Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[NH:17][C:16]2=[O:29])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[N+:41]([C:44]1[CH:54]=[CH:53][C:47]([CH2:48][O:49][CH2:50][CH2:51]Cl)=[CH:46][CH:45]=1)([O-:43])=[O:42].P([O-])([O-])([O-])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[N:17]([CH2:51][CH2:50][O:49][CH2:48][C:47]3[CH:53]=[CH:54][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)[C:16]2=[O:29])[CH3:14])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
1.00 g (2.25 mmole) of (3S, 4R)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)carbonyl-methyl]-2-azetidinone was dissolved in 20 ml of methylene chloride. To the solutiion were added 350 mg (2.71 mmole) of diisopropylethylamine and then 660 mg (2.71 mmole) of p-nitrobenzyloxyethyl chloride, with stirring at 0° C. After 15 minutes, a further 230 mg (1.78 mmole) of diisopropylethylamine and 433 mg (1.78 mmole) of p-nitrobenzyloxyethyl chloride were added, and the mixture was stirred at that temperature for 15 minutes. After completion of the reaction, 30 ml of a 0.1M phosphate buffer solution (pH 7.1) was added to the reaction mixture and the organic layer was separated. The aqueous lager was extracted with chloroform. The organic layer was combined with the chloroform extract and then the solvent was distilled from the mixture. The residue was dissolved in 50 ml of a 1:1 by volume mixture of benzene and ethyl acetate, washed successively with 0.02N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off, to afford 1.47 g (yield 100%) of the title product as crystals which were recrystallized from a mixture of benzene and ethyl acetate, to afford the pure product melting at 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[S:28]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=S)c2ccccc12
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.8 g.) and phosphorus pentasulphide (2.5 g.) in xylene (100 ml.) was stirred and heated under reflux for 1 hour. The reaction solution was then cooled to room temperature, ethyl acetate (25 ml.) was added and the mixture was filtered through chromatographic silica (20 g.), the subsequent filtrate was evaporated and the residual solid obtained was recrystallised from ethanol to give ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-thioxophthalazin-4-ylacetate (1.1 g.), m.p. 124°-126° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:8]([CH3:9])[N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:18]1[N:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[CH:24]=2)[N:19]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([N:4]1[CH2:3][CH:2]([CH3:1])[CH:8]([CH3:9])[N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1)[N:27]=[CH:26]2
Reactant: Fc1ccc2nc(Cl)ncc2c1
Reactant: CC1CNCCN(C(=O)OC(C)(C)C)C1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(c2ncc3cc(F)ccc3n2)CCN(C(=O)OC(C)(C)C)C1C
Temperature: 130 °C

Procedure:
The amine 1-4 (270 mg, 1.18 mmol) was combined with 2-chloro-6-fluoroquinazoline 1-8 (216 mg, 1.18 mmol; see example 1-D), and triethylamine (412 uL, 2.96 mmol), in DMF (5 mL) and heated to 130° C. for 3 hours. The reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution and brine and the organic layer concentrated in vacuo and the residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide 1-10. Data for 1-10: LC/MS: m/z (M+Na)=375.2 found; 375.4 calculated.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
N-Hydroxyphthalimide (12.0 g) in 130 ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6 g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenzyl chloride (20 g) and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off. Recrystallisation from ethanol gives N-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4 g, 82%), m.p. 156°-157° C.
Reaction SMILES: N(C=CC=O)C1C=CC=CC=1.NC1C=CC=CC=1.[C:19]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])#[N:20].[C:33]([N:36]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)/[CH:37]=[CH:38]/[CH:39]=C(\C#N)/C(OCCCC)=O)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C>[C:33]([N:36]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)/[CH:37]=[CH:38]/[CH:39]=[C:21](\[C:19]#[N:20])/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])(=[O:35])[CH3:34]
Reactant: CCCCOC(=O)/C(C#N)=C/C=C/N(C(C)=O)c1ccccc1
Reactant: CCCCCCCCOC(=O)CC#N
Agent: O=CC=CNc1ccccc1
Solvent: Nc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCOC(=O)/C(C#N)=C/C=C/N(C(C)=O)c1ccccc1
Yield: 79 %

Procedure:
3-Anilinoacrolein-aniline (27.7 g, 0.125 mol) and n-octyl cyanoacetate (26.3 ml, 0.125 mol) are heated in 70 ml of acetic anhydride at 115° C. for 2 hours while bubbling with nitrogen. After cooling, 80 ml of methanol are added and precipitation is allowed to take place. The solid obtained is filtered off and rinsed with methanol. Drying is carried out. 36.4 g of a yellow powder (yield: 79%) of butyl (2E,4E)-5-[acetyl(phenyl)amino]-2-cyanopenta-2,4-dienoate are recovered, which powder is used as is in the following stage.
Reaction SMILES: O.Cl.[CH2:3]([NH:7][NH2:8])[CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:11]([NH:15][C:16]([N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNN
Reactant: CCCCN=C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNC(=O)N(N)CCCC
Yield: 53.4 %

