Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:38][C:37]=3[F:50])[C:20](=[O:34])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>O>[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[C:48]4[NH:3][C:4](=[O:7])[O:5][N:49]=4)=[CH:38][C:37]=3[F:50])[C:20](=[O:34])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(-c3ccc(OC(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc2c(=O)n(-c3ccc(OC(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-(4-isopropoxyphenyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. The solid was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.37 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].N1C=CC=C[CH:16]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)(Cl)Cl>[CH3:16][C:3]1[C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: Cc1c(NS(C)(=O)=O)cc([N+](=O)[O-])cc1C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of methyl 3-amino-5-nitrobenzoate 24.7 g (126 mmol), pyridine 51 mL (630 mmol), methanesulfonyl chloride 12 mL (151 mmol) and chloroform (250 mL) was stirred at 40° C. for 5 hours. The solvent was evaporated and to the residue was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate 500 mL. The organic layer was washed with 1N hydrochloric acid and 5% aqueous sodium chloride solution and dried on magnesium sulfate. The solvent was evaporated and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 32.1 g (117 mmol) of the title compound (yield: 93%).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=CC=C[CH:25]=1.[C:30]([C:32]1[CH:33]=[N:34]C=C(Br)C=1)#[N:31].IC1C=CC=CC=1>>[C:33]([C:32]1[CH:29]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:25]=[N:31][CH:30]=1)#[N:34]
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: N#Cc1cncc(Br)c1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(C#N)c3)c(=O)c2)cc1

Procedure:
4-[3-(5'-Cyano-2-oxo-2H-[1,3']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 3-cyano-5-bromopyridine for the iodobenzene in Step 3.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:19])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:19])[CH:9]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
12.8 g of ethyl chloroformate are added while stirring to a solution of 20 g of 4-chloro-2-fluoro-5-isopropoxyaniline in 100 ml of methylene chloride at room temperature. 9.4 g of pyridine are subsequently added dropwise during 20 minutes at 20° C. while stirring and cooling. The reaction mixture is stirred for 20 minutes, washed three times with in each case 200 ml of a solution of 20 ml of 2N hydrochloric acid in 200 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. There is obtained ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate, m.p. 89°-91° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([C:18]1[N:19]([CH2:31][CH2:32][CH2:33][OH:34])[C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:55]1[C:59](=[O:60])[C:58]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:57]2[C:56]1=[O:65]>O1CCCC1.C(OCC)(=O)C.ClCCl>[CH2:15]([C:18]1[N:19]([CH2:31][CH2:32][CH2:33][O:34][N:55]2[C:59](=[O:60])[C:58]3[C:57](=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:56]2=[O:65])[C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:16][CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc2cnc3cccnc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
Diisopropyl azodicarboxylate (8.10 mL, 48.4 inmol) was added dropwise over ten minutes to a stirred solution of 3-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol (10.9 g, 40.3 mmol), triphenylphosphine (12.7 g, 48.4 mmol), and N-hydroxyphthalimide (7.89 g, 48.4 mmol) in tetrahydrofuran (160 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford an oil that was dissolved in ethyl acetate (200 mL) and extracted with 2 M HCl (3×100 mL). The aqueous layers were combined, and the pH was adjusted to 7 with the addition of solid sodium bicarbonate. A precipitate formed, was isolated by filtration, and was dissolved in dichloromethane (300 mL). The solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 17.38 g of 2-[3-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:35])[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(C(=O)NNC(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (150.0 mg, 0.52 mmol), N′-isopropyl-4-methylbenzohydrazide (150.0 mg, 0.78 mmol) and HATU (296.6 mg, 0.78 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.78 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methylbenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (141.0 mg, 58.8%).
