Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].CO[C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:15]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][O:6][C:14]([CH:16]1[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH2:25][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:23])[CH2:20][CH2:21]1)=[O:15])[CH2:2][CH3:3]
Reactant: CCCCCC(CO)CCC
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(CCC)COC(=O)C1CCC(C(=O)OCC(CCC)CCCCC)CC1
Temperature: 185 °C

Procedure:
2-Propylheptyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 1.7%, trans 98.3%, Eastman, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(2-propylheptyl)cyclohexane-1,4-dicarboxylate (cis 3%, trans 97%) was obtained with a purity of 99.8% in the same manner as in Example 1.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=O)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1.[S-:14][C:15]#[N:16].[K+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:16][C:15](=[S:14])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: N#C[S-]
Reactant: Cc1cc(C(=O)CN)ccn1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc(-c2c[nH]c(=S)[nH]2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a stirred solution of crude 1-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.50 g, 35.8 mmol) in water (60 ml) was added at room temperature potassium thiocyanate (16.4 g, 168 mmol) and the reaction mixture was heated under reflux conditions for 3 h and at 0° C. for 2 h. The precipitated solid was collected by filtration, saturated sodium bicarbonate solution (100 ml) was added and the mixture was stirred at room temperature for 2 h. The product was collected by filtration to give 4-(2-methyl-pyridin-4-yl)-1,3-dihydro-imidazole-2-thione (5.44 g, 79%) as a light brown solid; MS (ISP) 192.2 [(M+H)+].
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (14.9 mg, 53.5%), MS (ISP) m/z=398.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-cyanoacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1.C(O[K])(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1
Reactant: c1ccc2scnc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Product: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N(C)C(C)C)nc2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 9.4 %

Procedure:
Into a 10-mL sealed was placed methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (400 mg, 1.36 mmol), 1,3-benzothiazole (368 mg, 2.72 mmol), Pd(PPh3)4 (80 mg, 0.06 mmol) and AcOK (272 mg, 2.72 mmol) under nitrogen atmosphere. After stirring 4 h at 150° C., the reaction mixture was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to afford methyl 2-(1,3-benzothiazol-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (50 mg, 9.4%).
Reaction SMILES: COC1C=C(C(F)(F)[F:10])C=C([N+]([O-])=O)C=1.[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:26]([F:32])([F:31])C(F)(F)F)=[C:23]([OH:25])[CH:24]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:26]([F:31])([F:32])[F:10])=[C:23]([OH:25])[CH:24]=1)([O-:18])=[O:17]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1

Procedure:
5-Nitro-2-trifluoromethyl-phenol was prepared from 1-Methoxy-3-nitro-5-trifluoromethyl-benzene similar to that described in the preparation of 5-nitro-2-pentafluoroethylphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([O:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:15]4[CH2:22][CH2:21][CH2:20][C:16]4=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.[I-].[Na+].[H-].[Na+].[P:31]([O:43][CH2:44]Cl)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[P:31]([O:43][CH2:44][N:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:18](=[O:19])[C:17]2[C:12]1=[C:13]([O:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:15]1[CH2:22][CH2:21][CH2:20][C:16]1=2)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:32]
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)CCC2
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a DMF solution (10 ml) of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (400 mg, 1.15 mmol) and sodium iodide (343 mg, 2.29 mmol) was added sodium hydride (60% oil base, 74.9 mg, 1.72 mmol), and the mixture was then stirred for 10 minutes at room temperature. To the resulting mixture was added a DMF solution (20 ml) of di-tert-butyl chloromethyl phosphate (888 mg, 3.43 mmol), and the mixture was then stirred at 40° C. for 4 hours. The reaction mixture was ice-cooled, ice water was added thereto, and then the reaction mixture was subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using medium pressure liquid chromatography (NH silica gel, n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure, giving a white powder of di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl phosphate (263 mg, yield: 40%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C>[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[N:21]([CH2:35][C:36](=[O:37])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])cn2CC(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 20 h
Yield: 43.9 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide trifluoroacetate salt (30 mg) in DMF (4 mL) was added Cs2CO3 (70 mg). The mixture was stirred for 30 min at RT after which 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (27 mg) was added. Stirring was continued for 20 h at RT. The mixture was filtered and directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA) to give 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (15 mg) as its trifluoroacetate salt. MS (ESI+): m/e=449 [M+H]+, chloro pattern.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H-].[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>CN(C=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[N:5]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]4)[N:22]3[CH3:25])=[C:18]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[N:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COCc1cc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 180 °C
Yield: 18.9 %

