Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C1(C)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Yield: 87.8 %

Procedure:
In 80 ml of toluene is dissolved 5.9 g of 2,4,5-trimethoxybenzaldehyde, followed by addition of 4.8 g of diethyl malonate, 0.3 ml of piperidine and 0.3 g of benzoic acid. The mixture is heated under reflux for 4 hours, water being removed via an ester tube. After cooling, the solvent is distilled off under reduced pressure and the residual crystals are recovered by filtration with n-hexane to give 8.9 g (87.3%) of diethyl 2,4,5-trimethoxybenzylidenemalonate, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])OCC)#[N:4]>C(O)C.O>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:4]
Reactant: CN
Reactant: CCOC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Solvent: O
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Yield: 75 %

Procedure:
90 ml of a 30% aqueous solution of monomethylamine is added dropwise with cooling by ice to 4.3 g of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-O-ethylisourea dissolved in the mixture of 90 ml of ethanol and 60 ml of water. After reaction at 0° C. overnight, the solution is concentrated under reduced pressure and chromatographed similarly as in Example 1 (iii) to separate a reaction solution. Thus obtained solution is concentrated under reduced pressure and is crystallized from isopropyl alcohol-ether to yield 3.0 g of cimetidine, namely N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (yield: 75.0%)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH3:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:23](=[O:29])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][N:10]([CH3:11])[C:23](=[O:29])[NH:8]2
Reactant: CNCc1c(N)cccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-methylaminomethyl-phenylamine (1.153 g, 5.36 mmol) in CH2Cl2 (50 ml) was added NEt3 (1.5 ml, 10.76 mmol), triphosgen (555 mg, 1.87 mmol) at 0° C. The reaction was allowed to warm up to room temperature and stirred overnight. After the solvent was removed by using a rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was washed by H2O and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one as white solid. (650 mg, 50%) MS: (M+H)+241.1.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.S([O:17][CH2:18][CH2:19][O:20][NH2:21])(O)(=O)=O>>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:21][O:20][CH2:19][CH2:18][OH:17])=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NOCCOS(=O)(=O)O
Product: Nc1ccccc1C(=O)NOCCO
Yield: 66.6 %

Procedure:
1H-3,1-benzoxazine-2,4-dione (320 mg, 1.96 mmol) and 2-(aminooxy)ethanol hemisulfate (990 mg, 3.92 mmol) were reacting using the procedure of example 15.07, starting material. The crude product was purified by flash chromatography on silica gel eluting with 0 to 80% EtOAc in DCM. The solvent was evaporated to dryness to afford 2-amino-N-(2-hydroxyethoxy)benzamide (256 mg, 66.5%) as a pale yellow oil which solidified on standing. NMR Spectrum: (DMSOd6) 3.57-3.64 (m, 2H), 3.85-3.92 (m, 2H), 4.75 (bs, 1H), 6.27 (bs, 2H), 6.49 (dd, 1H), 6.71 (d, 1H), 7.15 (ddd, 1H), 7.34 (dd, 1H), 11.39 (bs, 1H); Mass spectrum: MH+ 197
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCOCC1.C(OCC)(=O)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A room temperature solution of Example 1C (2.36 g, 10.0 mmol) and cyclohexylamine (2.0 mL) in dioxane (5 mL) was stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 3M HCl (20 mL), water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Br:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Br:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Br:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Br:16]
Reactant: Nc1c(Br)cc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
conc. H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature and the reaction mixture was then stirred at 80° C. for 8 h. The reaction mixture was brought to ambient temperature, volatiles were evaporated and ice cold water was added to the residue and which was then extracted with EtOAc. The organic layer was washed with an aqueous NaHCO3 solution followed by brine and water. The solution was then dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (5.0 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m/z 307.0 ([M]+); IR (thin film) 3312, 2953, 1726, 595 cm−1.
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)C>[CH2:33]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Reactant: CCCCCCCCCCCCO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O

