Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[O:10][CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([C:23]([CH3:25])([CH3:24])[C:22]#[N:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)C#N
Reactant: COc1c(F)ccc(C)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C#N)ccc(C)c1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 54.4 %

Procedure:
14.48 g (91.56 mmol) of 2,6-difluoro-3-methylanisole is dissolved in 800 ml of toluene. After 272.2 ml (137.35 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added, 25.31 g (366.26 mmol) of isobutyronitrile is added in drops. The batch is stirred for 10 days at room temperature and then added to a 1 M HCl solution. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 10.32 g (49.5%) of the desired compound is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1>[C:2]1([C:15]2[C:14]([C:17]3[C:22]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1

Procedure:
The reaction is carried out as in Example 9 except that the 18.7 parts of 4-bromoanisole are replaced by 23.3 parts of 4-bromobiphenyl, and 110 parts of xylene are added as a solvent. After the reflux period, the reaction mixture is not steam distilled, but is cooled, and the solids present are collected by filtration, and washed on the filter with water and with 200 parts of toluene. The filter cake is dried, transferred to a Soxhlet extractor and continuously extracted for 96 hours with 100 parts of boiling dimethyl formamide. Quaterphenyl crystallises when the dimethyl formamide is cooled, and is collected and dried. 7.3 parts of quaterphenyl, m.p. 313°-317° are thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[S:17]([Cl:21])([CH3:20])(=[O:19])=[O:18]>N1C=CC=CC=1>[ClH:21].[CH3:20][S:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c2c(nc3ccccc13)CCN(S(C)(=O)=O)CC2
Product: Cl
Yield: 73 %

Procedure:
3-Methylsulfonyl-1,2,4,5-tetrahydro-11-methyl3H-azepino[4,5-b]quinoline hydrochloride was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-azepino[4,5-b]quinoline with mesyl chloride in pyridine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=1.[S-:14][C:15]#[N:16].[K+].BrBr>C(O)(=O)C.C1CCCCC1>[CH3:11][C:6]1[C:7]2[N:8]=[C:15]([NH2:16])[S:14][C:9]=2[CH:10]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=1
Reactant: N#C[S-]
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Agent: BrBr
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: Cc1cc(OC(F)(F)F)cc2sc(N)nc12
Yield: 71.1 %

Procedure:
The procedure is as in Example 1, starting with 4-trifluoromethoxy-2-methylaniline (0.65 g), potassium thiocyanate (1.3 g) and bromine (0.35 cc) in acetic acid (12 cc). After purification on a column of silica (200 g; particle size: 0.063-0.200 mm), eluting with a cyclohexane/ethyl acetate mixture (50:50 by volume), the white solid obtained (0.65 g) is ground in cyclohexane (20 cc), drained and dried at 60° C. under reduced pressure (1 mm Hg; 0.13 kPa), to give 4-methyl-6-trifluoromethoxy-2-benzothiazolamine (0.6 g), m.p. 162° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][NH2:31].[C:32]([O-])(O)=O.[Na+]>CC(O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][NH:31][C:16]1[N:15]=[N:14][C:13]([CH:11]([C:8]2[N:6]3[CH:7]=[C:2]([CH3:32])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)[CH3:12])=[CH:18][CH:17]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:14]=[N:15][C:16]([NH:31][CH2:30][C:23]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=4[O:21][CH3:20])=[CH:17][CH:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(C(C)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Product: COc1ccc(CNc2ccc(C(C)c3nnc4ccc(C)cn34)nn2)c(OC)c1
Temperature: 140 °C
Yield: 166.5 %

