Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1.C(OCC)(=O)C>C(#N)C>[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CN1CCCCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95 (0.22 g, 0.56 mmol, 1 eq) in acetonitrile (10 ml) is treated with potassium carbonate (0.31 g, 2.24 mmol, 4 eq) and 2-methylpyrrolidine (60 μl, 0.67 mmol, 1.2 eq) and the resulting mixture is stirred at 110° C. overnight. Ethyl acetate is then added and the organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification over silicagel (eluent: dichloromethane/methanol/ammonia) affords 90 mg of ethyl 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i96.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)pyrimidin-4-yl)propanoate (233 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered through silica gel and the solvent was evaporated under reduced pressure to give the title compound (214 mg) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](O)=O)[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:63]([NH2:71])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:63]([NH:71][C:25]([CH2:19][C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:17]=[CH:16][CH:15]=2)=[O:29])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NCCc1ccccc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)NCCc2ccccc2)cc2c(OCc3ccccc3)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (0.20 g) in DMF (10 mL) was added TBTU (0.23 g), HOBt (0.11 g) and DIEA (0.27 mL). After 5 min., phenethylamine (0.11 mL) was added and stirring was continued overnight under nitrogen at room temperature. The residue remaining after DMF evaporation was dissolved in EtOAc; washed with dilute HCl, saturated NaHCO3, and brine; dried over MgSO4; and concentrated at reduced pressure to give the intermediate product N-phenethyl 4-benzyloxy-1-methyl-1H-indole-2-carboxyamide (0.18 g) which was used without further purification. Hydrogenation of this product by a method analogous to that described in Example 9 give 0.14 g of the title compound. MS CI (M++H)=295.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11]CC(C=O)C[CH2:7]1.[NH:24]=[C:25]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[N:26]1C(C1C=CC=CC=1)=O.[CH3:40][C:41]([CH3:44])([O-])[CH3:42].[K+].[Cl-].[NH4+]>C(O)C>[NH2:24][C:25]1=[N:26][C:27](=[O:31])[N:28]([CH3:30])/[C:29]/1=[CH:40]/[CH:41]1[CH2:44][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:3]=2[C:2]([F:23])([F:22])[F:1])[CH2:7][CH2:42]1
Reactant: CN1CC(=N)N(C(=O)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: CN1C(=O)N=C(N)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (26.0 g) in ethanol (100 mL) were added 4-imino-1-methyl-3-(phenylcarbonyl)imidazolidin-2-one (16.7 g) and potassium tert-butoxide (8.60 g) under ice-cooling, and the reaction mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate under reduced pressure, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethanol/water to give the title compound (220 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:18]2[NH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1

Procedure:
A mixture of p-nitrobenzaldehyde (2.510 g.) and hydantoin (1.671 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.53 g., 1.5 molar ratio) was added and the mixture was stirred magnetically and heated at 90°-92° (bath temperature) for 41/4 hours. The mixture was cooled in an ice-bath and acidified with HCl. After refrigeration overnight the mixture was filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a brown solid (3.258 g.), m.p. 252°-253° decomp.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10](Cl)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)(Cl)Cl>[C:1]([O:28][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:28])(=[O:3])[CH2:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:9]/[CH:8]=[CH:7]\[CH2:6]/[CH:5]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: c1ccncc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 60 °C
Yield: 44 %