Procedure:
A mixture of 2 (10 g), triethylamine (15 ml) and dodecanol (22 ml) in ethanol-free chloroform (100 ml) was refluxed for 22 hours. Workup in the usual fashion gave the crude product (15.3 g, 86%) as a semi-solid. GC analysis indicated the mixture contained an 89:6 mixture of the major and minor isomers together with about 4% of unreacted 2. Crystallization of this material gave 11.8 g of 3c with mp 74.8°-75.6° C. Recrystallization gave 3c with mp 74.7°-75.3° C., which migrated as a single spot on TLC and as a broad peak, Rt 10.88-10.93, by GC, after derivatization.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:27][NH2:28]>C1COCC1.CCO>[CH3:27][NH:28][CH2:6][CH:7]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)CCCCC1
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNCC(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propyl methanesulfonate in 16 mL of THF, and 10 mL of 33% wt. methylamine in EtOH was heated at 70° C. for 3 h. After cooling to rt, the reaction mixture was evaporated under reduced pressure. The crude benzyl 1-(methylamino)-3-(1-methylcyclohexyl)propan-2-ylcarbamate was used directly in the next step without further purification. MS ESI +ve m/z 319 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34](OC3C=CC=CC=3)=[C:29]2[CH:28]=[N:27]1>C1COCC1>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[N:27]=[CH:28][C:29]=12)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2nccn2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil) (28.8 mg, 0.72 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (143 mg, 0.60 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (193 mg, 0.66 mmol) in THF (1 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents to afford the product (90 mg, 34.4%, 100% ee). 1H NMR (400 MHz, CDCl3) δ 1.18 (6H, t), 2.29 (3H, s), 3.65 (3H, s), 3.67-3.76 (1H, m), 4.08 (2H, d), 6.01 (1H, t), 7.01 (1H, d), 7.17 (1H, d), 7.49-7.55 (1H, m), 8.06-8.14 (2H, m), 8.42 (1H, s), 8.65 (1H, s), 8.68 (1H, s); m/z (ES+) (M+H)+=437.51; HPLC tR=1.89 min.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([CH:17](OS(C)(=O)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH:13]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([S:1][CH:17]([C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:7]=1
Reactant: CCOC(=O)C(OS(C)(=O)=O)C1=CCCC1
Reactant: COc1cc(OC)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C1=CCCC1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
10.4 g of 2-mercapto-4,6-dimethoxypyrimidine, 15.0 g of ethyl 2-(1-cyclopentenyl)-2-(methylsulfonyloxy)acetate, 100 ml of N,N-dimethylformamide and 9.2 g of anhydrous potassium carbonate were stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and then diluted with water. The aqueous mixture was extracted with ethyl ether. The ethyl ether extract was washed with water and dried. Then, ethyl ether was removed by distillation under reduced pressure to obtain an yellow oily substance. The yellow oily substance was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =10/1) to obtain 9.7 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349 mmol) was reacted with N-(2-azidoethyl)-4-hexylbenzamide (0.096 g, 0.349 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-hexylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 2H), δ 7.55 (t, 1H), δ 7.26 (s, 1H), δ 7.09 (d, 2H), δ 6.39 (s, 1H), δ 6.04 (s, 2H), δ 4.48 (t, 2H), δ 3.83 (q, 2H), δ 2.56 (q, 4H), δ 2.24 (t, 2H), δ 1.50 (m, 13H), δ 1.21 (m, 1H), δ 0.77 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 148.3, 147.3, 138.7, 131.4, 128.7, 127.4, 122.2, 106.4, 84.9, 73.9, 49.5, 40.2, 36.0, 31.8, 31.3, 29.9, 29.3, 29.1, 28.9, 28.2, 28.1, 28.0, 25.6, 22.8, 14.3 ppm; HRMS (ESI) calcd for C30H45N7O3 (M+) 551.3584. found 551.3581, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-hexylbenzamide hydrochloride (0.164 g, 96% yield). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), δ 7.67 (d, 2H), δ 7.21 (d, 2H), δ 6.43 (s, 1H), δ 4.72 (s, 2H), δ 3.87 (s, 2H), δ 2.74 (s, 2H), δ 2.58 (t, 2H), δ 2.31 (t, 2H), δ 1.66 (s, 2H), δ 1.55 (s, 4H), δ 1.35 (s, 2H), δ 1.25 (s, 6H), δ 0.66 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD)-δ 169.2, 159.5, 147.4, 147.3, 131.2, 108.4, 51.2, 48.5, 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 39.5, 36.5, 35.6, 31.6, 31.7, 31.2, 28.8, 28.2, 27.9, 27.7, 24.1, 23.9, 22.6, 13.3, 9.9 ppm; HRMS (ESI) calcd for C25H37N7O (M+) 451.3059. found 451.3058.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:35])=[C:18]([O:23][CH:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([O:27]C)=[O:26])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:37])[CH3:36])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]>O1CCCC1.CO>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3[C:17]([CH3:35])=[C:18]([O:23][CH:24]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:25]([OH:27])=[O:26])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:37])[CH3:36])=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)C(Oc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1OC(C(=O)O)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
An aqueous solution of 2 N sodium hydroxide (2.5 mL) was dropwise added to a solution of methyl α-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxy]phenylacetate (1.20 g, 2.54 mmol) in a mixture of tetrahydrofuran (24 mL) and methanol (6 mL), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 2 N hydrochloric acid. Then, this was extracted twice with ethyl acetate. The organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from hexane to obtain the title compound (0.31 g, yield 27%), which was a mixture of diastereomers (ratio: 8/1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]([OH:34])[CH3:33]>C(#N)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:31][CH:32]([OH:34])[CH3:33])[CH2:21][CH2:20][C:6]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(C)O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.95 mmol) and 1-bromopropan-2-ol (135 mg, 0.977 mmol) were added and stirred the reaction mixture at 100° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-ol. 1H NMR, (CDCl3, freebase) δ (ppm): 8.58 (s, 2H), 7.36 (m, 2H), 7.2 (m, 2H), 7.02 (d, 1H), 5.1 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 2H), 3.56 (m, 1H), 3.37 (m, 1H), 3.1-3.3 (m, 2H), 2.8 (m, 2H), 2.42 (s, 3H), 1.2 (d, 3H). Separation by chiral HPLC provides diastereomers II-83a-d.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:13]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30](OC)(OC)OC>>[CH2:20]([N:19]1[C:14]2[CH:13]=[C:12]([C:11]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[N:9][C:10]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:17]=[CH:16][C:15]=2[N:18]=[CH:30]1)[CH:21]([CH3:23])[CH3:22]
Reactant: COC(OC)OC
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Product: CC(C)Cn1cnc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc21
Temperature: 25 °C
Yield: 73 %

