Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6](C(O)=O)=[CH:5][N:4]=1)#[N:2].CCN(CC)CC.Cl[C:20](OCC)=[O:21].[BH4-].[Na+]>C1COCC1>[OH:21][CH2:20][C:5]1[N:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][CH:6]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CO)n1
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 6-cyanonicotinic acid (12 g, 0.081 mol; see step (i) above) in THF at 0° C., Et3N (12.4 mL, 0.0892 mol) was added followed by ethyl chloroformate (8.53 mL, 0.0892 mol). The reaction mixture was stirred for 15 min and NaBH4 (6.14 g, 0.162 mol) was added. Then the mixture was stirred at RT overnight, quenched with water and extracted with methylene chloride. The organic layer was concentrated and purified by column chromatography to yield 4 g (20%) of the alcohol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]([CH3:22])(=O)=O)[N:3]=1.[C:23]1(S)[CH:28]=[CH:27]C=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][C:22]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 348 (M+, 96), 347 ([M—H]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H].[ClH:18]>O.[Pd]>[ClH:18].[ClH:18].[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC(=O)c1cc(N)cc(N)c1

Procedure:
3,5-dinitrobenzamide (18) (412.0 g, 2.00 moles, Aldrich) was added to a suspension of 10% Pd/C (10.4 g) in concentrated HCl (360 ml) and water (3.64 L). The mixture was hydrogenated at 60psi in a Parr hydrogenation apparatus until hydrogen was no longer being consumed. The solution was filtered through a Celite pack and washed with 500 ml water. The filtrate and washings of 3,5-diaminobenzamide bis-hydrochloride (19), were combined and used for the subsequent iodination.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH:12]=[CH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(OC)c(C(=O)C=Cc2c[nH]c3ccccc23)c1
Yield: 44 %

Procedure:
2',5'-Dimethoxyacetophenone (1.80 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 72 hours. The precipitated crystals were collected by filtration, and the obtained crude crystals were recrystallized from ethanol to give Compound 89 (1.35 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[NH2:14][CH:15]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:16]([CH:15]([NH:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)#[N:17]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CON1CCC(CC(N)C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CON1CCC(CC(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Reaction time: 0.5 h

Procedure:
At room temperature, (2,4,6-trimethyl-phenyl)-acetyl chloride (10.6 g, 54 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionitrile (6.6 g, 36 mmol) and K2CO3 (9.9 g, 72 mmol) in 100 ml of THF. After the addition, the mixture was stirred for 0.5 h. The reaction mixture was diluted with 50 ml of water and extracted with EtOAc five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel Yield: 10.6 g of N-[1-cyano-2-(1-methoxy-piperidin-4-yl)-ethyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>COCCOC>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(Cl)nc1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(Cl)nc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 6-chloro-3-pyridinol, using dry DME as reaction solvent: MS (APCI) m/z 424 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[OH-].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl.C(OC(C)C)(C)C>CO>[O:30]1[CH2:29][CH:28]1[CH2:26][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:10](=[O:21])[CH2:9][CH:8]3[C:13]([C:4]4[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=4[CH2:6][CH2:7]3)=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To 50 ml of methanol is added 9 g of 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and 1.7 g of sodium hydroxide dissolved in 70 ml of methanol is added to the mixture under stirring at room temperature. Thereto is added 13 g of epichlorohydrin, and the mixture is heated under reflux for 2 hours. After the reaction mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off to give 12.5 g of a brown oily substance. This oily substance is subjected to column chromatography. Isopropyl ether is added to the resulting crystals, and the crystals are collected by filtration to give 4 g of 2-[4-(2,3-epoxypropoxy)phenyl]-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as white crystals, m.p. 128°-130° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl.ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L×3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][C:5]=1[F:19].[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:10][C:9]1[CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[C:5]([F:19])[C:4]=1[C:3]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH3:21])=[O:20]
Reactant: COC(=O)c1c(F)cc(OCc2ccccn2)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2,6-Difluoro-4-(pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 416.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](N(OC)C)=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (X) (0.290 g, 0.78) in dry THF (5 mL) stirred at 0° C. under nitrogen was added lithium aluminum hydride (36 mg, 0.94 mmol). The solution was further stirred at 0° C. for 30 min. The reaction was quenched with a 0.4 N NaHSO4 solution (10 mL). The solution was extracted with DCM (3×15 mL). The combined organic layer was washed subsequently with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) as a viscous liquid (218 mg, 0.70 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.52-1.74 (m, 2 H), 1.95-2.18 (m, 2H), 2.37-2.49 (m, 2H) 3.87-3.98 (m, 1 H), 3.99 (m, 1H), 6.18 (dd, J=10.20, 2.39 Hz, 1 H), 8.73 (d, J=3.01 Hz, 1 H), 8.85 (d, J=3.01 Hz, 1 H), 10.16 (s, 1 H); ESIMS found for C12H12BrN3O2 m/z 310.4 (M+H).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.BrC[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:32][O:33][C:2]1[CH:12]=[C:6]2[N:7]([CH2:11][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(F)c(F)c1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CN2CCCn3c2cc(OCc2ccc(F)c(F)c2)nc3=O)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one, 1-(bromomethyl)-4-methoxybenzene and (3,4-difluorophenyl)methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27]OS(C3C=CC(C)=CC=3)(=O)=O)[O:24][C:23]2=[O:39])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[N-:40]=[N+:41]=[N-:42].[Na+].CCOC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][N:40]=[N+:41]=[N-:42])[O:24][C:23]2=[O:39])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Yield: 98.3 %

