Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS([Cl:39])(=O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Cl:39])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (4.0 g) and N,N-diisopropylethylamine (3.2 mL) in dichloromethane (100 mL) at 0° C. was added, dropwise, methanesulfonyl chloride (125 mL). The mixture was stirred at 0° C. for 18 hrs, then washed (water, brine) and dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from hexane to give 3-(4-fluorophenyl)-3-chloro-1-(diphenylmethyl)azetidine (16) (22 g), m.p. 108-109° C. (hexane). Found: C, 75.13; H, 5.46; N, 3.93. C22H19CIFN C, 75.10; H, 5.44; N, 3.98%.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])=[CH:6][C:5]=1[N+:16]([O-])=O)=[N+]=[N-]>CCO.[Pd]>[CH3:13][O:12][CH2:11][C:10]([C:7]1[CH:6]=[C:5]([NH2:16])[C:4]([NH2:1])=[CH:9][CH:8]=1)([CH3:15])[CH3:14]
Reactant: COCC(C)(C)c1ccc(N=[N+]=[N-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COCC(C)(C)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Azido-4-(1-methoxy-2-methylpropan-2-yl)-2-nitrobenzene (1.102 g, 3.52 mmol) was dissolved in EtOH (30 ml) and Pd/C (10% wt.) (0.110 g, 10% wt) was added. The reaction was purged 3 times with N2 then 3 times with H2 and the reaction stirred at r.t. overnight. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 100% EtOAc as eluent to give the product as a pale brown oil which solidified into a dark orange solid (0.481 g, 63%, 90% pure): MS (ESI+) for C11H18N2O m/z 195.1 [M+H]+; LC purity 87% (ret. time, 0.99 min); 1H NMR (500 MHz, CDCl3) δH 16.65 (dd, J=11.2, 1.9 Hz, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.26 (s, 2H), 3.24 (s, 3H), 1.20 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[OH:9].[H-].[Na+].[CH3:14]I>C1COCC1>[CH3:14][O:9][CH:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: COC1(OC)CCOCC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1COCCC1(OC)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4,4-dimethoxytetrahydro-2H-pyran-3-ol (6.00 g, 37.0 mmol) in THF (100 mL) at 0° C. was added sodium hydride (1.48 g, 37.0 mmol). After being stirred at 0° C. for 1 h, methyl iodide (4.61 mL, 74.0 mmol) was added dropwise. The reaction was allowed to warm up to ambient temperature and quenched using aqueous NH4Cl. The product was extracted with ether three times. The combined extracts were dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel (10% ether to 60% ether/hexanes) provided the desired product. 1H NMR (CDCl3) δ 4.05-3.95 (1H, m), 3.80-3.70 (1H, m), 3.60-3.50 (3H, m), 3.50 (3H, s), 3.30 (3H, s), 3.10 (3H, s), 2.00-1.70 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:12]I>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH3:12][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccc2c(C=O)cccc21

Procedure:
34 g of indol 4-carboxaldehyde in 800 ml of methylene chloride were mixed for 4 hours at ambient temperature with 79.5 g of tetrabutyl ammonium hydrogen sulfate and 16.04 ml of methyl iodide in 400 ml of 5N sodium hydroxide and 300 ml of methylene chloride were added, followed by decanting and extraction was effected with methylene chloride. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. Tho residue was chromatographed on silica (eluant: methylene chloride) to obtain 36.8 g of the expected product melting at <40° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([C:12]([F:15])([F:14])[F:13])[CH2:9][CH:10]=C)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:25].[Na+].O=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO.O=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCC(NC(=O)OC(C)(C)C)(c1ccccc1F)C(F)(F)F
Agent: O=O
Agent: O=[O+][O-]
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCO)(c1ccccc1F)C(F)(F)F
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
A suspension of [[1-(2-fluoro-phenyl)-1-trifluoromethyl-but-3-enyl]-carbamic acid tert-butyl ester (9.27 g, 27.8 mmol) and NaHCO3 (3.50 g, 41.7 mmol) in 168 ml DCM and 56 ml MeOH was cooled to −75° C. A mixture of O3 in oxygen gas was introduced till the blue color persisted. The excess ozone was removed by bubbling through oxygen gas for 10 minutes. Solid NaBH4 (2.10 g, 55.6 mmol) was added in two portions. The mixture was stirred 10 min at −75° C. and then allowed to warm to 0° C. After 30 minutes, the mixture was poured onto ice-cold 1N HCl and extracted with TBME. The organic phase is washed with 1N HCl, brine, dried with MgSO4.H2O and evaporated. Crystallization from hexane provided 7.83 g of the title compound as white crystals.