Procedure:
To a solution of 2-(methoxymethyl)-1H-indole (57 mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion, 15 mg, 0.38 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes before the addition of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (120 mg, 0.29 mmol). The mixture was then heated in the microwave at 180° C. for 15 minutes. The reaction mixture was then diluted with water. The mixture was extracted with three times with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-100% gradient EtOAc-heptane) followed by RP-HPLC to give 127 (29.2 mg, 19%). LCMS: M+H+=534.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H), 7.57 (d, 1H), 7.20 (t, 1H), 7.12 (t, 1H), 6.66 (s, 1H), 4.98 (s, 2H), 4.25 (s, br, 4H), 4.02 (s, 1H), 3.81 (s, 3H), 3.77 (m, 4H), 3.72 (s, 2H), 2.90 (d, 2H), 1.99 (m, 2H), 1.67 (m, 2H), 1.21 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH2:31][CH2:32][CH3:33]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[O:28][N:29]=[C:30]([CH2:31][CH2:32][CH3:33])[N:26]=5)[CH2:23][CH2:24]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCCC(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 2): tR=1.40 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:21]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[C:15]([OH:21])=[O:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCC[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentan-1-ol (37.1 g, 109 mmol in dry acetonitrile (500 mL) at −78° C. was added a solution of periodic acid (71.7 g) and chromium trioxide (144 mg) in dry acetonitrile (630 mL) over 1 hour. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was concentrated under reduced pressure to a total volume of approximately 500 mL. A solution of citric acid (22 g in 250 mL H2O) was added and the mixture was extracted with ethyl acetate (800 mL). The solution was washed with freshly prepared NaHSO3 (2×200 mL, 25 g solid dissolved to 200 mL with water) brine (300 mL), dried over MgSO4, filtered, and evaporated to give a pale orange solid, which was triturated with 5% ethyl acetate/hexanes to give (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid. Additional acid was obtained by concentrating the mother liquors, partitioning the residue between ether and aqueous NaHCO3, acidifying the aqueous layer with citric acid, extracting with ethyl acetate, drying over MgSO4, filtering, and evaporating the solvent.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].O=[C:6]=[CH2:7].O=C=C.C(#N)C=C.[CH:15]([O:17][C:18]([CH3:21])(C)C)=[CH2:16].N(C(C)(C)C#N)=NC(C)(C)C#N>CS(C)=O>[C:1](#[N:4])[CH:2]=[CH2:3].[CH2:18]([O:17][CH:15]=[CH2:16])[CH2:21][CH2:6][CH3:7]
Reactant: C=COC(C)(C)C
Reactant: C=C=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=CC#N
Solvent: CS(C)=O
Product: C=COCCCC