Procedure:
A mixture of 6-bromo-3-(1-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (650 mg, 1.920 mmol), (2,4-dimethoxyphenyl)methanamine (0.577 mL, 3.84 mmol), and NaHCO3 (645 mg, 7.68 mmol) in IPA (10.0 mL) was heated in a microwave on high absorbance for 18 hrs at 140° C. The reaction was cooled to ambient temperature, stripped to dryness via rotary evaporation, and reconstituted in EtOAc (25 mL). The insolubles were filtered off and the filtrate was reduced to dryness. The resulting residue was purified via MPLC (DCM:MeOH, 98:2) to provide the title compound, 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine 48E (750 mg, 1.598 mmol, 83% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=7.07 Hz, 3 H) 3.72 (s, 3 H) 4.37 (d, J=5.81 Hz, 2 H) 4.95 (d, J=7.07 Hz, 1H) 6.44 (dd, J=8.34, 2.53 Hz, 1 H) 6.54 (d, J=2.27 Hz, 1 H) 6.85 (d, J=9.35 Hz, 1H) 7.03 (s, 1 H) 7.12 (d, J=8.34 Hz, 1 H) 7.29 (d, J=9.35 Hz, 1 H) 7.45 (dd, J=9.73, 1.64 Hz, 1 H) 7.69-7.79 (m, 1 H) 8.59 (s, 1 H). ESI-MS:m/z 469.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([S:15][CH2:16][CH2:17]O)[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1.C(#N)C>[ClH:23].[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([S:15][CH2:16][CH2:17][Cl:23])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CC#N
Product: Cl
Product: ClCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
12.1 g (40 mmoles) of 5-benzyl-2-(2-hydroxyethylthio)-benzimidazole are reacted with 5.15 ml of thionyl chloride in a mixture of 100 ml of benzene and 10 ml of acetonitrile. After teh evolution of the gas is ceased, the reaction mixture is evaporated, 30 ml of ethyl alcohol are added to the residue and the solution is evaporated off again. The product thus obtained is purified by chromatography. It is dissolved in ethyl acetate, introduced onto the colomn and thereafter eluted with ethyl acetate then ethanol. The target compound appears in the third fraction, its weight is 8.26 g. M.p.: 140°-145° C.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH2:35])=[CH:28][CH:27]=1>O1CCOCC1.CC(N(C)C)=O>[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH:35][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:28][CH:27]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(I)c2c1OCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
4.0M HCl in Dioxane (0.37 ml) was added to a stirred suspension of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (500 mg) and 7-iodo-1,3-benzodioxol-4-amine (0.39 g) in DMA (1 ml). The resultant mixture was stirred and heated to 80° C. for 10 mins. A grey precipitate was formed which was filtered and washed with further DMA followed by diethyl ether and dried to give N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine as a beige solid (0.59 g); NMR Spectrum: (DMSOd6) 2.29-2.37 (m, 2H); 3.03-3.14 (m, 2H); 3.22-3.30 (m, 2H), 3.40-3.51 (m, 2H), 3.78-3.88 (m, 2H), 3.94-4.00 (m, 5H), 4.31 (t, 2H), 6.11 (s, 2H), 6.80 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H); Mass Spectrum: M+H+ 562.9.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([Br:24])[C:11]2=[O:25])=[CH:6][CH:5]=1.CN1CC[O:30][CH2:29][CH2:28]1.C(Cl)(=O)C.CN=C=O>CN(C)C=O.ClCCl>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:29](=[O:30])[CH3:28])=[CH:5][CH:6]=2)[C:11](=[O:25])[C:12]=1[Br:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN1CCOCC1
Reactant: NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Agent: CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC(=O)NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one hydrochloride (0.150 g, 0.389 mmol) was dissolved in N,N-dimethylformamide (3.5 mL). A stock solution of 4-methylmorpholine in N,N-dimethylformamide (1.5 mL, 1.0 M) was added and the reaction stirred at room temperature for 10 minutes. A stock solution of acetyl chloride in N,N-dimethylformamide (3.0 mL, 0.2 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at 200 RPM for 2 hours at room temperature. At this time the reaction was diluted with dichloromethane (4 mL) and treated with approximately 1.8 g of polyamine resin (2.63 mmol/g) and approximately 0.8 g of methylisocyanate functionalized polystyrene (1.7 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were further rinsed with dichloromethane (3×5 mL) and combined with the partially concentrated filtrate. The resulting filtrate was concentrated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) to give an off-white solid (0.083 g, 50%). 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J=7.79 Hz, 1H), 7.48-7.29 (m, 9H), 6.55 (d, J=7.79 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H), 1.98 (s, 3H). ES-HRMS m/z 427.0625 (M+H C21H19BrN2O3 requires 427.0652).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)=O.Cl.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([O-:22])=[O:21].