Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=2[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCOCC1>[CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a solution of methyl 4-cyclopentyl-3-(trifluoromethyl)benzoate (8.16 g, 30.0 mmol) in 1,4-dioxane (200 mL) was added lithium borohydride solution (2 M in tetrahydrofuran, 30.0 mL, 59.9 mmol). The mixture was heated under reflux for 2.5 h. The mixture was allowed to cool to room temperature and carefully quenched with 1N aqueous HCl solution to pH 5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatograhy to give the title compound as a colorless oil (1.21 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.63 (m, 2H), 1.66-1.77 (m, 2H), 1.81-1.91 (m, 2H), 2.03-2.15 (m, 2H), 3.37 (quintet, J=8.00 Hz, 1H), 4.71 (d, J=4.29 Hz, 2H), 7.45-7.47 (m, 1H), 7.49 (d, J=1.14 Hz, 1H), 7.60 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C)cn1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 2-bromo-5-methylpyridine [purchased from TCI] (0.827 g, 4.81 mmol), (5-(tert-butyl)-2-methoxyphenyl)boronic acid [Intermediate 5] (1.2 g, 5.77 mmol) and potassium carbonate (0.997 g, 7.21 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (277.8 mg, 0.24 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 35% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-methoxyphenyl)-5-methylpyridine (1.216 g, 99% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.CO.N.[SH2:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[S:36])[NH2:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reactant: S
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=S)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 48 h
Yield: 70 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]-benzamide (50 mg, 0.11 mmol) and 1:2 methanol:tetrahydrofuran (3 mL); and the solution was treated with ammonia (g), sealed, and allowed to stir for 2 days. The mixture was then treated with hydrogen sulfide (g), sealed and allowed to stir for 2 days. The mixture was concentrated and the residue purified by column chromatography (SiO2: 2% methanol in methylene chloride) affording 38 mg (70%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.[CH:26]1([C:32]2C=C[C:35]([OH:38])=[CH:34][CH:33]=2)CCCC[CH2:27]1.C(OC)(=O)C#CCCC>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:35](=[O:38])[CH:34]=[C:33]([CH2:32][CH2:26][CH3:27])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: CCCC#CC(=O)OC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Yield: 27 %

Procedure:
(S)-5-(4-Cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.37 g, 1.35 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, was dissolved in ethanol (6 mL). Methyl 2-hexynoate (0.34 g, 2.70 mmol) was then added and the reaction mixture was heated at reflux for 24 hrs and then cooled to room temperature. The resulting crystalline solid was isolated by filtration, washed with heptane 3 times, and dried under vacuum to afford 135 mg (27% yield) of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(phenyloxy)ethyl 2-propenoate (5 g, 26.0 mmol) in dichloromethane (50 mL), was cooled to 0° C. Chlorosulfonic acid (5.21 mL, 78 mmol) was added dropwise over 15 minutes at 0° C. then the mixture was allowed to warm to room temperate over 30 minutes. The reaction mixture was stirred overnight (16 hours) at room temperature. The solution was then poured onto ice and extracted with dichloromethane (3×50 mL). Resulting emulsion was diluted with ethyl acetate (200 mL) and brine (50 mL) in order to achieve separation of phases. The aqueous layer was further extracted with ethyl acetate (100 mL). The combined organic fractions were dried with magnesium sulphate then evaporated in vacuo to give an oily solid, which was dried under high vacuum overnight. After drying, a sticky solid was isolated (3.2 g) and this was taken on to the next step without further purification. LCMS [LCMS1] Rt 0.47 min, m/z (ES−) 272 (M−Cl+OH).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)[CH3:2].[I-:12].[Na+].ClN>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([I:12])[C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2]
Reactant: CCc1ccc(O)c(C=O)c1
Reactant: [I-]
Agent: NCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(I)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 30.0 g of 5-ethyl-salicylaldehyde (Reg. No. 52411-35-5) in 500 ml of DMF was treated with 36.0 g of sodium iodide and 67.6 g of Chloroamine T and stirred for one hour at room temperature. The reaction mixture was concentrated in a high vacuum, poured into ice-water, made acid with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were washed with aqueous sodium thiosulphate solution, saturated sodium chloride solution and ice-water, dried over sodium sulphate and concentrated. The residue was taken up in ether-hexane (1:1) and filtered. The filtrate was concentrated and gave 45.8 g of 5-ethyl-2-hydroxy-3-iodo-benzaldehyde; MS (EI) m/z 276 M+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Solvent: O
Product: CCOC(=O)C(CC)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1