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[OH:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:29]=[CH:30]C(O)=O.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:30]=[CH:29]/[C:28]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:26]([OH:25])[CH:27]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 3-Hydroxy-4-methoxycinnamic acid (predominantly trans) (0.070 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18f (0.01 g, 8%) as a yellow solid: mp 215–218° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 9.13 (s, 1 H), 8.73 (dd, J=4.1, 1.4, 1 H), 8.36 (dd, J=8.5, 1.4, 1 H), 8.17 (bs, 1 H), 7.57 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.25 (d, J=2.0, 1 H), 7.20 (dd, J=8.4, 2.0, 1 H), 6.99 (d, J=8.1, 1 H), 6.96 (d, J=15.0, 1 H), 4.54 (dd, J=10.5, 9.4, 1 H), 4.44 (dd, J=11.1, 2.6, 1 H), 4.00 (dd, J=11.2, 3.3, 1 H),3.88 (dd, J=11.1, 7.5, 1 H), 3.83 (s, 3H). C22H1935ClN2O4 requires M+H 411.1112. Found (FAB) 411.1127.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:62])[CH:24]([NH:25][C:26](=[O:61])[C:27]([C:36]4[N:37]=[C:38]([NH:41]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:39][CH:40]=4)=[CH:28][C:29]([O:31]C(C)(C)C)=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:63][S:64][C:65]2[S:66][C:67]([CH3:70])=[N:68][N:69]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:71][C:72]([F:77])([F:76])[C:73]([O-:75])=[O:74].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:27](=[CH:28][C:29]([OH:31])=[O:30])[C:26]([NH:25][CH:24]2[C:23](=[O:62])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH2:63][S:64][C:65]4[S:66][C:67]([CH3:70])=[N:68][N:69]=4)[CH2:19][S:20][C@H:21]23)=[O:61])[N:37]=1.[F:71][C:72]([F:77])([F:76])[C:73]([O-:75])=[O:74]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=CC(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=CC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
7-[2-(2-tritylaminothiazol-4-yl)-2-t-butoxycarbonylmethylene-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethylester (Z-isomer) (60 mg) was dissolved in anisole (0.5 ml), and the resultant solution was ice-cooled. The cooled solution was admixed with trifluoroacetate acid (2 ml), and the admixture obtained was stirred for 4 hours at 0° to 5° C. The resulting reaction solution was poured into isopropylether (50 ml), to precipitate the titled compound. The precipitate was removed by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethylene-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (Z-isomer) trifluoroacetate (20 mg) as powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](O)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCO)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-dimethoxyphenylacetic acid (2 g) in anhydrous THF (40 ml) at 0° C. under N2 was added dropwise borane-methyl sulfide complex (10 M, 1.5 ml). The mixture was stirred at room temperature for further 4 hrs. Cold water (5 ml) was added to destroy any excess of borane followed by the addition of H2SO4 (1 M, 50 ml). The mixture was extracted three time with ethyl acetate (50 ml). The organic layer was separated and evaporated off to give a colourless liquid which was then purified by column chromatography to afford a colourless solid in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)cc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)c1
Yield: 43.6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (300 mg, 1.3 mmol), 3-methoxybenzoic acid (172 mg, 1.3 mmol), EDC (386 mg, 2 mmol), and triethyl amine (303 mg, 3 mmol) were stirred in DCM (5 mL) at ambient temperature for 6 hours. The reaction was diluted with DCM (50 mL) and the organic phase was washed with aqueous 0.1 N HCL (150 mL) followed by aqueous 1N NaOH (150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated on the rotovap. The crude product was purified by silica gel chromotography (40% ethyl acetate in hexanes) to afford 225 mg of an off white solid. The solid was triturated with ethyl acetate/hexanes (1/9) and the white solid was collect by filtration. The pure product was dissolved in absolute ethanol and concentrated on the rotovap (4×, 25 mL) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-methoxybenzamide (185 mg, 43%) as a white solid. 1H NMR (CDCl3, 400 MHz): 2.20 (s, 3H), 2.42 (s, 3H), 3.85 (s, 3H), 5.03 (s, 2H), 7.09-7.06 (m, 1H), 7.37-7.35 (m, 2H), 7.41 (m, 1H), 7.51 (s, 1H), 7.93 (bs, 1H), 8.03 (s, 1H). LC/MS; [M+H] calculated for C, 17; H, 18; N, 4; O, 3; expected 327.14; found 327.30. Melting point: 127-129° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[K].Cl.S([O-])([O-])=[O:13].[Na+].[Na+]>[OH-].[Na+].C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: O=S([O-])[O-]
Reactant: Oc1cccc(F)c1F
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 mol of 2,3-difluorophenol is dissolved in 1 l of 10% sodium hydroxide solution, and a saturated aqueous solution of 1.1 mol of potassium peroxodisulphate is added dropwise over the course of 4 hours with ice cooling. During this addition, the temperature must not exceed 20o The mixture is stirred overnight at room temperature and neutralized using hydrochloric acid, and unreacted starting material is extracted with ether. 3 1 of toluene and 2 mol of sodium sulphite are added to the aqueous phase, and the mixture is strongly acidified using 1 1 of concentrated hydrochloric acid and refluxed for 20 minutes. After cooling, the toluene layer is separated off, the aqueous phase is extracted with ether in a perforator, and 2,3-difluorohydroquinone is obtained by evaporating the combined toluene and ether extracts.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.S(O[CH2:22][CH2:23][O:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:6]1([CH2:5][CH2:4][O:3][CH2:22][CH2:23][O:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CC[C@H](OCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 86.7 %