[CH3:31][C:32](O)=[O:33]>O>[C:32]([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[N:30]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)=[CH:8][CH:9]=1)(=[O:33])[CH3:31]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(CCO)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 4,4,4-trifluoro-1-[4-(2-hydroxy-ethyl)phenyl]-1,3-butanedione (670 mg) and (4-nitrophenyl)hydrazine hydrochloride (439 mg) in AcOH (5 ml) and H2O (0.5 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 1M HCl. The organic layer was washed with 1M HCl for two times, saturated aqueous sodium bicarbonate solution for three times, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=10% and 15% to give 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate (501 mg) as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C1(P(O[NH2:50])(C2C=CC=CC=2)=O)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[N:27]([NH2:50])[C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(N)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
Sodium hydride (60% oily; 760 mg) was suspended in tetrahydrofuran (200 mL), and thereto was added dropwise a solution of tert-butyl {2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbamate (8.80 g) obtained by Reference Production Example 4 in tetrahydrofuran (50 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added O-(diphenylphosphoryl)-hydroxylamine (6.0 g) at room temperature, and the mixture was stirred at the same temperature for 15 hours. To the mixture were added water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (6.58 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][CH2:25]O)=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:27])([CH3:3])[CH3:2].C(#N)C.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].CS(Cl)(=O)=[O:40]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22][CH2:23][CH2:24][CH2:25][N:33]4[CH2:34][CH2:35][O:40][CH2:32][CH2:31]4)=[CH:20][CH:21]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:27])([CH3:2])[CH3:3]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(SCCCO)cc3)n2)n1C(C)C
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ncc(-c2ccnc(Nc3ccc(SCCCN4CCOCC4)cc3)n2)n1C(C)C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
4-(1-Isopropyl-2-methylimidazol-5-yl)-2-[4-(3-hydroxypropylthio)anilino]pyrimidine (Method 84; 250 mg, 0.65 mmol) was suspended in DCM (8 ml) and acetonitrile (2 ml) and the stirred at room temperature under nitrogen. Triethylamine (100 μl) was added followed by dropwise addition of methane sulphonyl chloride (50 μl). The mixture was stirred for 2.5 hours and then allowed to stand for 18 hours. The volatiles were removed by evaporation, the residue dissolved in acetonitrile (5 ml), and morpholine (120 μl) and potassium carbonate (50 mg) were added. The mixture was stirred and heated at 80° C. for 3.5 hours and then the volatiles were removed by evaporation. The residue was partitioned between EtOAc (50 ml) and water (20 ml). The aqueous layer was basified to pH 9 with sodium bicarbonate solution. The phases separated and the aqueous layer re-extracted with EtOAc. The extracts were combined, washed with water (10 ml) and brine (10 ml), dried and then evaporated to give the title compound (260 mg, 88%) m/z 453.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[C:3]=1[CH3:19].N12CCCN=C1CCCCC2.Cl[CH:32]([F:34])[F:33].O>CN(C)C=O>[F:33][CH:32]([F:34])[O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:3]=1[CH3:19]
Reactant: Cc1c(O)ccnc1CSc1nc2ccccc2[nH]1
Reactant: FC(F)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(OC(F)F)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
In N,N-dimethylforamide (DMF) (100 ml) was dissolved 2-[(4-hydroxy-3-methyl-2-pyridyl)methylthio]benzimidazole (10.5 g). To the solution was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (7.1 g), to which was introduced chlorodifluoromethane for 3 hours at room temperature. The reaction mixture was poured into water (500 ml), which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to a silica gel column chromatography. From the portion eluted with chloroform-methanol (100:1, v/v), 2-[(4-difluoromethoxy-3-methyl-2-pyridyl)methylthio]benzimidazole was obtained (2.5 g, 20%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[C:36]([CH3:41])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[C:36]([CH3:41])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: Cc1cccc2c1CCC2N
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3c(C)cccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-4-methyl-indane
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[P:15]([Cl:20])(Cl)(Cl)(Cl)[Cl:16].C(O)=[O:22]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:12][P:15]([Cl:20])([Cl:16])=[O:22])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(N)=O)cc1
Reactant: O=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc(C(=O)NP(=O)(Cl)Cl)cc1