Procedure:
A mixture of ethyl-2-(p-aminobenzyl)-butyrate (4.4 g) and phthalic anhydride (3 g) is heat melted until ceasing of water evolution (5 minutes). After cooling, the solid as obtained is crystallized from ethanol. Yield: 4.8 g (68.6%); m.p. 86°-87° C. Analysis:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
6-(3,5-dichloro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3,5-dichlorophenyl boronic acid according to the procedure of Example 4, as a white solid: mp 245-246° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.77 (m, 2H), 7.67-7.64 (m, 2H), 7.56 (bs, 1H), 6.96 (d, 1H, J=7.98 Hz), 1.7 (s, 6H); MS (EI) m/z 321 ([M+H]+, 40%); Anal. Calcd. For C16H13Cl2NO2: C, 59.32; H, 4.11; N, 4.32. Found: C, 59.13; H, 4.29; N, 4.17.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:18](OC(OCC)OCC)C>>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[N:1]=[CH:18][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: COc1cccc(C(=O)Nc2nnn[nH]2)c1N
Reactant: CCOC(OCC)OCC
Product: COc1cccc2c(=O)n(-c3nnn[nH]3)cnc12

Procedure:
A suspension of 5.3 g of 2-amino-3-methoxy-N-(1H-tetrazol-5-yl)benzamide in 30 ml of triethoxymethane was refluxed for 14 hours to give 8-methoxy-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 260°-261° C. (dec) after recrystallization from dimethylformamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][C:15]([CH2:17][OH:18])=[CH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][C:15]([CH2:17][O:18][Si:30]([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31])=[CH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCCC(CCOCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1=CCCC(CCOCc2ccccc2)C1
Yield: 53.4 %

Procedure:
Intermediate R3 was dissolved in THF (100 mL) and added to a solution of DIBAL (70 mL, 1M in hexanes) in THF (160 mL) at −35° C. for 35 minutes. The mixture was quenched with Rochelle's salt solution, and extracted with ether. The dried residue was purified by chromatography on SiO2 with 30% EtOAc:Hx to yield [5-(2-benzyloxy-ethyl)-cyclohex-1-enyl]-methanol 4.6 g (80%). A solution of the alcohol (4.0 g, 18.7 mmol) in DMF (60 mL) was treated with triethylamine (3 mL) followed by TBSCl (3.0 g, 22.4 mol) for 20 minutes at room temperature. The residue was isolated from an aqueous work-up and purified by chromatography to give [5-(2-benzyloxy-ethyl)-cyclohex-1-enylmethoxy]-tert-butyl-dimethyl-silane (Intermediate R4) 3.6 g (63%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:17](=[O:24])[NH:18][C:19]1([C:22]#[N:23])[CH2:21][CH2:20]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[C:22]([C:19]1([NH:18][C:17]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:12][NH:8]2)=[O:24])[CH2:20][CH2:21]1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.39 mmol) in dichloromethane was added trifluoroacetic acid (0.5 ml, 6.99 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 16 h. After complete consumption of starting material, the reaction mixture was evaporated in vacuo to get the crude title compound (500 mg, 1.39 mmol; quant.) which was used in next step without further purification. MS: m/z=258.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:44][C:45]([O:47][CH3:48])=[O:46])=[CH:34][CH:33]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:48][O:47][C:45]([NH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:27])[CH3:26])[C:15]2=[O:25])=[CH:37][CH:36]=1)=[O:46]
Reactant: COC(=O)Nc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 222 mg (0.594 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Step I) in 6 mL of dry dimethylformamide was treated with 30 mg of 60% sodium hydride oil dispersion (18 mg NaH, 0.75 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added 190 mg (0.594 mmol) of solid 4-bromomethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate followed by 50 mL of water. The organic layer was washed with water (4×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride/methanol (100:3) to give 231 mg (0.376 mmol, 63%) of the product. 1H NMR (400 MHz, CDCl3): 1.23 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 1.85 (m, 1H), 2.40 (dd, 2H), 2.49 (m, 1H), 2.54 (m, 2H), 3.68 (s, 3H), 4.53 (m, 1H), 4.94 (d, 1H), 5.17 (d, 1H), 6.53 (br s, 1H), 6.66 (d, 1H), 7.2 (m, 12H), 8.09 (d, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2([C:28]#N)[CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C[OH:31].Cl>CN(C=O)C.O>[O:31]=[C:28]1[C:24]2([CH2:27][CH2:26][CH2:25]2)[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[C:2](=[S:3])[N:1]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=1
Reactant: CO
Reactant: Cc1ccc(NC2(C#N)CCC2)cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1a (0.912 g, 4 mmol) and 7a (0.558 g, 3 mmol) in dry DMF (0.5 ml) was stirred at room temperature for 24 h. To this mixture were added methanol (30 ml) and HCl aq. 2N (6 ml). The second mixture was refluxed for 6 h. After being cooled to room temperature, the reaction mixture was poured into cold water (50 ml) and extracted with ethyl acetate (60 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7c (0.959 g, 2.31 mmol, 77%) as a white powder.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26][CH:25]=5)[CH2:19][C:18]=4[CH:34]=3)[CH:12]=[CH:13][C:7]=2[N:6]=1.F[P-](F)(F)(F)(F)F.Cl[C:44](N(C)C)=[N+](C)C.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:44][N:4]([CH3:3])[C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26][CH:25]=5)[CH2:19][C:18]=4[CH:34]=3)[CH:12]=[CH:13][C:7]=2[N:6]=1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Reactant: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CN(C)c1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Yield: 47.7 %

