Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[C:22]([O:36][CH:37]4[CH2:40][CH2:39][CH2:38]4)=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][CH3:34])=[O:32])[C@@H:26]([CH3:35])[CH2:25][CH2:24]4)[N:20]=2)(F)[CH2:11][CH2:10]1)=O)(C)(C)C.[O:41]1CCOCC1>>[CH:37]1([O:36][C:22]2[C:21]([C:19]3[N:20]=[C:16]([C:12]4([OH:41])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)[S:17][CH:18]=3)=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][C@H:26]([CH3:35])[N:27]3[C:31]([O:33][CH3:34])=[O:32])[CH2:40][CH2:39][CH2:38]1
Reactant: C1COCCO1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(F)CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl
Product: COC(=O)N1c2ccc(-c3csc(C4(O)CCNCC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4 M in 1,4-dioxane, 0.32 mL, 1.28 mmol) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.072 g, 0.128 mmol) in 1,4-dioxane (0.5 mL), and the reaction mixture stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford the methyl (S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 460 [M+H]+.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: BrCCc1cc2ccccc2[nH]1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCc3cc4ccccc4[nH]3)(CC1)C2
Product: [Br-]
Yield: 43.6 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 2-(2-bromoethyl)-1H-indole (0.0494 g, 0.220 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0340 g, 43.4%). EI-MS m/z 432 (M+) Rt (1.94 min).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Product: BrCc1ccc2sccc2c1

Procedure:
5-Bromomethylbenzo[b]thiophene was prepared from 5-methylbenzo[b]thiophene and N-bromosuccinimide as in Example 6 except that the reaction was refluxed 15 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]1C=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[C:13]([F:30])=[CH:14][C:15]3[C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]4[CH:18]([CH3:22])[CH2:19]OC=1[C:16]=34)[CH2:6]2.C(OC(C1C(=O)C2C(=NC(Cl)=C(F)C=2)[N:38](C2CC2)C=1)=O)C.NC1C=CC=C2C=1CNC2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:12]1[N:38]=[C:16]3[C:15]([C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]3[CH:18]3[CH2:22][CH2:19]3)=[CH:14][C:13]=1[F:30])[CH2:8]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC1COc2c(N3Cc4ccc(CN)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Nc1cccc2c1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
310 mg of 1 cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 270 mg of 4-aminoisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(4-amino-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[C:14]([CH:16]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:36]=[CH:37][CH:38]=[CH:39][C:12]1=2>C(#N)C>[Cl-:1].[S:11]1[CH:15]=[C:14]([CH:16]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N+:22]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:36]=[CH:37][CH:38]=[CH:39][C:12]1=2
Reactant: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1csc2ccccc12
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: CN(c1ccccc1)C(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1csc2ccccc12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
2-Chloro-1-phenylethanone (42.6 mg, 0.27 mmol) was added to solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(methyl(phenyl)amino)acetate (C35) (112 mg, 0.27 mmol) in acetonitrile (3 ml). The reaction was stirred at room temperature for 3 hours, and then the solvent was evaporated under vacuum. The residue was triturated with Et2O, filtered and dried to obtain (3R)-3-(2-(benzo[b]thiophen-3-yl)-2-(methyl(phenyl)amino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (112.2 mg, 72.6% yield).
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>C1(C)C=CC=CC=1>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 56 °C
Yield: 92.9 %

Procedure:
Sodium methoxide (3.51 g. 0.065M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (12.5 g 0.050M) and cyclopropyl methyl ketone (7 ml, 0.070M) in toluene. The mixture was heated at 55-57° C. for 1 hour. Methanol was distilled under reduced pressure. After cooling to 20° C. the mixture was acidified and the organic phase washed (sodium bicarbonate solution and with water) and evaporated to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione as yellow crystals (14.03 g), m.p. 64° C. A yield of 92.9% was obtained. The purity of the product was 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34](=[N:36][OH:37])[NH2:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:35][C:38](=[O:39])[O:37][N:36]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (169 mg, 0.315 mmol) and 1,1′-carbonyldiimidazole (56.2 mg, 0.35 mmol) dissolved in acetonitrile (3.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.188 mL, 1.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H27ClF3N7O2 [M+H]+ 562. found 562. 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.95 (s, 1H), 8.80 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 5.40-5.31 (m, 1H), 3.95-3.85 (m, 1H), 3.80-3.72 (m, 2H), 3.59-3.51 (m, 1H), 2.44-2.33 (m, 1H), 2.11-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.42-1.32 (broad, 2H), 1.11-0.98 (broad, 2H), 0.89 (d, J=12.1, 1H), 0.67 (d, J=6.3, 3H), 0.65-0.53 (m, 2H), 0.53-0.34 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.CCCCC.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(C)C)cc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mg dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:17]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]3)=[O:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(Br)cc2)cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4′-bromo-[1,1′-biphenyl]-4-carboxylic acid (2 g, 7.22 mmol), (R)-pyrrolidin-3-ol (1.3 g, 14.92 mmol), and HATU (5.5 g, 14.46 mmol) were dissolved in DMF (60 mL). To this solution was added TEA (4 ml, 28.7 mmol) and the reaction mixture was stirred under N2 at room temperature for 24 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The organic layer was separated and washed with 1N HCl, saturated NaHCO3, and brine, and then dried over Na2SO4, filtered and concentrated in vacuo. Chromatography of the resulting residue over silica eluting with 3% MeOH in DCM afforded the desired product. LC-MS: calculated for C17H16BrNO2 345.04 observed m/e: 346.09 (M+H)+ (Rt: 1.62/4 min).
Reaction SMILES: BrC(Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.ClCCl.[CH3:29][O:30][CH2:31][O:32][CH3:33]>FC(F)(F)S([O-])(=O)=O.[Ag+].C(O)CO>[O:30]1[CH2:29][CH2:33][O:32][CH:31]1[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: COCOC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: OCCO
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCCO4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.5 %