Reaction SMILES: [CH2:1]([SH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[CH2:14][CH:15]=[C:16]=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C(OCC)C>[C:20]([O:22][CH3:23])(=[O:21])[CH2:19][CH2:18][CH:17]=[C:16]=[CH:15][CH2:14][S:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCS
Reactant: COC(=O)CCC=C=CCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCSCC=C=CCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A mixture of 376 mg of undecylmercaptan, 438 mg of methyl 7-bromohepta-4,5-dienoate and 0.278 ml of triethyl amine in 2 ml of diethyl ether were stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with hexane and toluene to give 210 mg of methyl 8-thianonadeca-4,5-dienoate having the following NMR spectrum which was run in deutochloroform solution with TMS as the internal standard.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1CCCC1=O>>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccnc1Cl
Product: N#Cc1ncccc1N

Procedure:
A mixture of 3-Amino-2-chloropyridine (5 g) and cuprous cyanide (5g) in 10 mL of N-Methylpyrrolidone was heated with stirring at 185° C. for 2h under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and concentrated ammonium hydroxide and 10% methanol/methylene chloride were added. The mixture was shaken and filtered, the organic layer separated and the aqueous layer extracted two times with methanol/methylene chloride. The combined organic extracts were dried over magnesium sulfate and the solvent removed in vacuo. The residue was recrystallized from ethyl acetate/hexane to afford 3-Amino-2-cyanopyridine as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:39]I>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][I:39]
Reactant: OCCCC#Cc1cc(Cl)ccc1Cl
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1ccc(Cl)c(C#CCCCI)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol), triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8 mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was stirred under nitrogen at 0° C., and to this was slowly added iodine (21.3 g, 83.8 mmol). The solution was allowed to warm to room temperature and stirring was continued for 18 hours. This was chromatographed on silica gel with hexane to give the title compound (14.7 g,72%), MS m/z 337.9 (M−H calcd. for C11H9Cl2I=338.0).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29](C#N)[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].[OH-].[Na+]>CO.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:4][CH3:3])[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(C#N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: COc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
A solution of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2 carbonitrile trifluoroacetate (0.13 g, 0.00023 mol) in MeOH (2.0 mL) was treated with 1N NaOH (0.5 mL). After stirring at room temperature for 3 h, it was heated at 60° C. for an additional 3 h and left overnight room temperature. The resulting solution was diluted with acetonitrile, and purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=452) were combined and freeze dried to afford the title compound (0.015 g) as a white powder: 1H NMR (CD3OD) δ8.84 (d, 1H, J=5.2 Hz) 7.62 (d, 1H, J=5.2 Hz), 7.05 (m, 2H), 6.57 (s, 1H), 5.49 (s, 2H), 5.32 (s, 2H), 3.96 (s, 3H), and 2.49 (s, 3H); ES-HRMS m/z 452.0440 (M+H C19H17N3O3BrF2 requires 452.0416).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(S(=O)(=O)NCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid. 1H NMR (DMSO) δ 1.33 (m, 2H), 1.86 (m, 2H), 2.67(m, 3H), 2.89(s, 3H), 2.99(m, 2H), 3.69(m, 2H), 3.85(s, 2H), 4.49(m, 1H), 6.83 (d, 1H, J=6.0 Hz), 7.00(m, 2H), 7.19 (s, 1H), 7.24 (m, 6H), 7.56 (d, 2H, J=6.6 Hz); MS (ES) m/z: 575.1 (MH+); HRMS for C27H34N4O6S2: 575.2015 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C(OO)=O)[CH:3]=1.[CH3:12][C:13]1([CH3:31])[NH:18][C:17](=[O:19])[C:16]2[CH:20]=[C:21](SC3C=CC=CC=3)[CH:22]=[CH:23][C:15]=2[O:14]1.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+]>ClCCl>[CH3:12][C:13]1([CH3:31])[NH:18][C:17](=[O:19])[C:16]2[CH:20]=[C:21]([S:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:35])=[O:33])[CH:22]=[CH:23][C:15]=2[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)NC(=O)c2cc(Sc3ccccc3)ccc2O1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)NC(=O)c2cc(S(=O)(=O)c3ccccc3)ccc2O1
