Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:18]2[C:19](=[O:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:32][C:28]1[N:18]2[C:19](=[O:27])[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH2:13][CH3:14])[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=1
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-9H-purine (Aldrich, 0.0152 g, 0.07656 mmol), 2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.019 g, 0.064 mmol), and N,N-diisopropylethylamine (0.0134 mL, 0.07666 mmol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. The mixture was cooled and purified on RP-HPLC at pH 10 (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the product as the free base. LCMS calculated for C23H22N7O (M+H)+: m/z=412.2. Found: 412.4. 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (2H, m), 7.60 (1H, dd, J=9.0 and 6.9 Hz), 7.39-7.32 (7H, m), 7.00 (1H, m), 6.85 (1H, br d, J=6.9 Hz), 5.13 (1H, m), 2.81 (3H, s), 1.72 (2H, m), 0.65 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:7]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:35])(=[O:32])=[O:31]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN)cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylamine and 2-chlorobenzensulfonyl isocyanate. MS (ESI) m/z 509 [M+H]+, 507 [M−H]−, 1H-NMR (DMSO-d6) δ 1.17 (3H, t, J=7.3 Hz), 2.63 (2H, q, J=7.5 Hz), 2.73 (2H, t, J=7.1 Hz), 3.19-3.27 (2H, m), 6.45 (1H, br), 7.20 (1H, t, J=7.3 Hz), 7.30-7.41 (6H, m), 7.49-7.55 (1H, m), 7.61 (1H, br), 7.73 (1H, s), 7.80 (2H, d, J=8.4 Hz), 8.03 (1H, dd, J=7.31 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[ClH:14]>C(O)C.[Pd]>[ClH:14].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 2-azido-1-(4-fluoro-phenyl)-ethanone (8.0 g, 44.7 mmol) in ethanol (125 mL) was added concentrated aqueous HCl (6 mL) and 10% Pd/C (10 mol %). The mixture was stirred under hydrogen (H2) atmosphere at 45 psi for 1 hour. The mixture was filtered through celite and the celite cake was washed with copious amounts of methanol. The solvent was under reduce pressure and the semisolid was triturated with diethyl ether, filtered and dried to give 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (5.0 g, 26.5 mmol) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:21][C:18]=4[C:19]#[N:20])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1cc(F)ccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: N#Cc1cc(F)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 59.6 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.199 g), 5-fluoro-2-(piperazin-1-yl)benzonitrile (0.203 g), triethylamine (0.110 g), and ethylene glycol (2 mL) give 0.218 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 179-180° C.; MS m/z 369; IR (mineral oil) 1494, 1329, 808, 1452, 1072 cm-1. 1H NMR (CDCl3) δ2.78, 3.20, 3.78, 6.99, 7.13, 7.19, 7.26, 7.51, 7.52.8.14.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(N)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline and 8.4 mL (60.28 mmol) triethylamine dissloved in 30 mL dichloromethane was added 5.0 mL (40.19 mmol) 4-fluorobenzyl bromide. The mixture was stirred at room temperature for 12 h, partitioned between dichloromethane and sat. aqueous ammonium chloride, dried over MgSO4 and concentrated. Purification by column chromatography, eluting with ethyl acetate/hexane, provided 3.10 g of 4-[(4-fluorobenzyl)amino]thioanisole, along with recovered starting material.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])[CH3:16]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([NH:14][CH:23]2[CH2:24][CH2:25][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:21][CH2:22]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
In a reactor fitted with a water trap, a solution of 1,1-diphenylmethylamine (5.0 g) and 1-ethoxycarbonyl-4-piperidone (4.7 g) in toluene (70 mL) was refluxed for 4 hours. This reaction mixture was concentrated under reduced pressure and he residue was dissolved in 50 mL of ethanol. After the solution was cooled with ice, 2.1 g of sodium cyanoborohydride and a small amount of bromocresol green were added. Then, 4N-HCl solution in methanol was added dropwise until the reaction mixture had turned yellow and the mixture was further stirred for 20 minutes. This reaction mixture was poured into an access of aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 to 65:35) to provide 8.4 g of the title compound. Yield 91%.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C([O-])(=O)C.[Zn+2:14].C([O-])(=O)C.O.N>O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Zn+2:14].[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn+2]
Solvent: O
Product: O=C([O-])c1cccnc1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