Procedure:
1,30-Triacontadiol (38) (2.5 g, 5.5 mmol) was dissolved in dry, ethanol free chloroform at 60° C. under nitrogen and treated with pyridine (0.49 ml; 6.05 mmol). The resulting solution was treated with a solution of linoleoyl chloride (39) (1.64 g; 5.5 mmol) in chloroform (20 ml) over a twenty minute period and then maintained at 60° C. for a further thirty minutes, then cooled, diluted with chloroform, washed with water three times, dried, filtered and evaporated. The crude product obtained in this manner was purified on silica (30 g). Elution with chloroform gives the title compound (40) as a white solid (1.73 g; 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]#[N:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:18]1([CH2:24][CH:25](O)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(=O)(=O)(O)[OH:40]>ClC1C=CC=CC=1Cl>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:17][CH:25]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:40])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC#N)cc1OCC
Reactant: O=S(=O)(O)O
Reactant: OC(CC1CCCCC1)c1ccccc1N1CCCCC1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCCC2)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 23°-25° C., a solution of ethyl 2-ethoxy-4-cyanomethyl-benzoate (2.35 g, 10 mmol) and α-cyclohexylmethyl-2-piperidino-benzyl alcohol (2.88 g, 10 mmol) in o-dichlorobenzene (15 ml) is added dropwise to a mixture of concentrated sulphuric acid (15 ml) and o-dichlorobenzene (15 ml). The mixture is stirred for 2 hours at ambient temperature. The o-dichlorobenzene phase is then separated off and the residue is added to ice. After being made alkaline with soda solution, it is extracted with chloroform. The extracts are dried over sodium sulphate and concentrated by evaporation. The residue is purified by column chromatography on silica gel (toluene/acetone=10/1). Yield: 1.1 g
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[CH3:24][C:25]1([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:27][O:26]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:24][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)([OH:26])[CH3:27])[C:4]=2[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3c1ccccc1
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)C(c2ccccc2)N(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
2,6-Dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline (300 mg, 1.08 mmol) was dissolved in DMF (4 mL). Sodium hydride (172 mg, 4.32 mmol) was added and the mixture was stirred at RT for 30 min. 3-(2-Methyl-oxiranyl)-pyridine (733 mg, 5.43 mmol) in 1 mL DMF was added dropwise into the reaction mixture, which was stirred for 5 h at RT. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction was quenched with ice and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude that was purified by column chromatography (silica gel 100-200 mesh, Eluent: 6% MeOH in DCM) to obtain 120 mg of 1-(2,6-dimethyl-1-phenyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol (racemate) and followed by chiral separation. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.25 (s, 1H), 8.2 (d, 1H), 7.6 (d, 1H), 7.4 (m, 3H), 7.2 (s, 1H), 7.19 (m, 3H), 6.65 (d, 1H), 6.4 (d, 1H), 5.5 (s, 1H), 4.0 (d, 1H), 3.43 (d, 1H), 3.2 (m, 1H), 3.0 (m, 3H), 2.6 (s, 3H), 2.3 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided diastereomers II-112a-b.
Reaction SMILES: [Cl:1]C1C(=O)NC(=O)C1(S(O)(=O)=O)C1C=CC=CC=1.Cl[S:20]([OH:23])(=[O:22])=[O:21].[CH2:24]([C:31]1[C:32]([NH:34][C:35](=[O:37])[CH:36]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][N:34]1[C:35](=[O:37])[C:36]([S:20]([OH:23])(=[O:22])=[O:21])=[C:31]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]1=[O:33]
Reactant: O=C1C=C(Cc2ccccc2)C(=O)N1
Reactant: O=C1NC(=O)C(c2ccccc2)(S(=O)(=O)O)C1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C1C(Cc2ccccc2)=C(S(=O)(=O)O)C(=O)N1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In the apparatus mentioned under (b), 87.4 g (0.75 mol) of chlorosulfonic acid and 18.7 g (0.1 mol) of benzylmaleimide are mixed together for 5 hours at 60° C. The solution is afterwards added dropwise to ice water, and the mixture is stirred for 30 minutes. The mixture is then extracted with methylene chloride as described under (b). The initially liquid product slowly crystallises on standing.
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:16]1[C:21]([CH2:22][CH:23]([OH:25])[CH3:24])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[NH:28][C:29](=[O:31])[CH3:30])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)Cl>[C:1]([NH:4][N:5]=[C:6]([C:16]1[C:21]([CH2:22][CH:23]([O:25][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:24])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[NH:28][C:29](=[O:31])[CH3:30])[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CC(C)O)c(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(C)OS(C)(=O)=O)c(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c1NC(C)=O
Reaction time: 0.5 h

