Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: FC(F)(F)c1ccc(Cl)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 2-chloro-5-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 153. 1H NMR(CDCl3) δ: 9.20-9.05 (broad m, 2H), 7.67 (s, 1H), 7.52-7.40 (m, 2H), 6.43 (broad s, 1H), 6.32 (broad s, 1H), 4.39 (broad s, 2H), 4.35-4.10 (m, 2H), 3.75-3.30 (overlapping m, 4H), 3.30-2.79 (overlapping m, 5H), 2.65-2.50 (m, 1H), 2.20-2.05 (m, 2H). LRMS (ES)+: 454.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O-:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.F[C:48]1[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=1[F:58]>C(OCC)(=O)C>[Cl:21][C:20]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17](=[O:22])[N:18]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=2[F:58])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([O-])ncc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3F)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A two liter round bottom flask was charged with tetrabutylammonium 4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g, 158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene (30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for 12 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (500 mL) and distilled water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the residue was added 500 mL of 20% ethyl acetate in diethyl ether and the mixture was stirred for 12 hours at room temperature. The slurry was then cooled to 4° C. and stirring was continued for additional 1 hour. The solid was collected by filtration and dried under vacuum for 4 hours at 45° C. to yield t-butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (58 g, 70% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.85-7.89 (m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m, 1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m, 4H), 1.48 (s, 9H); MS m/e 501.2 (M+H+).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Br)C1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 66 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:28])[N:11]([CH3:27])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[CH:14]=2)=[CH:5][C:4]([CH3:29])=[N:3]1.C1C(=O)N([Cl:37])C(=O)C1>ClCCCl.C(#N)C.O>[Cl:37][C:5]1[C:4]([CH3:29])=[N:3][N:2]([CH3:1])[C:6]=1[CH2:7][NH:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[N:12]=[C:13]([O:15][CH2:16][C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3cc(C)nn3C)c(=O)n(C)n2)nc1
Solvent: O
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3c(Cl)c(C)nn3C)c(=O)n(C)n2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one (10 mg, 0.025 mmol) in 1,2-Dichloroethane (2.0 mL) was added NCS (4.0 mg, 0.030 mmol). After stirred for 1 h at rt, the reaction mixture was concentrated. The residue was purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% acetonitrile in water with 10 mmol NH4HCO3 modifier) to obtain product. 1H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 7.53 (d, 1H), 7.14 (d, 1H), 5.91 (s, 1H), 4.42 (s, 2H), 4.21-4.16 (m, 1H), 4.11-4.06 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 2.12-2.06 (m, 1H), 1.82-1.79 (m, 1H), 1.25-1.20 (m, 1H), 1.10-1.05 (m, 1H); LRMS m/z (M+H) 429.1 found, 429.17 required.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[ClH:24].[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3c(c2)CNC3)CC1

Procedure:
5-(4-Methyl-piperazin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (247 mg, 0.78 mmol) was treated with 4M HCl in dioxane (4 mL, 4 mmol) for 24 hours. Concentration in vacuo afforded the title compound quantitatively, which was used directly in the coupling reaction. 1H NMR (DMSO-d6) 11.13 (1H, br.s), 9.99 (2H, br.s), 7.27 (1H, d), 7.02-7.00 (2H, m), 4.43-4.37 (4H, m), 3.82-3.75 (2H, m), 3.49-3.43 (2H, m), 3.15-3.10 (4H, m), 2.79-2.78 (3H, s), 1.52 (9H, s). MS: [M+H]+ 218.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([SH:29])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[NH2:16])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(Sc2ccc(C)cc2N)cc1OC
Yield: 71.3 %