Procedure:
Heat a mixture of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (83 mg, 0.21 mmol) and 3 mL trimethyl orthoformate at 120° C. for 6 hours. Cool to room temperature and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 3:1 ethyl acetate:hexanes to provide the title compound (73%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:15]Br>CO>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:15][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COc1cc(CBr)ccc1C
Reactant: COC(=O)CC(=O)OC
Solvent: CO
Product: COC(=O)C(Cc1ccc(C)c(OC)c1)C(=O)OC
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
A solution of 2.6 g (0.1124 g-atom) of Na in 50 mL of MeOH was treated with 12.9 mL (0.1124 mol) of dimethyl malonate and allowed to stir for 45 minutes. This was then treated dropwise with 24.17 g (0.1124 mol) of 3-methoxy-4-methylbenzyl bromide and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc. This was washed with 6% HCl, H2O, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave 28.54 g (95.5% yield) of the product as a pale yellow oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[N:23]1([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](OC)=[O:36])=[CH:30][CH:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:35](=[O:36])[CH2:34][C:31]4[CH:30]=[CH:29][C:28]([N:23]5[CH:27]=[CH:26][N:25]=[CH:24]5)=[CH:33][CH:32]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Reactant: COC(=O)Cc1ccc(-n2ccnc2)cc1
Agent: C[Al](C)C
Product: O=C(Cc1ccc(-n2ccnc2)cc1)N1CCOc2ccc(-n3ccnc3)cc2OCC1

Procedure:
In a manner similar to preparation 7, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, trimethylaluminum, and 4-(1H-imidazol-1-yl)benzeneacetic acid, methyl ester to obtain the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:47])([F:46])[C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=1)[O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([O:34][C:33]4[CH:43]=[CH:44][CH:45]=[C:31]([C:30]([F:29])([F:46])[F:47])[CH:32]=4)[CH:36]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc(Oc2cccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-(3-trifluoromethyl phenoxy)-benzaldehyde. MS (ESI) m/z 629.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClC1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:4]2[C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[S:7][C:3]=2[N:2]([CH3:12])[CH3:1])=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1cc2ccccc2s1
Solvent: Clc1ccccc1
Product: CN(C)c1sc2ccccc2c1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
A mixture of 5.00 g (28.2 mmol) of 2-dimethylaminobenzo[b]thiophene (Vesterager et al., Tetrahedron, 1973, 29, 321-329) and 6.3 g (33.9 mmol) of 4-nitrobenzoyl chloride in 100 mL of chlorobenzene was heated at 105° C. for 6 h. The reaction was cooled and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2; 5% then 10% then 25% EtOAc in hexanes) afforded 7.51 g (23.0 mmol; 82%) of the title compound as burgundy flakes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 30.2 %

Procedure:
Nitrogen was bubbled through dioxane (100 mL) followed by the addition of 4-bromo-1-(methyloxy)-2-nitrobenzene (5.0 g, 21.55 mmol, Transworld). To the solution were added 3-pyridinylboronic acid (3.16 g, 25.90 mmol, Boron Molecular), dichloro(triphenylphosphine)palladium (0.76 g, 1.08 mmol, Strem) and degassed aqueous Na2CO3 (65 mL, 1 M, 65 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was recrystallized from hexanes/ethyl acetate to afford 3-[4-(methyloxy)-3-nitrophenyl]pyridine (1.5 g, 76%). ESIMS (M+H)+=231.