Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:22])[NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.CO>>[CH2:14]([NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:23])=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Yield: 78 %

Procedure:
To a suspension of 3-(3-phenethylsulfamoyl-phenyl)-acrylic acid methyl ester (4h) (0.20 g, 0.58 mmol) in methanol (3.0 ml) 1N NaOH solution (1.75 ml, 1.75 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was washed with ether to give the title compound as a white solid (0.15 g, 77%).
Reaction SMILES: [C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[ClH:34].Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CN(C=O)C>[ClH:36].[ClH:34].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.5 %

Procedure:
(1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 3; 1.01 g, 3.0 mmol) was dissolved in DMF (10 mL). DIPEA (1.74 mL, 5.0 mmol) and, 4-(4-chlorophenyl)piperazine dihydrochloride (808 mg, 3.0 mmol) were added and the reaction mixture was stirred at room temperature for 14 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1M aq Na2CO3 solution (5×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 96:4 mixture of DCM:MeOH) followed by reverse phase column chromatography (gradient eluting with MeOH in water, 0-100%). The residue was dissolved in DCM (10 mL) and 2M HCl in Et2O (3 mL) was added. The reaction mixture was then concentrated in vacuo to give [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-chlorophenyl)piperazine-1-carboxylate dihydrochloride (468 mg, 39.5%) as white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:12][N:11]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[O:2][CH3:1]
Reactant: NO
Reactant: COC1CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC1CCCCC1=NO
Temperature: 70 °C

Procedure:
A mixture of 2-methoxycyclohexanone (39.0 mmol), hydroxylamine hydrochloride (72 mmol), and sodium acetate (48.8 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-2-methoxycyclohexane.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.O.C([O-])(=O)C.[Na+].[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[CH3:23]>C(#N)C>[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)c1ccc(CCl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(CNc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
To a 1-liter (1) 3-necked round-bottomed flask equipped with an overhead stirrer, reflux condenser and dropping funnel and containing a stirred mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm (~65° C.) water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The temperature of the resulting yellow solution was stabilized at about 70° C. and a solution of 33.8 g (0.20 mole) of 4-(1-methylethyl)benzyl chloride in 75 ml of acetonitrile was added over 70 minutes. The solution was then refluxed for an additional 31/2 hrs, and 95 ml of acetonitrile was removed by distillation over a 30 minute period, during which time 50 ml of concentrated hydrochloric acid (con. HCl) was added dropwise. The resulting mixture was filtered hot (~80° C.) and the collected solids were slurried in 300 ml of boiling methanol for 15 min. and then vacuum filtered. The slurrying and vacuum filtration process was repeated first with 300 ml of warm (65° C.) water and then again with 300 ml of boiling methanol. Air-drying of the collected solids gave 12.51 g (20.5% yield) of purified 4-(((4-(1-methylethyl)phenyl)methyl)amino)benzenesulfonic acid as a white powder, having a melting point greater than 275° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCC(C)C)C(C)=O
Yield: 77.6 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52.7 g.) and iso-butyl bromide (34.94 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-iso-butoxyimino-3-oxo-butyrate (syn isomer, 42 g.).
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.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:22]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:20][CH2:21][NH:16][C:17](=[O:22])[CH2:18]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: O=C1CNCCN1
Product: Cc1ccc(-c2oncc2C(=O)N2CCNC(=O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and piperazinone (6.0 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.6 mg). Calcd for C15H15N3O3: 285.1113, found 285.1113.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:17][CH3:18])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]1[OH:16].CN(C)C=O.[H-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][C:3]1([O:17][CH3:18])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH:4]1[O:16][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CCN(Cc2ccccc2)CC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a stirred mixture of 37.8 parts of 4,4-dimethoxy-1-(phenylmethyl)-3-piperidinol and 135 parts of N,N-dimethylformamide were added portionwise 4.8 parts of sodium hydride dispersion 78%. The whole was heated to 60°-70° C. and stirring was continued for 30 minutes at 50° C. After cooling to room temperature, there were added dropwise 18.9 parts of (chloromethyl)benzene (exothermic reaction: temperature roses to 37° C.). Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was poured onto 500 parts of water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was distilled, yielding 33.1 parts (64.6%) of 4,4-dimethoxy-3-(phenylmethoxy)- 1-(phenylmethyl)piperidine; bp. 180°-185° C. at 0.3 mm. pressure (intermediate 43).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][C:3]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:20])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CC(NCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)O
Yield: 5.6 %

