Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](/[N:13]=[CH:14]/[N:15](C)C)=O)=[N:8][C:4]=2[CH:3]=1.[NH2:28]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11]3[N:13]=[CH:14][NH:15][N:28]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-meth-(E)-ylidene]-benzamide (230 mg, 0.538 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with sat. NaHCO3 and brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-4% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (180 mg, 84%) as an off-white solid. LCMS (ESMS): m/z 396.68, 398.64 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[O:23]1[CH:24]=[CH:25][C:21]([C:19]2[N:12]3[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:11]3)=[C:16]([CH3:17])[N:18]=2)=[CH:22]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccoc4)n3n2)cc1
Yield: 53.5 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-furancarboxamide (Intermediate 58) (110 mg, 0.32 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 7-(3-furanyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (55 mg) as a yellow solid. MS m/z 322 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([C@@H:10]([C@H:12]([C:14]([O:16]CC)=O)[OH:13])[OH:11])([O:7]CC)=O.O>CO>[CH2:1]([NH:4][C:5](=[O:7])[C@@H:10]([C@H:12]([C:14]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16])[OH:13])[OH:11])[CH2:2][CH3:3]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCCN
Solvent: CO
Solvent: O
Product: CCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
N,N′-Di-n-propyl L-tartaramide was prepared by the reaction of n-propyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.027 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Propyl amine (12.038 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min at ambient temperature, the product began to crystallize from solution. The reaction mixture was allowed to sit at ambient temperature for two hours. The flat, white crystals were filtered, washed with methanol (2×50 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The first crop of product was obtained in 35% yield (7.977 g, 34.34 mmole). Subsequently, a second crop of crystals (1.80 g, 7.75 mmole) was isolated from the mother liquor.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6](O)[C:7](=[CH2:15])[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2].S(Br)([Br:23])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][Br:23])[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CCCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane, and 1.9 ml (24.6 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a brown oil, which is reacted further in the crude state.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]3[O:24][CH2:23][CH2:22][N:21]4[C:17](=[N:18][C:19]([C:25]5[N:26]([CH:30]([CH3:32])[CH3:31])[N:27]=[CH:28][N:29]=5)=[CH:20]4)[C:16]=3[CH:33]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([S:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:24][CH2:23][CH2:22][N:21]4[CH:20]=[C:19]([C:25]5[N:26]([CH:30]([CH3:31])[CH3:32])[N:27]=[CH:28][N:29]=5)[N:18]=[C:17]4[C:16]=3[CH:33]=2)=[O:35])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)C)CC3)ccc1OCC2
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 9-(1-tert-butylpiperidin-4-ylsulfanyl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 10-(1-tert-butylpiperidin-4-ylthio)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 139 (280 mg, 0.60 mmol) in DCM (30 mL) at 0° C. was added TFA (139 μL, 1.81 mmol) followed by a solution of m-CPBA (114 mg, 0.66 mmol) in DCM (10 mL). The resulting mixture was stirred for 30 min then washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-12% 2M NH3/MeOH in DCM then C18, gradient 10-35% MeOH in H2O) affording racemic 140 as a white solid (227 mg, 78%). LCMS: RT 2.55 min [M+H]+ 483.4. 1H NMR (DMSO, 400 MHz): δ 8.77 (1H, d, J=2.30 Hz), 7.94 (1H, s), 7.81 (1H, s), 7.58 (1H, dd, J=8.59, 2.31 Hz), 7.29 (1H, d, J=8.58 Hz), 5.89-5.88 (1H, m), 4.59 (4H, s), 3.18 (2H, s), 2.23 (2H, s), 1.91 (1H, s), 1.87 (2H, s), 1.69-1.64 (2H, m), 1.56 (6H, dd, J=6.63, 3.37 Hz), 1.07 (9H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH4+:15].[OH-]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH2:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [OH-]
Product: NC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Methyl 2-(3-nitrophenyl)acetate (9.6 g, 49 mmol) was treated with conc. NH4OH (24 ml, 172 mmol). The suspension was stirred briskly at RT until complete, then chilled thoroughly in an ice bath. The solids were collected by filtration, rinsed sparingly with ice H2O and dried to yield pure 2-(3-nitrophenyl)acetamide as an off-white solid (7.47 g, 84% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.18-8.02 (m, 2H), 7.75-7.70 (m, 1H), 7.61-7.57 (m, 3H), 7.00 (brs, 1H), 3.58 (s, 3H); MS (ESI) m/z: 181.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](=S)=[S:39]>C(O)C>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[NH:1][C:38](=[S:39])[N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: S=C=S