Procedure:
The product from Example 4a (11.25 g, 39.5 mmol) was reacted with 3,4-dimethoxy-benzenethiol (6.71 g, 39.5 mmol) for 18 h following the procedure from Example 4b giving the product as a solid (7.75 g, 64%).
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]1[C:7]([OH:15])=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[CH:9]=[O:10].P([O-])(O)(O)=[O:17].[Na+].CC(=CC)C.Cl>C(O)(C)(C)C.O>[F:5][C:6]1[C:7]([OH:15])=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:9]([OH:17])=[O:10]
Reactant: Cc1ccc(C=O)c(O)c1F
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)O)c(O)c1F
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To an aqueous solution (50.0 mL) of sodium chlorite (22.2 g) was added a mixture of 3-fluoro-2-hydroxy-4-methylbenzaldehyde (9.47 g), sodium dihydrogenphosphate (33.2 g) and 2-methyl-2-butene (32.5 mL) in tert-butanol (200 mL)-water (100 mL) under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. The pH of the reaction mixture was adjusted to 2-3 with 2N hydrochloric acid. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.5 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5].Cl[CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.[CH2:30]([SH:34])[CH2:31][CH2:32][CH3:33]>C1COCC1.O>[CH2:30]([S:34][CH2:17][CH2:18][S:19]([OH:21])(=[O:5])=[O:20])[CH2:31][CH2:32][CH3:33].[F:1][C:2]([F:14])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCCCS
Agent: COc1ccc(C(=NO)C(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCSCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 40 mL of THF are dissolved 4.38 g (20.0 mmol) of 2,2,2-Trifluoro-1-(4-methoxyphenyl)-ethanone oxime and the solution is cooled in an ice-bath. To the solution are added successively 2-chloroethanesulfonyl chloride (2.3 mL, 22.0 mmol) and triethylamine (6.4 mL, 46.0 mmol), and the reaction solution is stirred at 0° C. for 1 h. Then, 1-butanethiol (2.4 mL, 22.0 mmol) and triethylamine (4.2 mL, 30.0 mmol) are added successively, and the reaction solution is stirred at room temperature for 0.5 h. After the reaction mixture is poured into water, the crude product is extracted with ethyl acetate twice, washed with water, dried over MgSO4 and concentrated. The residue is purified by column chromatography on silica gel with hexane—ethyl acetate (10:1 to 5:1) as an eluent to afford the product as yellow oil. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 0.92 (t, 3H), 1.41 (m, 2H), 1.57 (m, 2H), 2.56 (t, 2H), 2.93 (t, 2H), 3.66 (t, 2H), 3.87 (s, 3H), 7.00 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: [N:1](CCOCCOCC(=O)CCC(O)=O)=[N+:2]=[N-:3].C(Cl)CCl.[CH3:22][CH2:23][C@@:24]1([OH:47])[C:29](=[O:30])[O:28][CH2:27][C:26]2[C:31]([N:33]3[C:45](=[CH:46][C:25]1=2)[C:44]1[N:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[CH2:34]3)=[O:32]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:22][CH2:23][C@@:24]1([OH:47])[C:29](=[O:30])[O:28][CH2:27][C:26]2[C:31]([N:33]3[C:45](=[CH:46][C:25]1=2)[C:44]1[N:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[CH2:34]3)=[O:32].[N-:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCC(=O)CCC(=O)O
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: [N-]=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 70 mg of 5-[2-(2-azidoethoxy)ethoxy]-4-oxopentanoic acid in 10 mL of dichloromethane was cooled in an ice-water bath, and treated with 55 mg of EDC, followed by 35 mg of DMAP and 50 mg of camptothecin. The reaction was then allowed to warm to room temperature and stirred overnight as the solution slowly became homogeneous. The reaction mixture was then concentrated and applied to a silica gel column, which was eluted first with 1-2% methanol in dichloromethane. The appropriate fractions were then concentrated to give the desired conjugate as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=0.98 (t, J=7.6H), 1.98 (quintet, J=7.2 Hz, 2H), 2.13-2.32 (complex m, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.51-2.65 (complex m, 2H), 3.35 (t, J=5 Hz, 2H), 3.63-3.68 (m, 4H), 4.21-4.25 (m, 2H), 5.30 (br s, 2H), 5.41 (d, J=17.2 Hz, 1H), 5.68 (d, J=17.2 Hz, 1H), 7.21 (s, 1H), 7.68 (t, J=6.8 Hz, 1H), 7.84 (app t, J=8.4 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][N:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:30][CH:31]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(O)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 6-hydroxynicotinate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Colorless oil (78%). MS (Turbo Spray): m/z=526.2 [M+H].
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]1[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=[C:5]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[Ca+2]>C(Cl)(Cl)Cl>[Cl:1][C:6]1[CH:7]=[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[N:4]([CH3:3])[C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: ClCl
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1c(Cl)cc(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 4.26g (0.06 mole) of chlorine in 75 ml. of chloroform is added rapidly to a mixture of 16.2g. (0.06 mole) of methyl 1-methyl-5-(p-toluoyl)- pyrrole-2-acetate, 16g (0.12 mole) of calcium carbonate, and 0.48g. (0.003 mole) of ferric chloride in 75 ml. of chloroform. The temperature rose somewhat. After an hour, when the chlorine has been consumed, the solids are removed by filtration and the filtrate is evaporated in vacuo to yield a red oil. The oil is chromatographed on 2lb. of Silica (Mallinkrodt SILIC-AR CC-4) 100-200 mesh and eluted successively with hexane, benzene, and chloroform. The first compound-bearing fraction is eluted with chloroform. The solvent is evaporated and the residue is recrystallized from methanol to give white crystalline methyl 3-chloro-1-methyl-5-(p-toluoyl)pyrrole-2-acetate; m.p. 144°-146° C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2]>[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][CH2:5][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 140 °C
Yield: 80 %

