 100 ml. of 1,4-dioxane. The resulting suspension was stirred at room temperature overnight and then was extracted with two 500 ml. portions of ethyl ether. The ether extracts were combined, dried over Na2SO4, and evaporated in vacuo to yield 23.5 grams of m-isopropylthioaniline.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CN1C(=O)N(C)CCC1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=O)[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=[CH:3][C:1]#[N:2])[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC[C@@H](C=CC#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (126 μL, 0.799 mmol) and DMPU (481 μL, 3.99 mmol) in THF (1.33 mL) was added 60% sodium hydride in mineral oil (24.0 mg, 0.599 mmol) at 0° C. The mixture was stirred for 30 min, and then treated with a solution of (2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal prepared above in Step D (207 mg, 0.399 mmol) in THF (1.33 mL). After being stirred for 4 h, the reaction was quenched (water), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 30 to 40% EtOAc/Hex, gradient elution) provided the title compound as a colorless liquid.