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1c(=S)[nH]c2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 502.7 mg (1.19 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of ethanol were added 1.66 ml (11.9 mmol) of triethylamine and 10 ml (166 mmol) of carbon disulfide, followed by overnight stirring at room temperature in an atmosphere of argon. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][CH2:16][O:17][CH3:18])[CH:6]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:7]1[C:8]([Br:19])=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1
Reactant: COCCc1cc(OCOC)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc(OCOC)cc(OCOC)c1Br
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(2-methoxyethyl)benzene (5.00 g, 19.5 mmol) obtained in Example 1, Step 3 was dissolved in N,N-dimethylformamide (40 mL). After the solution was cooled to 4° C., N-bromosuccinimide (3.47 g, 19.5 mmol) was added thereto, followed by stirring for 1 hour. To the reaction mixture was added water (0.10 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/1, 0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)benzene (5.7 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:25])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:35][CH2:36][OH:37]>CC(C)=O>[OH:37][CH2:36][CH2:35][O:24][C:20]1[CH:19]=[C:18]([C@@H:17]2[N:13]([C:10]3[CH:9]=[N:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=4)=[CH:12][N:11]=3)[C:14](=[O:25])[CH2:15][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: OCCI
Reactant: O=C1CC[C@H](c2cccc(O)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CC[C@H](c2cccc(OCCO)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Temperature: 70 °C
Reaction time: 65 h
Yield: 70.1 %

Procedure:
A mixture of (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-hydroxyphenyl)pyrrolidin-2-one (276 mg, 0.72 mmol), acetone (9 mL), K2CO3 (996 mg, 7.2 mmol) and 2-iodoethanol (1.86 g, 10.8 mmol) is stirred at 70° C. for 65 h. Then, acetone is removed by evaporation and the residue is dissolved in ethyl acetate (120 mL), washed with brine (20 mL) and dried over Na2SO4. After concentration, the residue is purified on silica gel (0-50% ethyl acetate in hexane) to give the title compound (215 mg, 70%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.12 (s, 1H), 7.99 (s, 1H), 7.37-7.32 (m, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.08-7.03 (m, 2H), 6.84-6.74 (m, 3H), 5.68 (dd, J=8.0, 3.2 Hz, 1H), 4.09-3.99 (m, 2H), 3.98-3.92 (m, 2H), 2.89-2.75 (m, 1H), 2.72-2.58 (m, 2H), 2.09-1.98 (m, 1H). HPLC-MS calculated for C22H20ClN3O4 (M+H+) 426.12, found 426.10.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].B(F)(F)F.CCOCC.[CH3:19][C:20]1([CH:26]=[CH2:27])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>O1CCOCC1.CCOCC>[CH3:19][C:20]1([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:26][CH2:27][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][CH:5]=2)[O:9]1
Reactant: Cc1cccc(O)c1C
Reactant: C=CC1(C)CCC(=O)O1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane. M.P.: 93-94° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[C:4]([CH3:20])[N:3]=1.[N+:21]([O-])([OH:23])=[O:22]>OS(O)(=O)=O.O.C([O-])([O-])=O.[Na+].[Na+]>[NH2:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1nc(N)ccc1CN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)c([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-6-methyl-5-(phthalimidomethyl)pyridine (3.00 g, 11.2 mmol) in H2SO4 (17 mL) at 0° C. was added HNO3 (583 μL) dropwise. The solution was stirred for 1 h at 0° C. and was then warmed to room temperature at which it was stirred for an additional 3 h. The reaction was diluted with water and neutralized with solid Na2CO3. The resulting orange precipitate was filtered and washed with water. Silica gel chromatography (gradient 3% MeOH/CHCl3 to 4% MeOH/CHCl3) afforded the title compound as a bright yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)[CH2:41][C:37]1[NH:36][CH:40]=[CH:39][N:38]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCOCc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCOCc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