Procedure:
To a solution of [2-[4-chloro-3-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)carbamoyl-phenylamino]-ethylamino]-propionic acid, 1,1-dimethylethyl ester (0.20 g, Example 7a) in dichloromethane (5 ml), was added trifluoroacetic acid (2 ml). After 15 h the solution was concentrated and purified by RPHPLC (eluting with 15-95% MeCN in 0.1% AcONH4 aqueous) to afford the title compound as a solid (0.010 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([NH2:42])=[O:41]>CC(C)=O>[C:40]([CH2:39][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=4)=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)(=[O:41])[NH2:42]
Reactant: NC(=O)CBr
Reactant: Cc1cccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c1-c1ccc(C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc(N3CCN(CC(N)=O)CC3)cc2)c1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of 4′-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (206 mg) in acetone (20 mL) containing K2CO3 (206 mg) was added 2-bromo-acetamide (100 mg) and the mixture was heated at reflux for 16 hours. After cooling at room temperature the salts were removed by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (93/7) and the solid obtained was recrystallized from CH2Cl2/diisopropyl ether to give the title compound (190 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](O)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([Cl:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (325 mg, 0.670 mmol), thionyl chloride (0.0978 mL, 1.34 mmol) and catalytic amount of dimethylformamide in tetrahydrofuran (6.7 mL) was stirred at room temperature for 2 h. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (297 mg, 0.590 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=[O:5].[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=3[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (24 mg, 0.048 mmol) in anhydrous pyridine (1 mL) was added methane sulfonyl chloride (9 mg, 0.075 mmol). The resulting mixture was stirred at room temperature for 2 h was poured into 1 M HCl and extracted with EtOAc. The extracts were concentrated under reduced pressure and the residues was purified by flash column chromatography to trissulfonamide Mass spectrum m/z: 515.0 (M+H). To this trisulfonamide (14 mg, 0.021 mmol) in THF was added TBAF (1 M in THF, 40 μL, 0.04 mmol) and the resulting mixture was stirred overnight. The reaction mixture was quenched with 1 M HCl and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (combi-flash) to provide 4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 9.60 (br, 2 H), 8.38 (d, J=2.0 Hz, 1 H), 8.16 (d, J=2.0 Hz, 1 H), 8.04 (d, J=2.0 Hz, 1 H), 7.87 (dd, J=8.4, 2.4 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.62-7.57 (m, 1 H), 7.53 (d, J=8.4 Hz, 1 H), 7.29 (dd, J=8.0, 2.4 Hz, 1 H), 7.08-7.05 (m, 1 H), 3.07 (s, 3 H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reaction time: 12 h

Procedure:
0.01 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzisothiazol-3(2H)one 1,1-dioxide is dissolved in 30 ml of absolute pyridine and, via cooling in ice, 0.02 mol of ethyl chloroformate is added. The mixture is then allowed to reach room temperature and is stirred for 12 hours. The solvent is evaporated off, ice-water is added and the mixture is extracted by shaking several times with methylene chloride. Colourless crystals are obtained after evaporating off the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccnc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing methyl 2-(4-chlorophenyl)nicotinate from the previous step (6.0 g, 24.2 mmol) in methyl alcohol (30 mL) was added 1N sodium hydroxide (29 mL). The mixture was stirred at room temperature overnight then neutralized with 1N hydrochloric acid (29 mL), evaporated in vacuo and dried overnight to yield the solid 2-(4-chlorophenyl)nicotinic acid (7.3 g, Theo. Yield=5.65 g, balance is NaCl; HPLC RT=2.17 min; LC-MS m/z=234).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(OCC)(=O)C>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].I[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CN(C)C=O.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: IC1CCCC1
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC2CC(C#N)(C3CCCC3)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a was dissolved in 30 mL of N,N-dimethylformamide followed by addition of iodo-cyclopentane (5.4 g, 27.5 mmol) and lithium hexamethyldisilazide (27.5 mL, 27.5 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 10 mL of water and concentrated to remove N,N-dimethylformamide and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-cyclopentyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16a (2.6 g, yield 42%) as a light yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=O)(C)(C)C.Cl>>[NH2:8][C@H:9]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Agent: Cl
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2

Procedure:
A solution of (S)-benzyl 8-((tert-butoxycarbonyl)amino)-6-azaspiro[3.4]octane-6-carboxylate (0.324 g, 0.900 mmol) in HCl (4.0 N in dioxane) (5.0 mL, 20.00 mmol) was stirred for 1 hr 25 min. +/−MS analysis after 1 hr indicated that essentially no starting material remained (m/e 261.3, M+H for desired product). HCl/dioxane was removed under vacuum, co-evaporated with ether, to yield the hydrochloride salt of the title compound as a white, glassy solid (quantitative yield). +/−MS: m/e 261.3 (M+H), 217.2 (M+M-44 CO2). 1H NMR (400 MHz, METHANOL-d4) d 7.55-7.20 (m, 5H), 5.20-5.07 (m, 2H), 3.67-3.66 (m, 1H), 3.81-3.64 (m, 2H), 3.62-3.47 (m, 2H), 2.26 (d, J=6.2 Hz, 1H), 2.18-1.87 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1cccc(Cl)c1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 3-chlorophenol (1.28 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature, filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by flash chromatography using as eluent a mixture of ethyl acetate and petroleum ether to give 7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.11 g, (mp 124°-126° C.).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[N:21](OC(C)(C)C)=[O:22]>C(Cl)Cl>[N:21]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)ON=O
Solvent: ClCCl
Product: O=NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Triphenylmethyl mercaptan (0.050 g, 0.18 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. Tert-butyl nitrite (0.186 g, 1.80 mmol) was added and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The solvent and excess of tert-butyl nitrite were evaporated to give the title compound as a green solid (0.054 g, 98%). 1H NMR (CDCl3) δ: 7.13-7.18 (m, 4H), 7.25-7.39 (m, 11H).