Procedure:
A copolymer of acrylonitrile/oxoethylene containing 121/2 moles of oxoethylene per 100 moles of acrylonitrile was prepared by (a) copolymerising a mixture of acrylonitrile and tertiarybutyl vinyl ether dissolved in dimethyl sulphoxide solvent using azobisisobutyronitrile as an initiator to form an acrylonitrile/butoxyethylene copolymer, (b) dissolving the copolymer in an aqueous solution of sodium thiocyanate and hydrolysing the tertiarybutoxy grouping with hydrobromic acid to form an acrylonitrilehydroxyethylene copolymer and (c) oxidising this copolymer with dimethyl sulphoxide/acetic anhydride to form the acrylonitrileoxoethylene copolymer. The experimental details are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 50 was prepared from bis(4-chlorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.96 (br s, 1H), 7.77 (s, 1H), 7.64 (t, 1H, J=8.4 Hz), 7.31–7.26 (m, 8H), 6.88 (dd, 1H, J=0.8, 7.6 Hz), 4.84 (s, 1H), 3.39 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=11.6 Hz), 2.59 (m, 1H), 2.47 (t, 2H, J=6.0 Hz), 2.28 (m, 1H), 2.07–2.00 (m, 2H), 1.89 (dd, 2H, J=2.0, 12.4 Hz), 1.76–1.67 (m, 4H), 1.14 (d, 6H, J=6.8 Hz); ESMS m/e: 567.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[OH:26][CH2:27][CH:28]([CH2:30]O)[OH:29]>ClCCl.O1CCCC1>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: OCC(O)CO
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OCC(O)CO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of glycerine (0.9 mL) in tetrahydrofuran (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) to provide, after crystallization from ethyl acetate-hexane, 0.25 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2,3-dihydroxypropyl ester as a colorless solid, mp 124°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23](F)=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35][O-:36].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:36][CH3:35])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(1-t-Butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (300 mg) was dissolved in 3 ml of DMF, followed by the addition of 32 mg of 55% sodium hydride under ice cooling. After the resultant mixture was stirred for 10 minutes, 72 mg of sodium methoxide was added. The mixture thus obtained was stirred further for 18 hours at room temperature. The reaction mixture was diluted with chloroform and then washed successively with 10% aq. citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness, whereby 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. It was used directly in the reaction of the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[CH:8]([F:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:34])[F:33])([OH:26])[CH:8]([F:35])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1F
Yield: 48.4 %

Procedure:
To 6,7-dichloro-2-fluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.2 g, 0.35 mmol) in THF (10 mL), KOH (98 mg, 1.7 mmol) in H2O (10 mL) was added and the resulting mixture was refluxed for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography [EtOAc-hexane (1:9) as eluant] and the solid obtained was washed with cold pentane to give the title compound (58 mg, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.25 (bs, 1H), 7.62 (s, 1H), 7.5 (s, 1H), 5.25-5.14 (m, 1H), 3.25 (d, J=6.5 Hz, 1H), 2.94-2.89 (m, 1H), 2.80-2.74 (m, 1H), 2.44-2.39 (m, 1H), 2.35-2.29 (m, 1H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:19])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)Oc2ncccc2C1=S

Procedure:
To a solution of 59 g (0.25 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)one hydrochloride in 1500 ml of chloroform was added 41.5 g (0.19 mole) of phosphorus pentasulfide and the mixture was heated to reflux for 18 hr. The mixture was filtered and the filtrate was extracted with dilute sodium hydroxide. The chloroform layer was concentrated and the residue was dissolved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g (44%) of yellow solid precipitated. A portion was recrystallized from isopropyl alcohol, m.p. 134°-136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH2:66])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH:66][C:5]([C@H:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)[C@H]2CC2(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of (S)-2,2-dimethylcyclopropanecarboxylic acid (194 mg, 1.70 mmol), and carbonyldiimidazole (275 mg, 1.70 mmol) in THF was stirred at 50° C. for 3 hrs. To this was added dropwise a solution of DBU (258 mg, 1.7 mmol) and 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (300 mg, 0.57 mmol) (from Example 16, Step C) in THF. After stirring at 50° C. overnight, the reaction mixture was quenched by addition of 5% citric acid and extracted with EtOAc. The organic layers were combined and washed with water, 5% NaHCO3, and brine, and dried over anhydrous Na2SO4. The crude material obtained after filtration and evaporation of volatiles was flash chromatographed over 60 mL silica gel (gradient elution using 0.5-5.0% MeOH/CH2Cl2) to afford the title compound in 74% yield (263 mg) as a white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 627 (M+1)+, 649 (M+Na)+ ; mp 93°-95° C.