Procedure:
A solution of 4-(4-quinolin-4-yl-2,3,4,5-tetrahydrobenzoxazepin-7-yl)benzene-1,2-diamine (example 2) (50 mg, 0.13 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (44 mg, 0.16 mmol) and N-methylmorpholine (0.20 g, 1.9 mmol) in N,N-dimethylformamide (10 mL) was heated to 140° C. for 1 hour. After cooling the reaction was diluted with ethyl acetate (80 mL), and washed twice with water (2×20 mL) and brine (20 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid residue. The residue was then taken into N,N-dimethylformamide (3 mL), then diluted with chloroform (15 mL). The resulting solid was collected by filtration and the filter cake was precipitated once more using the same technique to give N,N-dimethyl-6-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine (27 mg, 48% yield) as a gray powder. 1H NMR (400 MHz, d6-DMSO): 8.56 (d, 1H), 8.30 (d, 1H), 8.06-7.97 (m, 2H), 7.90 (br s, 1H), 7.72 (t, 1H), 7.62 (br s, 1H), 7.56 (m, 2H), 7.48 (d, 1H), 6.99 (dd, 2H), 5.28 (s, 2H), 4.61 (s, 2H), 4.38 (s, 2H), 3.28 (s, 6H); MS (EI) for C27H25N5O: 436 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)[CH:16]=2)[NH:11][CH:10]=1.[H-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[OH2:36]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][N:20]([S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])[N:19]=3)[CH:16]=2)[N:11]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:32])=[O:36])[CH:10]=1
Reactant: O
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cc[nH]n3)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccn(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Reaction time: 19 h
Yield: 68.4 %

Procedure:
3-(2-Methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.12 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled in an ice bath. Sodium hydride (60% oil dispersion, 103 mg, 2.58 mmol) was added, followed by p-toluene-sulfonylchloride (TsCl) (361 mg, 1.89 mmol). After stirring 19 h, deionized water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (1×) and brine (1×) and dried over sodium sulfate. The material was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-5-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (458 mg, 68.4%). MS: m/z 599 (M+H+).
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]([Br:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCc1ccc(C=C(Br)Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C=C(Br)Br)cc1
Yield: 64.6 %

Procedure:
The above alcohol (3.18 g) was oxidised using the conditions of Swern oxalyl chloride, 0.96 ml, dimethyl sulphoxide, 1.56 ml; triethylamine, 6.9 ml) in dichloromethane to give 4-(2,2-dibromoethenyl)benzaldehyde (2.04 g). NMR 1H 10.94 (1H,s), 7.86(2H,d), 7.61(2H,d), 7.45(1H,s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:28]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc(Oc2ccccc2)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 3-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenoxybenzamide as a white powder, m.p. 105.0-107.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.4 Hz, 1H), 8.34 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.2 Hz, 1H), 7.58-7.29 (m, 9H), 7.19-7.13 (m, 2H), 7.04-6.99 (m, 2H), 4.65 (t, J=7.2 Hz, 2H), 3.28 (m, 2H), 1.89 (quintet, J=7.2 Hz, 2H), 1.58 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 451.2012 (451.2008 calcd for C27H25N5O2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>C(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:14](=[O:26])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 264 h
Yield: 29.5 %

Procedure:
To a stirred solution of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine 1-carboxylate (48 g, 220 mmol) in chloroform (900 mL) was added ruthenium (IV) oxide hydrate (6.0 g, 45 mmol) followed by a solution of sodium periodate (150 g, 700 mmol) in water (900 m L). The resulting heterogenous reaction mixture was stirred at room temperature for 11 days before being filtered through a short column of celite. The organic layer was removed and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with a 10% solution of sodium thiosulfate in water twice, and once with brine. This solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, 20% EA/hexanes) to give 22.5 g (64.8 mmol) of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-2-oxopiperidine-1-carboxylate (29%).