Procedure:
To a cooled (water bath), stirred mixture of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was added 1.7 g powdered potassium hydroxide. The resulting mixture was stirred and maintained under a nitrogen atmosphere as n-butyl isocyanate (1.49 g, 0.015 moles) in 30 mL tetrahydrofuran was added dropwise. After addition, the solution was stirred overnight at ambient temperature. Work up as in Example 5 above yielded 1.5 g N,1-dibutylhydrazinecarboxamide b.p. 135°-6° C. at 0.08 torr, m.p. 34°-36° C. This structure was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[ClH:18].N([O-])=O.[Na+]>[Cl-].[Na+].O.O>[Cl:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A mixture of 7-ADCA (25 g, 0.117 mol), ethanol (700 ml), water (163 ml) and concentrated hydrochloric acid (163 ml) was cooled to 5° C. Sodium nitrite (11.5 g, 0.167 mol) was added in small portions over 25 minutes and the mixture was stirred for 3.5 hours at 0°-5° C.; 300 ml of brine was added and the reaction mixture was extracted with methylene chloride. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated (16.1 g, 58.9%). This crude acid was directly used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:19]2[NH:20][CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:13][C:14]1[C:19]2[N:20]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)[CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Reaction time: 2 h

Procedure:
1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.36 g, 26.6 mmol) was added to a stirred solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.0 g, 26.6 mmol) and cesium carbonate (10.40 g, 31.9 mmol) in DMA (30.0 ml) at room temperature and was stirred for 2 h. Water was added, and the solids were filtered and dried overnight. Crude 1H NMR showed ˜4:1 ratio of undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine:desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. The crude residue was purified by silica gel chromatography (EtOAc/DCM, 0% to 20%) to afford the desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (fraction 1) and the undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine (fraction 2). 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine: MS ESI calc'd for C14H8Cl2F3N3 [M+H]+ 346. found 346.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].FC(F)(F)C(O)=O.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1.[NH4+].[OH-]>ClCCl>[NH2:1][C:2]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1)=[O:3]
Reactant: [N-]=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of potassium isocyanate (1.5 g) dissolved in dichloromethane (20 ml) was cooled to 5° C. and a solution of trifluoroacetic acid (1.9 g) in dichloromethane (20 ml) was added dropwise. To the resulting mixture was added dropwise a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) in dichloromethane (10 ml). The temperature was allowed to raise to room temperature. After stirring for another 3 hours the mixture was poured on ice (500 g) and diluted aqueous NH4OH was added until pH >9. The organic phase was separated and worked-up as above. The crude title product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethanol/ethyl acetate 1:3). The purified product (2 g) was dissolved in acetone (20 ml) and added to a solution of fumaric acid (0.6 g) in ethanol (20 ml). The precipitated hemifumarate salt was filtered off and dried. Yield: 1.6 g, mp: 172-174° C. 1H NMR (DMSO-d6): δ 1.65-1.90 (m, 5H); 2.10-2.35 (m, 3H); 2.45-2.90 (m, 5H); 3.10-3.25 (m, 2H); 3.45 (qui, 1H); 6.85 (s, 2H); 6.60 (s, 1H); 7.00-7.15 (m, 4H); 7.30 (dd, 2H); 7.45 (s, 1H); 8.45 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][C:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C=O.O.O1CCCC1>[N:29]1[CH:30]=[CH:31][C:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccncc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)c2ccncc2)cc1)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 35 °C
Yield: 4.4 %

Procedure:
Tetrahydrofuran (5 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.29 g, 6.1 mmol) and 1,1'-carbonyldiimidazole (.99 g, 6.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was heated at 35° C. for 15 min. The reaction was treated with a solution of 4-(4-pyridylsulfonyl)benzeneamine (1.43 g, 6.1 mmol) in dimethylformamide (15 ml,dry), and heated to 69° C. in an ultrasonic bath for 19.5 hrs. The reaction was poured into water (300 ml), and extracted with ethyl ether (3×300 ml). The combined organic portions were evaporated and preabsorbed onto silica gel (10 gm). Chromatography of this material on silica gel, eluting with methylene chloride/ethyl acetate (first 100:0 and then 70:30) provided a white solid. Recrystallization from acetone gave starting 4-(4-pyridylsulfonyl)benzeneamine. The filtrate was evaporated and chromatographed on silica gel eluting with chloroform/methanol (first 100:0 and then 98:2) provided the title compound (0.115 g, 6%) as a white solid; mp 235°-237° C. 1H-NMR (250 MHz,d6 -DMSO): 7.90 (d, J=4.6, 2H, ArH), 8.04 (d, 4H, ARM), 8.89 (d, J=4.68 Hz, 2H, ArH), 9.90 (s, 1H, OH), 10.97 (s, 1H, NH). MS(CI,CH4): 429 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)CC>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC=O
Product: CCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized by the method, described for 4-Ethylamino-piperidine-1-carboxylic acid tert-butyl ester (16), using propionaldehyde instead of acetaldehyde. Rt=1.43 min (Method B). Detected mass: 243.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.[OH:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26](O)=[O:27]>>[OH:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26]([N:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1)=[O:27]
Reactant: CCCCCCCCC(O)C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Product: CCCCCCCCC(O)C(=O)N1CC=C(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)CC1