5.0 g of nicotinic acid was dissolved in 100 ml of deionized water with stirring in a hot bath. Similarly, 4.5 g of zinc acetate.2H2O was dissolved in 100 ml of deionized water in a hot bath and both were mixed with vigorous stirring. Subsequently, ammonia water (1:1 mixture of 25% ammonia water and distilled water) was added to adjust the pH to 8.5. The mixture was heated in a hot bath of about 80° C. for 10 minutes to complete the reaction, was continuously heated to concentrate the mixture, then being evaporated to about 20 ml. After cooling in a refrigerator, the precipitate was filtered with a No. 5B paper filter, and washed with deionized water. The obtained material was dissolved with heating in 200 ml of deionized water, followed by concentration to 20 ml. The concentrate was cooled down at room temperature, and washed three times with deionized water. The obtained material was dried sufficiently at 65° C. or lower temperature in an electric oven to obtain 3.0 g of zinc nicotinate (hereinafter abbreviated as Compound A).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH:12]1([C:20]#[N:21])[CH2:16][CH2:15][N:14]2C=[CH:18][CH:19]=[C:13]12>ClCCl>[CH3:9][S:10][C:11]1[N:14]2[CH2:15][CH2:16][CH:12]([C:20]#[N:21])[C:13]2=[CH:19][CH:18]=1
Reactant: N#CC1CCn2cccc21
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1ccc2n1CCC2C#N
Reaction time: 0.17 h

Procedure:
A solution of 1.15 g N-chlorosuccinimide in 40 ml of dry dichloromethane was cooled, in an atmosphere of nitrogen, to -10° C. (bath temp.) and a solution of 1 ml dimethylsulfide in 10 ml of anhydrous dichloromethane was added dropwise with stirring over a 10 min. period. After a further 10 min. at this temperature, the bath temperature was lowered to -55° C. and a solution of 1.08 g of 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbonitrile (I) in 10 ml of dry dichloromethane was added with stirring over a 10 min. period. The cooling bath was then removed and when the internal temperature had reached ambient the solvent was removed in vacuo. The residual solid sulfonium salt (II) was suspended in toluene (100 ml) and heated at reflux temperature in a nitrogen atmosphere for 5 min. The solvent was decanted from an insoluble tar, 100 ml of toluene was added to the tar and the mixture was heated at reflux temperature for 20 min. The toluene solutions were combined and evaporated. The residue was taken up in ether, the ether solution was washed with water, dried over sodium sulfate and evaporated in vacuo to give an oil which was passed through a short column of silica gel with dichloromethane. The nearly colorless oil obtained on evaporation of the solvent (1.20 g) was sufficiently pure for use in the next reaction. For analysis a sample was purified by HPLC (lichrosorb column, 50 cm×3/8 in.) using hexane-ethyl acetate (85:15) as the eluting solvent at 1100 p.s.i.g. and a flow rate of 9.7 ml/min. The sulfide (III) had a retention time of 13.5 min. On evaporation of the solvent it crystallized and then it was recrystallized from ether-hexane. m.p.: 58°-58.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4 g, 13.6 mmol) in absolute ethanol (30 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified by 1N HCl, and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH:9]1[CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH:10]([N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][CH2:18]2)[CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution containing 113 (2.6 g) in DMF (20 mL) was cooled to 0° C. NaH (60%, 0.28 g, 6.91 mmol) was added in one portion. After 10 min, the reaction mixture was carefully quenched by the addition of saturated aqueous NH4Cl. The mixture was diluted with diethyl ether and water and the layers were separated. The ether layer was washed five times with water to remove DMF then once with brine. The combined aqueous washes were back-extracted with diethyl ether. The combined ether extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.59 g of crude 114 which was used without further purification. 1H NMR (300 MHz, CDCl3): δ7.36 (m, 5H), 5.15 (m, 2H), 4.35 (m, 2H), 3.77-3.66 (m, 2H), 3.26-3.14 (m, 2H), 2.26 (m, 1H), 2.23 (m, 1H), 1.94 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([OH:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.[C:45](Cl)(=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:45](=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of benzyl 3-(N-FMOC-L-valyloxy)-2-hydroxypropionate (4.6 g 8.89 mmole) and pyridine (1.41 g, 17.8 mmole) in 80 ml dichloromethane was added dropwise a solution of stearoylchloride (3.64 g, 12 mmole) in 20 ml dichloromethane and the mixture was stirred overnight at room temperature. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture stirred for 30 minutes. The organic phase was seperated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel chromatography. Yield: 6.1 g=87%