Procedure:
The [[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate (29.661 g, 52 mmol) was dissolved in dry DMF (125 mL) and then treated with solid NaN3 (10.19 g, 156 mmol) at room temperature. The reaction was heated to 60° C. for three hours and then allowed to cool to room temperature overnight under N2. The reaction was found to he complete by TLC (30% EtOAc/hexane, run twice, UV short wave). The reaction mixture was concentrated in vacuo to give a cream colored solid. The crude product was dissolved in 600 mL EtOAc and then washed with both H2O (2×500 mL) and brine (500 mL). The aqueous portions were back-extracted with more EtOAc (2×400 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield 22.41 g (91%) of the title compound as a pale yellow solid with mp 115°-117° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:32]([O:31][C:29]([C:28]([CH3:34])=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:22][CH:23]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)C(C)=Cc1ccc(CCl)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(Cn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.08 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF under nitrogen at 10°-15°. After complete addition the mixture is stirred at room temperature for 0.5 hour and is treated with a solution of 2.39 g of ethyl 3-(p-chloromethylphenyl)-2-methylacrylate in 5 ml of DMF dropwise. The resulting mixture is stirred at room temperature overnight and poured in 100 ml of water. The resulting mixture is extracted with ethyl acetate (2×50 ml) and the organic layer is washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 1-[p-(2-ethoxycarbonylpropen-1-yl)benzyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[NH:4][C:3]=1[CH3:28].[H-].[Na+].[P:31](Cl)([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[P:31]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])([O:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[N:4]=[C:3]([CH3:28])[C:2]=1[Br:1])=[O:32]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1c(Br)c(C)nc(C)c1-c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-Bromo-5-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (4.44 g) in dry DMF (30 ml) under nitrogen was added sodium hydride (0.39 g of a 60% dispersion in mineral oil). After stirring at rt for 30 min diethyl chlorophosphate (2.1 ml) was added dropwise. The mixture was stirred at rt for 48 hr then filtered. The filtrate was diluted with toluene (200 ml), washed with 2M sodium carbonate, dried over magnesium sulphate and concentrated in vacuo. The residue was chromatographed on silica, eluting with 1:4 ethyl acetate:dichloromethane to afford the title compound (1.22 g), m.p. 80°-81°, NMR δH (CDCl3) 7.35-7.0 (8H, m), 4-3.8 (4H, m), 2.7 (3H, s), 2.25 (3H, s), 1.25-1.15 (6H, 2×t).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=3[N:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)ncn2CC1CCCCC1
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc2c(ncn2CC2CCCCC2)c1Br
Yield: 40 %