Procedure:
To a suspension of 0.13 g of NaH (60% dispersion in mineral oil) in 15 ml of anhydrous dimethylformamide, 0.37 g of 1-(2-hydroxyethyl)pyrrolidine were added at room temperature in a nitrogen atmosphere. The mixture was kept at reflux for 2 hrs, then 0.90 g of 3β-(2-tosyloxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex. 7, were added. The mixture was kept at reflux temperature for 4 hrs; then 50 ml of water were added cautiously. The residue was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using acetone/methanol 85/15 as eluant to give 0.70 g of the title compound (I-ah) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O>CCOC(C)=O>[C:11]1([NH:10][C:9]2[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ncccc1Nc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ncccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A mixture of (2-nitropyridin-3-yl)phenylamine (6.75 mmol) in EtOAc (40 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (200 mg) and was stirred at RT under a hydrogen atmosphere for 16 h. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a white solid (520 mg, 42% over two steps). 1H NMR (CDCl3, 400 MHz): δ 7.92 (1H, dd, J=4.98, 1.64 Hz), 7.36 (1H, ddd, J=7.62, 1.65, 0.69 Hz), 7.26-7.20 (2H, m), 6.90-6.85 (1H, m), 6.78-6.73 (2H, m), 6.68 (1H, dd, J=7.61, 4.98 Hz), 5.13 (1H, br s), 4.57 (2H, br s).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1.O>[C:22]1([NH:28][C:29]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=3)[CH2:17]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 52 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate and 2.62 g (0.022 mole) of phenyl isocyanate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated. The tetrahydrofuran-water portion was decanted and the residue solidified on standing. Recrystallization from ethanol-water yielded 3.5 g (53.4%) of fine white crystals, m.p. 174.5°-176° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 20 °C
Yield: 51.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.4 g), sodium bicarbonate (0.7 g) and 4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydropyridine (2 g) in dimethylformamide (15 cc) and tetrahydrofuran (15 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (50 cc), then recrystallization from boiling acetonitrile (50 cc), 2-{3-[4(5-chloro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1 g) is obtained, m.p. 189° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:27]5[CH2:30][CH2:29][CH2:28]5)=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (81 mg, 79%), MS (ISP) m/z=411.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].N1CCCC1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].CN(C=O)C>C(OCC)(=O)C>[CH3:23][N:24]([CH:26]=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 19 h

Procedure:
Combine 1-methyl-2-nitro-4-trifluoromethoxybenzene (3.73 g, 16.86 mmol), pyrrolidine (1.32 g, 18.55 mmol), N,N-dimethylformamide dimethyl acetal (6.03 g, 50.58 mmol), and dry DMF (35 ml). Heat to about 105°. After 19 hours, remove the DMF under reduced pressure to give an oily residue. Combine the residue and ethyl acetate, wash with brine, dry (Na2SO4), then concentrate to give N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.N1C=CC=CC=1.[F-:20]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([F:20])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [F-]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(F)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-1H-indole-2-carboxylic acid (10.0 g, 51.1 mmol) and pyridine (33.1 mmol) in acetonitrile was added to a solution of byanuric fluoride (2.76 g, 20.4 mmol) in acetonitrile (total 340 mL) at 25° C. The reaction was followed by TLC on aliquots quenched with butylamine and appeared nearly complete at 1 hour. The mixture was poured onto ice, extracted with ether, dried (Na2SO4), and concentrated giving a solid which was used without purification (10.0 g, 99%). TLC of a butylamine-quenched aliquot showed some 5-chloroindole-2-carboxylic acid and the less polar N-butylamide. A sample was purified by chromatography on silica gel eluting with ethyl acetate-hexanes (50-100%) for characterization (16368-130-1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.BrC1C=C([C@@H]2[C@@H:21]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3F)[O:20][C:19](=[O:30])[NH:18]2)C=NC=1.BrC1C=NC=C(CBr)C=1>>[Cl:9][C:6]1[N:7]=[CH:8][C:3]([C@@H:2]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([F:28])[CH:27]=3)[O:20][C:19](=[O:30])[NH:18]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Agent: BrCc1cncc(Br)c1
Product: O=C1N[C@H](c2ccc(Cl)nc2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared from 5-(bromomethyl)-2-chloropyridine in similar fashion to the preparation of (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one from 3-bromo-5-(bromomethyl)pyridine. 1H NMR (500 MHz, CDCl3) δ ppm 8.19-8.36 (1H, m), 7.72 (1H, dd, J=8.39, 2.59 Hz), 7.42-7.49 (1H, m), 7.32-7.42 (1H, m), 6.94-7.08 (2H, m), 5.56 (1H, s), 5.23 (1H, d, J=7.63 Hz), 4.77 (1H, d, J=7.63 Hz). Mass Spectral Anal. Calcd. for [M+H]+ C14H10ClFN2O2: 293.0. found 293.1.