Procedure:
Using an analogous procedure to that described in Example 20, the TFA salt of Example 2 was reacted with 2-hydroxydecanoic acid in place of N-acetylglycine, to give the title compound. Yield=252 mg, 65%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.52 g, 2.59 mmol) in anhydrous CH2Cl2 (5 mL) under argon were added acetic anhydride (0.37 mL, 3.89 mmol) and Pyridine (0.31 mL, 3.89 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with saturated 1 N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.62 g, 100%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:36](=[O:38])[CH3:37]>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=4[C:36](=[O:38])[CH3:37])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cc(C)ccc1OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 95 °C
Yield: 46.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (2.87 g, 11.23 mmol), K2CO3 (2.5 g), 1-[2-(3-bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C. for 6 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over MgSO4, then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% CH3OH:dichloromethane: 1.2 l; 3% CH3OH:dichloromethane: 600 ml). The material thus obtained was crystallized from a small volume of ether. and hexane to provide 2.13 g (46%) of off-white 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5methylphenyl]ethanone, m.p.=92-93° C.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.Br.[IH:23].O>C(O)C.C(OCC)C>[IH:23].[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: Br
Agent: I
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]c(N3CCCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (16.7 g, 58 mmol) and aqueous 48% hydrobromic acid solution (80 mL). Heat to reflux. After 3 hours, cool to ambient temperature, add to ethanol (700 mL), and cool to 0° C. to give a solid. Combine the solid with aqueous 48% hydriodic acid (80 mL) and water (150 mL). Heat on a steam bath. After about 1 hour, cool to ambient temperature, dilute with ethanol (500 mL), and add to diethyl ether (8 L) to give a solid. Collect solid by filtration and dry in vacuo to give the title compound: mp; >290° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14]([N:17]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH:18]2[CH2:19][N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:21]3)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Li+].[OH-].O1CCCC1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>CO>[F:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:20]2[CH2:21][CH:22]3[N:17]([S:14]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]5[C:12]=4[CH2:13][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]5)(=[O:16])=[O:15])[CH:18]([CH2:25][CH2:24][CH2:23]3)[CH2:19]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester (13 mg, 0.025 mmol), 1N LiOH (2 mL), tetrahydrofuran (8 mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic extracts were dried, filtered, and concentrated to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo [3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.19 (d, 2H), 6.92 (d, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H), 3.44-3.30 (m, 3H), 3.26-3.10 (m, 2H), 2.96-2.86 (m, 2H), 2.26-2.15 (m, 1H), 1.86-1.72 (m, 4H), 1.51-1.43 (m, 1H); MS (ESI): 511.4 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.ClCCl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
(a-1) To a stirred solution of 50.2 parts of α-methyl-4-nitrobenzenemethanol and 48.6 parts of N,N-diethylethanamine in 390 parts of dry dichloromethane was added dropwise a solution of 37.8 parts of methanesulfonyl chloride in 65 parts of dry dichloromethane at -5~0° C. The whole was stirred for 1 hour at 0° C. 75 Parts of cold water were added and the dichloromethane layer was decanted, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was shaked with 2,2'-oxybispropane. The product was filtered off and dried, yielding 67.1 parts (91%) of [1-(4-nitrophenyl)ethyl] methanesulfonate; mp. 70° C. (int. 112).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[N:6]3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: BrCc1ccc2nccnc2c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccc3nccnc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 6-(bromomethyl)quinoxaline (900 mg, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.1 mmol), and triethylamine (1.1 mL, 7.8 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was evaporated and then co-evaporated with EtOAc. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (3×20 mL), and hexanes (3×20 mL), and then dried in vacuo, affording 6-methyl-2-[(quinoxalin-6-ylmethyl)sulfanyl]pyrimidin-4-ol (658 mg, 75% yield). The product was used without further purification.