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 27.6 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid, and 4.2 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further strirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:33][CH2:32][N:31]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:30]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Clc1ccccc1C1CCNC1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (2.5 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1141.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]#[C:15][C:16]1([OH:24])[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)[CH:2]=[CH2:3].[C-]#N.[Na+].[CH3:28][N:29]([CH3:33])[CH2:30]CO>>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH2:28][N:29]([CH3:33])[CH3:30])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]#[C:15][C:16]1([OH:24])[CH:21]2[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]2)[CH2:17]1)[CH:2]=[CH2:3]
Reactant: CN(C)CCO
Reactant: C=CCc1cc(C(=O)OC)ccc1C#CC1(O)CN2CCC1CC2
Agent: [C-]#N
Agent: [Na+]
Product: C=CCc1cc(C(=O)OCCN(C)C)ccc1C#CC1(O)CN2CCC1CC2
Temperature: 90 °C

Procedure:
A mixture of 3-[2-(2-allyl-4-methoxycarbonylphenyl)ethynyl]quinuclidin-3-ol (0.64 g), sodium cyanide (50 mg) and N,N-dimethylethanolamine (10 ml) was heated at 90° C. for 24 hours. The mixture was evaporated to give an oil which was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) as eluent to give 3-[2-(2-allyl-4-(2-(N,N-dimethylamino)ethoxycarbonyl)phenyl)ethynyl]quinuclidin-3-ol as a gum (0.559 g); microanalysis found: C, 66.7; H, 7.6; N, 6.7%, C23H30N2O3.0.4CH2Cl2.0.1 H2O requires 7.47; N, 6.7%; NMR (CDCl3): 1.32-1.55(1H, m), 1.55-1.88(1H, m), 1.88-2.20(3H, m), 2.33(6H, s), 2.70(2H, t), 2.65-3.15(4H, m), 3.07(1H, d), 3.33(1H, dd), 3.56(2H, d), 4.41(2H, t), 4.98-5.15(2H, m), 5.29(CH2Cl2), 5.85-6.10(1H, m), 7.43(1H, d) and 7.71-7.90(2H, m); m/Z 383 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18](NC(C3CC3)=O)[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:36]([CH:35]3[CH2:33][CH2:34]3)=[O:32])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To the stirred solution of methyl 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoate (500 mg, 1.1 mmol) in tetrahydrofuran and water (1:1, 5 mL) was added sodium hydroxide (46 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then concentrated under vacuum and the aqueous residue was neutralized using dilute hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (470 m g, 97%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=442.0, tR (minutes, Method F)=2.99
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([OH:24])=[O:23])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(F)cc1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(F)cc1C1CCCC1
Temperature: 80 °C
Yield: 102.9 %

Procedure:
To a solution of 136 (78.0 mg; 0.2 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a brown solid (76 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:22])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccc(F)cc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a solution of 1.62 g (5.46 mmol) ((S)-2-Fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml tetrahydrofurane were added at −75° C. 4.57 g (5.46 mmol) lithium bis(trimethylsilyl)amide (20% in tetrahydrofurane) followed after 10 minutes by 0.34 ml (6.55 mmol) methyliodide. Stirring was continued overnight while the mixture was allowed to warm to room temperature. The solvent was removed by distillation and 300 ml saturated aqueous sodium hydrogensulfate solution was added. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 2:8 yielded 0.87 g (51%) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester as white solid, MS m/e (%): 333 (M+Na+, 15), 311 (M+H+, 70), 255 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(=O)CCC2
Yield: 100 %

Procedure:
7-Nitrotetralone (2.5 g, 13 mmol) was suspended in 50 mL of methanol and complete dissolution achieved by the addition of 10 mL of tetrahydrofuran. The solution was hydrogenated at room temperature and 20-30 psi over 100 mg of 10% Pd/C for 2 hours. The mixture was filtered through Celite, washed with methanol and evaporated to dryness under vacuum to afford 2.1 g (13 mmol, 100%) of the product. 1H NMR (300MHz, CDCl3): 2.09 (m,2H), 2.60 (t,6Hz,2H), 2.84 (t,6Hz,2H), 6.83 (m,1H), 7.06 (d,8Hz,1H), 7.32 (d,2Hz,1H). FAB-MS: calculated for C10H11NO 161; found 162 (M+H,100%).