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (70% purity, 4.64 g) was added with ice-cooling to a solution of 2,2-dimethyl-6-phenylthio-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.24 g) in dichloromethane (50 ml) and the mixture was stirred for 30 minutes. The reaction mixture was poured into an aqueous sodium sulfite solution and the mixture was extracted by addition of ethyl acetate. The organic layer was successively washed with an aqueous sodium carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with isopropyl ether to obtain 2,2-dimethyl-6-phenylsulfonyl-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.50 g) (Compound A-13). The physical properties are shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)cc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 32.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0290 g, 0.0628 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2-chloro-4-fluorobenzenesulfonyl chloride (0.0447 g, 0.195 mmol) to obtain 4-(2-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0133 g, yield 34%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].C(OC([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH2:31]Cl)=[CH:23]1)=O)(C)(C)C>C1COCC1>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:31][C:24]1[C:25]2[C:30](=[N:29][CH:28]=[CH:27][CH:26]=2)[NH:22][CH:23]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1ccn2Cc1c[nH]c2ncccc12
Reaction time: 4 h
Yield: 34 %

Procedure:
Sodium hydride (144 mg, 6 mmol) was added to a solution of 4-nitroindole (973 mg, 6 mmol) in THF, and the resulting mixture was stirred for 4 h. 1-(t-Butyloxycarbonyl)-3-chloromethyl-7-azaindole (Int-14, 1.5 g, 5.5 mmol) was then added. Upon completion (by TLC), the reaction was quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography to provide 3-[(4-nitro-1H-indol-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (547 mg, 34%).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O.[CH3:15][CH2:16]O>>[ClH:13].[CH2:15]([O:9][C:8](=[O:10])[CH2:7][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16]
Reactant: O=C(O)CNC1CCCC1
Reactant: O=S(Cl)Cl
Reactant: CCO
Product: CCOC(=O)CNC1CCCC1
Product: Cl

Procedure:
Cyclopentylglycine ethyl ester hydrochloride salt was prepared by the procedure in Example 1(B) utilizing cyclopentylglycine (5.0 g, 38.7 mmol), thionyl chloride (6.0 mL, 77.4 mmol) and EtOH (34.10 mL, 58.1 mmol). The ethyl ester 14aj was obtained as a white solid (2.25 g, 10.86 mmol, 56%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1
Reactant: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COc1cc(=O)n(Cc2nc3cc(CN)ccc3n2CCCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a cooled (0° C.) suspension of [1-(4-hydroxy-butyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (74 mg, 0.15 mmol) in DCM (3 mL) was added TFA (337 μL, 4.38 mmol). The solution was allowed to stir for 6 h at room temperature, followed by the removal of the volatiles in vacuo. The resulting trifluoroacetate was dissolved in methanol (3 mL) followed by the addition of acetyl cloride (104 μL, 1.46 mmol). After 10 minutes the solution was concentrated. This procedure was repeated allowing the reaction to run for 3 hrs. The solution was concentrated in vacuo and the residue stripped with methanol (twice) to yield 1-[5-Aminomethyl-1-(4-hydroxy-butyl)-1H-benzoimidazol-2-ylmethyl]-4-methoxy-1H-quinolin-2-one; HCl salt (65 mg, 100%) as an off white solid:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:26][CH:25]([NH2:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].N12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:19]([O:18][C:16]([N:23]1[CH2:26][CH:25]([NH:27][C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Yield: 43 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.350 g, 1.55 mmol), 1-BOC-3-aminoazetidine (0.400 g, 2.32 mmol), tetrabutylammonium bromide (0.120 g, 0.36 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.000 g, 6.00 mmol) in 1,4-dioxane (30 mL) was heated under reflux overnight. The solvent was evaporated. The residue was washed with 1 M citric acid (50 mL) and ethyl ether (50 mL) was added. Ultrasonication of the mixture followed by filtration afforded 3-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-ylamino]azetidine-1-carboxylic acid tert-butyl ester as a white solid in 43% yield (0.240 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][C:6]1[CH:13]=[C:12]([CH2:14][N:15]2[C:19]([CH2:20]O)=[CH:18][N:17]=[CH:16]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>C(Cl)Cl.CN(C=O)C>[N:38]([CH2:20][C:19]1[N:15]([CH2:14][C:12]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[Cl:2])[CH:13]=2)[CH:16]=[N:17][CH:18]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1Oc1ccccc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CN=[N+]=[N-])cc1Oc1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2-(2-chloro-phenoxy)-4-(5-hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile hydrochloride, as described in Example 15, (0.07 g, 0.186 mmol) in CH2Cl2 (4.0 mL), and triethylamine (0.078 mL, 0.558 mmol) at 0° C. was added methanesulfonyl chloride (0.016 mL, 0.205 mmol). The cooling bath was removed and the mixture was stirred for 1 hr. To this solution was added sodium azide (0.018 g, 0.277 mmol) in DMF (1.0 mL). After 1 hr. the reaction mixture was partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, and dried (MgSO4). Filtration and concentration in vacuo gave the title product which was used in the next step without further purification.