Procedure:
A mixture of 76 g (0.39 mole) of 4-butoxybenzamide, 81.9 g (0.39 mole) of phosphorus pentachloride and 700 ml of AR carbon tetrachloride was heated at 70° for 30 min. The resulting solution was cooled to 30° and 18.7 g (0.39 mole) of 97% formic acid was added. The reaction was chilled to 0°, filtered, washed with AR carbon tetrachloride and air-dried to give 52.1 g, m.p. 97°-98°.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH:11]1[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][N:11]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: COC(=O)C1CNC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-formylbenzonitrile (510 mg, 3.89 mmol), methyl azetidine-3-carboxylate (590 mg, 3.89 mmol), acetic acid (0.245 mL, 4.28 mmol) and ˜1 gm of powdered 4 Angstrom molecular sieves in DCE (15 mL) was stirred briskly at RT for 1 hr. At this time, sodium triacetoxyborohydride (907 mg, 4.28 mmol) was added and the reaction mixture was stirred at RT for 2 hr. After filtering through a sintered glass funnel, the filtrate was concentrated to a residue that was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford a colorless oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions were concentrated to afford methyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (765 mg, 3.32 mmol). HPLC retention time=0.49 minutes [broad peak] (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=231.23. 1H NMR (400 MHz, CDCl3) δ ppm 3.32-3.36 (m, 3H) 3.49-3.58 (m, 2H) 3.67 (s, 2H) 3.72 (s, 3H), 7.39 (d, J=8.6 Hz, 2H) 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[CH:8]=[N+:9]([O-:12])[C:10]=2[CH:11]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O>[CH2:25]([O:24][CH2:23][C:14]1[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:11][C:10]=3[N+:9]([O-:12])=[CH:8][C:7]=2[N:13]=1)[CH3:26]
Reactant: CCOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: C1CCNCC1
Solvent: O
Product: CCOCc1nc2c[n+]([O-])c3cc(N4CCCCC4)ccc3c2n1CCCOC(C)C
Temperature: 150 °C

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline-5-oxide (0.500 g), water (4.0 mL), and piperidine (1.0 mL) were added sequentially to a 20 mL steel pressure vessel. The vessel was sealed and then heated in an oven at 150° C. for 16 hours. The reaction mixture was allowed to cool and then was extracted with chloroform (×2). The combined extracts were washed sequentially with water and brine and then dried over sodium sulfate. This material was combined with that from another run on the same scale and then purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge and eluting with a gradient of 2-22% CMA in chloroform to provide 0.137 g of 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-(piperidin-1-yl)-1H-imidazo[4,5-c]quinoline-5-oxide as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:51][S:48]([C:45]3([CH3:44])[CH2:47][CH2:46]3)(=[O:50])=[O:49])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CC1(S(N)(=O)=O)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 58.1 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (105 mg, 0.177 mmol) and 1-methyl-cyclopropanesulfonic acid amide (31 mg, 0.23 mmol, prepared as described above). Flash chromatography (2% methanol/methylene chloride) gave 73 mg (58%) of [18-(isoquinolin-1-yloxy)-4-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: LC-MS (Method A, retention time: 3.50 min), MS m/z 710 (M++1).