Procedure:
A 1-liter flask is charged with 3000 mol. wt. polyether triol (200 g, PO/EO copolymer having about 15 wt. % internal oxyethylene content; a flex-slab polyol), acetic anhydride (500 g), and zinc chloride (35 g). The mixture is heated to 140° C. for 7 h. Propylene glycol diacetate is isolated by distillation in 80% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[C:25]([S-:27])#[N:26].[K+].BrBr>C(O)(=O)C>[NH2:26][C:25]1[S:27][C:7]2[CH:6]=[C:5]([CH:8]([OH:24])[CH:9]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][CH2:12]3)[CH3:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: CC(C(O)c1ccc(N)cc1)N1CCC(Cc2ccccc2)CC1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C(O)c1ccc2nc(N)sc2c1)N1CCC(Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 46.8 %

Procedure:
To a stirred solution of 4 g of 1-p-aminophenyl-2-(4-benzyl-piperidin-1-yl)-propan-1-ol and 4.6 g of KSCN in 35 ml of glacial acetic acid was added dropwise 3.8 g of Br2 in 10 ml of glacial acetic acid. After 5 hours, the yellow suspension was filtered and the solution was poured into 100 ml of a concentrated hydroxide ammonium solution. After extraction with ethylacetate, the organic phase was washed with brine and dried. The solvent was removed and the residue was filtered on a small of silica gel eluting with acetone/cyclohexane ¼, affording 2.2 g of the title compound, m.p. 197-200° C., [α]20D=−15.6±0.2.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([CH:11]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH2:4][CH2:3]1.[CH:25]1([CH:33]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:25]1([CH2:33][N:2]2[CH2:3][CH2:4][CH:5]([NH:8][C:9]([CH:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[O:18][C:19]4[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:10])[CH2:6][CH2:7]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(NC1CCNCC1)C1c2ccccc2Oc2ccccc21
Reactant: O=CC1CCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CC2CCCCCCC2)CC1)C1c2ccccc2Oc2ccccc21
Reaction time: 12 h
Yield: 45.4 %

Procedure:
1.16 g of N-(piperidin-4-yl)xanthene-9-carboxamide hydrochloride and 586 mg of cyclooctanecarbaldehyde were suspended in 60 ml of tetrahydrofuran at room temperature, and 1.60 g of sodium triacetoxyborohydride was added thereto, followed by stirring for 12 hours at the same temperature. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent: chloroform--chloroform/methanol=50/1), and 660 mg of the title compound as a white solid was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:14]([NH:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH:15]([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([NH:18][C:19]1[CH:24]=[C:23]([N:13]2[CH:12]=[CH:11][N:10]=[C:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH:15]([CH3:17])[CH3:16]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)CNc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CNc1cc(-n2ccnc2-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Add sodium hydride (60% oil dispersion, 94 mg, 2.36 mmol) to a solution of 2-phenylimidazole (340 mg, 2.36 mmol) in 8 mL dimethylformamide. Stir at room temperature for 15 minutes and then add N-[isobutyl]2-nitro-5-fluoroaniline (500 mg, 2.36 mmol). Stir at 60° C. over night under a nitrogen atmosphere. Dilute the reaction mixture with ethyl acetate and wash with dilute aqueous sodium bicarbonate. Dry the organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to radial silica gel chromatography, eluting with a gradient of 0.1%-5% methanol in dichloromethane to provide the desired compound as a yellow solid (450 mg, 57%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 58 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.05 g, 3.5 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound(0.93 g, 58%) as a beige solid, mp 244°-245° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[C:10]1[O:11][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1>CN(C=O)C>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[O:11][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([F:17])([F:16])[F:18])[N:14]=1
Reactant: O=C1CCCN1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(N2CCCC2=O)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
NaH (0.060 mg, 1.5 mmol) (60%) was added to a solution of 2-oxopyrrolidine (0.13 g, 1.5 mmol) in DMF (5.0 mL) at −78° C. followed by stirring for 15 mins at −78° C. Then ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate A-2 (0.29 g, 1.0 mmol) was added. The reaction mixture was stirred for 3 h while the temperature was slowly warmed to RT. The reaction mixture was purified by chromatography on a Prep Gilson HPLC to yield ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-30) as a white solid (0.15 g, 34% yield). 1H NMR (500 MHz, CDCl3) δ 4.44 (m, 2H), 4.09 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=8.2 Hz), 2.28 (m, 2H), 2.42 (t, 3H, J=7.3 Hz).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:4]2[S:3][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=2)=[CH:18][CH:17]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1ccc(Cc2nc3ccccc3s2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was added the product from step 1 (241 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (320 mg, 70%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.81-2.11 (m, 4H), 3.32-3.47 (m, 2H), 3.70-4.20 (m, 3H), 4.37 (s, 2H), 6.84-6.97 (m, 4H), 7.33 (t J=7.6, 1H), 7.45 (t, J=7.6, 1H), 7.78 (d, J=8.0, 1H), 7.98 (d, J=8.4, 1H).