Procedure:
To a solution of 23 (1.1 g) in 20 ml of CH2Cl2 was added 1.5 ml of triethyl amine, 0.60 ml of methanesulfonyl chloride at 0-10° C. After 30 min, no more starting material was detected on TLC. Water was added, extracted with CH2Cl2. The organic phase was washed with HCl (1N), brine, dried over Na2SO4. Removal of the solvent afforded product 24 (1.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Oc1cncc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(C(F)(F)F)c1

Procedure:
A 332.9. mg (1.56 mmol) sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 224.9 mg (1.30 mmol) of 3-hydroxy-5-trifluoromethylpyridine were reacted with triphenylphosphine and DEAD (1.56 mmol each) in 5 mL of THF according to the procedure of Example 14a, to give 386 mg of the title compound. MS (DCI/NH3) m/e 347 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.46 (s, 1H), 4.28-3.90 (m, 3H), 3.48-3.84 (m, 2H), 2.12-1.87 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:56])[N:20]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH:42]3[O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:56])[N:20]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH:42]3[O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CC3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A mixture of hydroxylammonium chloride (2.50 g), sodium hydrogen carbonate (3.70 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. The mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10.0 mL). N,N′-carbonyldiimidazole (0.36 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.02 g, 42%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:26]1([CH2:25][CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: BrCCCCn1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCCn1ccnc1
Yield: 34.2 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,4-dibromobutane (2.6 mL, 22.0) in THF (50 mL) was added 60% NaH (356 mg, 8.81 mmol), and the resultant mixture was refluxed for 2 h and stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and diluted with CH2Cl2 (75 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) resulted in partial decomposition of 1-(4-Bromo-butyl)-1H-imidazole. This material was used without any further purification. Using General Procedure A: 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (94.4 mg, 0.353 mmol), impure 1-(4-Bromo-butyl)-1H-imidazole (145 mg), KI (6.0 mg, 0.035 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.5 mL) were stirred for 48 h at 60° C. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (47 mg, 34% over 2 steps) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1>>[O:34]1[CH2:35][CH:36]=[C:37]([C:10]2[CH:9]=[C:8]([F:24])[C:7]3[O:6][C:5]4[C:14](=[CH:15][C:2]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)=[CH:3][CH:4]=4)[C@@:13]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:12]=3[CH:11]=2)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, pyridin-3-ylboronic acid and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]4[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=4)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=3)[N:20]=2)=[CH:11]1
Reactant: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc2nc(-c3c[nH]c4ccccc34)cc(C(=O)O)c2cc1OC

Procedure:
A stirred solution of (0.547 g) of 2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline, K2CO3 (0.380 g), MeOH (40 ml) and H2O (10 ml) are heated to reflux. The MeOH is evaporated in vacuo, and the aqueous residue diluted with more H2O, and acidified with 0.IN HCl to pH between 6°-7 while contained in an ice-bath. An orange solid precipitates. This is collected, washed with ether then dried under vacuum (0.1 mm at 22° C.) for a few hours to obtain 2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline m.p. 286° C. dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([Cl:17])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloroindole-2-carboxylic acid (59 mg, 0.30 mmol) was suspended in dichloromethane (10 mL). Oxalyl chloride (41 μL, 0.45 mmol) and N,N-dimethylformamide (5 μL) were added, and the reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated, and the residue was dried under high vacuum to provide the crude product which was used without additional purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24](OC(OCC)OCC)C>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH:24]=[N:23][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnco2)cc1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (50 mg) in triethylorthoformate (5 ml) was heated at 150° C. for 5 hours. The excess triethylorthoformate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-4′-(1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.