Procedure:
To a solution of 1-cyclohexylmethyl-5-aminobenzimidazole (2.5 g, 11 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.37 g (4.3 mmol, 40%) of the product.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.C(OCC)(=O)C>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: COC(=O)CN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
To a stirred suspension of methyl 2-(piperazin-1-yl)acetate dihydrochloride (0.67 g, 2.92 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.15 g, 1.07 mmol). The resulting mixture was stirred at rt for 10 min. Then 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.40 g, 1.33 mmol) was added as a solid. The reaction was heated at 90° C. for 4.5 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) followed by trituration with diethyl ether to give methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.357 g, 61%) as a light yellow solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (br s, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.63-7.71 (m, 1H), 6.80-6.86 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.77 (s, 3H), 3.67-3.73 (m, 4H), 3.34 (s, 2H), 2.73-2.79 (m, 4H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([OH:10])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][CH2:17][O:18][CH3:19])[CH:3]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCOc1cc(Cl)ccc1CO
Reaction time: 0.17 h
Yield: 92 %

Procedure:
4.00 g of 4-chloro-2-hydroxybenzyl alcohol [prepared as described in step (a) above] were dissolved in 80 ml of N,N-dimethylacetamide, and then 2.83 g of potassium t-butoxide were added to the resulting solution, whilst ice-cooling, and the mixture was stirred for 10 minutes. 2.09 ml of methoxymethyl chloride were then added to the reaction mixture, whilst ice-cooling, and the mixture was then stirred at room temperature for 1 hour. At the end of this time, 60 ml of water and 300 ml of ethyl acetate were added, and the ethyl acetate layer was separated and washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.69 g (yield 92%) of the title compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:18]=1[O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([S:27](Cl)(=[O:29])=[O:28])=[CH:22][C:21]=1[Cl:31].[CH:39]1[CH:44]=[C:43]([OH:45])[CH:42]=[C:41]([CH:46]([OH:49])[CH2:47][NH2:48])[CH:40]=1>>[Cl:31][C:21]1[CH:22]=[C:23]([S:27]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([NH:48][CH2:47][CH:46]([OH:49])[C:41]4[CH:40]=[CH:39][CH:44]=[C:43]([OH:45])[CH:42]=4)[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][C:18]1[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:17]=1[Cl:16]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Nc3ccc(N4CCC(NCC(O)c5cccc(O)c5)CC4)cc3)cc2Cl)c(Cl)c1

Procedure:
The title compound was prepared from 1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained in Example 224), 4-(2-chloro-4-nitrophenoxy)-3,5-dichlorobenzenesulfonyl chloride, and DL-norphenylephrine according to the procedure of Example 346; MS (ES) m/z: 709.1, 711.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2cccc(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-methoxybenzaldehyde gave the title compound as white crystals m.p.: 146° C.
Reaction SMILES: CO[C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10]N=2)=[C:5]([NH2:16])[CH:4]=1.[C:17](Cl)(=O)C.[N:21]1C=CC=C[C:22]=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:17][C:8]1([C:13]2[CH:12]=[CH:11][CH:10]=[CH:22][N:21]=2)[NH:7][C:6]2[CH:14]=[CH:15][CH:3]=[CH:4][C:5]=2[NH:16]1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: CC(=O)Cl
Product: CC1(c2ccccn2)Nc2ccccc2N1

Procedure:
The titled compound was prepared from 4-methoxy -2-amino-N-(2-pyridyl)aniline and acetyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(C(C)=O)cc2)c1
Yield: 77.4 %

Procedure:
Reaction of 4-aminoacetophenone (72 mg, 0.53 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-3-methoxy-benzamide (110 mg, 0.41 mmol, 77% yield) as a white powder after washing by dichloromethane.