The compound (81.2 mg) obtained in Example 60-4 was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 4 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The aqueous layer was washed with chloroform and then evaporated to dryness. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (63.0 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>C(C(C)=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: Oc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cccc2cc[nH]c12
Temperature: 55 °C
Yield: 90 %

Procedure:
To a stirred solution of 7-hydroxyindole and potassium carbonate (325 mg, 2.35 mmol) in methyl ethyl ketone (2.4 mL) was added iodobutane (1.24 mL, 10.8 mmol) at room temperature. After the mixture was heated at 55° C. for 12 h the solvent was removed and water was added. The mixture was extracted with EtOAc (3 times), dried over anhydrous MgSO4, filtered and evaporated. After chromatographic purification on silica gel, 7-n-butoxyindole was obtained in 90% yield (310 mg). 1H NMR (500 MHz, CDCl3) δ 8.39 (1H, brs), 7.23 (1H, d, J=8.0 Hz, 7.17 (1H, t, J=3.0 Hz), 7.01 (1H, t, J=7.5 Hz), 6.63 (1H, d, J=7.0 Hz), 6.53 (1H, t, J=2.5 Hz), 4.14 (2H, t, J=5.2 Hz), 1.88-1.80 (2H, m), 1.59-1.50 (2H, m), 1.00 (3H, t, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2cc(C(F)(F)F)cn2)c(C)c1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
To a mixture of 1-bromo-4-methoxy-2-methylbenzene (1.5 g, 7.5 mmol) in N,N-dimethylformamide (15 mL) was added 4-(trifluoromethyl)-1H-pyrazole (1.12 g, 8.21 mmol), copper(II) oxide (107 mg, 0.746 mmol), and cesium carbonate (4.86 g, 14.9 mmol). The mixture was heated in a microwave to 120° C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 1-(4-methoxy-2-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (550 mg, 29%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.81 (s, 1H), 7.74 (s, 1H), 7.16 (m, 1H), 6.74 (m, 2H), 3.77 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [S:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[S:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[C:2]#[N:3]
Reactant: N#CSc1ccc(N=C=O)cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Product: N#CSc1ccc(NC(=O)OCc2cccnc2)cc1
Yield: 47 %

Procedure:
To a solution of p-thiocyanophenyl isocyanate (5.25g., 0.0298 mole) in 100 ml. of benzene was added 3-pyridyl carbinol (3.25g., 0.0298 mole). An immediate exothermic reaction took place and a solid precipitated. After standing over the weekend 5.5g. of solid was isolated and after recrystallization from toluene this gave 4.0g. melting at 188°-191°C. This was a 47% yield of 3-pyridylmethyl N-(4'-thiocyanophenyl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.ClCCl>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[C:24]([O:26][CH3:27])=[N:25][C:20]([O:19][CH3:18])=[N:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (200.0 mg, 0.678 mmol) and 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) according to Method B except that the reaction was heated at 90° C. to fully dissolve the starting materials. After 4 hours, additional 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) was added and the reaction was refluxed overnignt. A third addition of 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) and an additional 5 mol % tetrakis(triphenylphospine)palladium(0) were required to force the reaction to completion. The reaction was then worked up as described in Method B using dichloromethane rather than ethyl acetate for the extraction and crystallizing the material obtained from the flash column from chloroform/hexanes to afford the title compound as a white solid (89.5 mg, 37%). 1H NMR (300.132 MHz, CDCl3) δ 8.47 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J=7.6, 2.1 Hz, 1H), 7.78-7.70 (m, 2H), 4.07 (s, 3H), 3.93 (s, 3H), 3.53 (dq, J=5.7, 7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). MS APCI, m/z=354 (M+H). HPLC 2.07 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) by reaction with trifluoroacetic acid in the presence of anisole according to the method of Example 28, Step G. Flash chromatography on silica gel (elution with 0.3% MeOH in CH2Cl2) yielded 60 mg (79%) of the product, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 576 (M+1)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:23]2[C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([O:27][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:24][C@H:23]2[C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere, the tert-butyldimethylsilyl chloride was added to a solution of compound 50 (750 mg, 1 eq.) and TEA (537 μL, 1 eq.) in DCM (6 mL). The reaction mixture was stirred overnight at room temperature and quenched with water. The organic layer was washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 51 in 70% yield.