Procedure:
A mixture of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g, 10.0 mmol), silver trifluoromethanesulfonate (0.500 g, 19.5 mmol), ethylene glycol (5.00 ml), dichloromethane and dimethoxymethane is stirred three days at room temperature and treated with additional silver trifluoromethanesulfonate (0.300 g, 11.7 mmol). The resultant mixture is stirred one day at room temperature and treated with additional silver trifluoromethanesulfonate (0.400 g, 15.6 mmol) and ethylene glycol (1.00 ml), stirred another day at room temperature and treated again with silver trifluoromethanesulfonate (0.300 g, 11.7 mmol) and ethylene glycol (1.0 ml). After stirring an additional day the mixture is filtered. The filtrate is diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is triturated with hexanes-ethyl acetate to afford the title compound as a white solid (0.070 g, 17.5%, mp 213-216° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-butyl-4-(4-oxo-1-piperidinyl)-N-(1H-tetraazol-5-ylmethyl)benzamide (which was obtained in Example 178) (0.14 g, 0.4 mmol) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) according to the procedure shown for Example 180 to give 0.22 g of an off-white solid; m.p. 168–170° C.; MS (ES) m/z: 587.5 (MH+); HRMS (ES) Calcd. for C27H39N8O5S (MH+): 587.2759. Found: 587.2751.
Reaction SMILES: Cl.N1C2=CC=CC3=CC=CC(=C23)N[B:3]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.C([O-])(O)=[O:29].[Na+].[OH-:33].[Na+]>C1COCC1.CCOC(C)=O>[NH2:27][C:22]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([B:3]([OH:29])[OH:33])=[CH:16][CH:17]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=C([O-])O
Reactant: [OH-]
Reactant: Nc1ncccc1-c1ccc(B2Nc3cccc4cccc(c34)N2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6N HCl aq. (1.1 mL) was added to a mixture of 3-(4-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)phenyl)pyridin-2-amine (396 mg) in THF (dry) (12 mL). The mixture was stirred at room temperature for 3 hr. The mixture was added with sat. NaHCO3 aq, EtOAc and 2N NaOH aq., and the separated aqueous phase was acidified by 6N HCl aq., then controlled pH ca. 8 by sat. NaHCO3 aq. The aqueous mixture was extracted with EtOAc, and the organic layer was separated, washed with brine dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (52.4 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCN2CCCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 69 from 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (0.1 g), piperidine (1 ml),triethylamine (0.5 ml) and tetrahydrofuran (3 ml). Purification by silica gel chromatography eluting with 5% methanol and 1% triethylamine in dichloromethane gave 2-chloro-5-(2-(piperidin-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a glass. Conversion to the hydrochloride salt upon treatment with excess ethereal hydrochloric acid (2M) gave the title compound as a yellow solid (0.062 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:20]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:29])=[CH:25][CH:26]=2)[C:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:20]1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: Cn1nc(-c2ccccc2)c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccccc2)c2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 54c (30.3 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1137 (48.1 mg). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.88 (d, J=3.2 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.49-7.58 (m, 3H), 7.39-7.48 (m, 2H), 4.16 (s, 3H), 4.09-4.62 (m, 6H), 3.86 (m, 2H), 3.21-3.33 (m, 1H), 2.39-2.63 (m, 4H). MS m/z (M+H+) 487.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]=[O:16])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]=[O:16])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1[nH]c2cccc(Br)c2c1C=O
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C=O)c2c(Br)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of EXAMPLE 107A (1.76 g) in N,N-dimethylformamide (10 mL) was added 1-(3-bromopropoxy)naphthalene (1.66 g) and Cs2CO3 (6.10 g). The mixture was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate (300 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water (×3) and brine and dried over Na2SO4. After filtration, concentration of solvent gave crude product, which was purified by column chromatography (5% ethyl acetate in hexane).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]1([C:25]2[CH:30]=[CH:29]C=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:25]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:26]=[CH:27][C:9]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(-c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.0 g of ethyl acetoacetate, 5.3 g of NaH 50% dispersion in oil, 60 mL of 1.6M n-butyl lithium in hexane, 16.3 g of 4-biphenylcarboxaldehyde and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 150°-152° C.). 1H NMR (CDCl3) δ 2.97 (dd, 2 H), 3.60 (dd, 2 H) 5.77 (dd, 1 H), 7.27-7.68 (m, 9 H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)=[O:7])C.[Li+].[OH-]>CO.O.C1COCC1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:5]([O:18][CH2:19][CH3:20])[C:4]([OH:21])=[O:3])=[CH:15][CH:14]=1)#[N:17]
Reactant: CCOC(=O)C(OCC)C(=O)NCc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(C(=O)O)C(=O)NCc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid ethyl ester (1.97 g) and LiOH (285 mg) in MeOH (14 ml), H2O (7 ml) and THF (14 ml) was stirred 3 h at 60° C. The solvents were evaporated, EtOAc was added and it was washed with HCl 0.1 N, water and brine. The aqueous phases were extracted again with more EtOAc. The combined organic phases were dried (MgSO4) and the solvent was removed to yield (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid, 1.53 g (86%); of white solid. MS 260.2 (100, [M+H]+), 277.2 (13, [M+NH4]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1C=[CH:43][CH:42]=[CH:41][C:40]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1ccccc1O
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccccc4OC)cc3C)c2cc1OC
Yield: 53.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methoxyphenol (29 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (39 mg, yield 51%).