Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16]([C:39]([F:42])([F:41])[F:40])=[N:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:48])([F:49])[CH2:44]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16]([C:39]([F:40])([F:41])[F:42])=[N:17][NH:18][CH:19]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)c2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c[nH]nc3C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of crude 5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, triethylsilane in TFA was stirred at room temperature for 3 h, concentrated and subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as white solid. MS (m/e): 431.3 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].Cl.[NH2:23][OH:24].C(N(CC)CC)C>CO>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[N:3][O:2][CH3:1])[C:20](=[N:23][OH:24])[NH2:21]
Reactant: NO
Reactant: CON=C(C#N)c1ccccc1COc1ccccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C(N)=NO)c1ccccc1COc1ccccc1C
Yield: 67 %

Procedure:
A mixture of part of the sample of isomer 1 of 2-(2-methylphenoxymethyl) benzoyl cyanide O-methyloxime (280 mg), hydroxylamine hydrochloride (80 mg) and triethylamine (110 mg) in methanol (5 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated and the residue, dissolved in ethyl acetate, was washed with water, dried, concentrated, and chromatographed using ethyl acetate:hexane (1:1) as eluant to give two stereoisomers of 2-[2-(2-methylphenoxymethyl)phenyl]-2-methoxyimino acetamide oxime. Isomer I (200 mg, 67% yield), eluted first, was a white solid, mp 140° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.05 (2H,s) ppm. Isomer II (100 mg, 33% yield), was also a white solid, mp 110°-2° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.2 (2H,s) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl-].[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:18]([O:17][CH3:16])=[O:28])=[CH:20][CH:21]=3)=[O:24])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
1,2,3,4-Tetrahydro-1,1,4,4-tetramethylnaphthalene (10.0 g, 53.2 mmol) and terephthalic acid monomethyl ester chloride (10.0 g, 50.5 mmol) were dissolved in dichloromethane (50 ml) and the mixture was added with AlCl3 (14.3 g, 107.5 mmol) over 10 minutes under ice cooling. After reflux for 1 hour, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried, and then concentrated to give methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoate (Compound 43, 18.5 g, 99%). A part of the product was recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:28][S:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:28][S:29][CH3:30])=[O:5]
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: CSCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CSC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a solution of 2.0 g (7.8 mmol) of the compound of Example 45 in 30 mL dry THF was added 7.9 mL (7.9 mmol) sodium bis(trimethylsilyl)amide (1.0 M in THF). To the resulting mixture was added 1.0 g (10.4 mmol) chloromethyl methylsulfide. The mixture was stirred for 15 min and another 0.65 g (6.7 mmol) of chloromethyl methylsulfide was added. Stirring at RT was continued for 1 h and the mixture was then heated to reflux for 28 hours. The mixture was allowed to cool to RT and was then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO4), and was filtered through silica gel. The filtrate was evaporated in vacuo and the residue was chromatographed (HPLC, 8% ethyl acetate/hexane) to yield 1.1 g (45%) of a colorless oil. nD25=1.5526.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-chloro-phenyl isocyanate (0.073 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 45 as a colorless solid (0.097 g, 54%). LCMS m/z (%)=421 M+H+ (37Cl, 53), 419 M+H+ (35Cl, 77) 1H NMR (400 MHz, CDCl3) δ: 7.689 (bs, 2H), 7.617 (s, 1H), 7.460 (d, J=2.62 Hz, 1H), 7.438 (d, J=2.52 Hz, 1H), 7.22-7.28 (m, 3H), 6.947 (d, J=8.93 Hz, 1H) 4.245 (m, 1H), 3.808 (s, 3H), 1.575 (d, J=6.35 Hz, 3H), 1.381 (d, J=6.35 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[CH:21][CH:22]=1.[OH-].[K+].O>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH:13]=[CH:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
To a stirred solution containing 196 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone and 150 mg of anisaldehyde in 3 ml of ethanol was added 50% aqueous potassium hydroxide (3 ml). After being stirred at room temperature for 3 days, the mixture was poured into 30 ml of cold water. The mixture was then extracted with three 30 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to give a crystalline residue. Recrystallization of the residue from methanol gave 182 mg (50% yield) of 2'-hydroxy-4,4',6'-trimethoxychalcone as yellow needles: m.p. 110.7° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:15])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Product: N#Cc1cc(F)cc(C(=O)Cl)c1

Procedure:
1.65 g (10.0 mmol) 3-cyano-5-fluorobenzoic acid were boiled for 2 h with 7.27 mL (100 mmol) thionyl chloride with stirring. The reaction mixture was evaporated to dryness i. vac. and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]1([C:19]#[C:20][CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:20]([CH:21]=[O:22])[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: O=CC#Cc1ccccc1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: O=Cc1nn2c(=O)[nH]c3ccccc3c2c1-c1ccccc1

Procedure:
4.8 g (0.030 mole) of 3-diazooxindole is suspended in 350 ml of benzene and 3.9 g (0.030 mole) of phenylpropargylaldehyde added. The reaction mixture is refluxed under nitrogen for 48 hours.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1>O.CS(C)=O>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4](=[O:1])[NH:9][CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: CN1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1:1; 15 mL) at 80° C. was added 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (obtained in Step 1 above; 2.5 g, 12 mmol). After being stirred for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 0.96 g (43%) of the title compound as an off-white solid. HPLC purity: 88%. MS m/z 195 (M+H)+. HRMS m/z calcd for C9H14N4O (M)+ 194.1168, found 194.1159.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[Na].[OH2:21]>C(O)CCC>[CH2:11]([O:21][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: O
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
7-Fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) was added to a solution of sodium (0.9 g) in butanol (50 ml) and the mixture was heated at 100° for 19 hours. The mixture was poured into water (200 ml). The resulting precipitate was collected and recrystallised twice from industrial methylated spirit to give the novel compound 7-butoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 187°-190°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[F:12][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=[C:3]([CH2:2][C:13]#[N:14])[CH:4]=1
Reactant: [C-]#N
Reactant: Fc1cc(CCl)cc2c1OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(F)c2c(c1)OCO2
Temperature: 30 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3 mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/E.A.=10/1) to afford 2-(7-fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 6.68-6.64 (m, 2H), 6.05 (s, 2H), 3.65 (s, 2H). 13C-NMR δ151.1, 146.2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)C[O:20]CCO.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:20])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: OCCOCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 2.186 g of diethylene glycol (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a third dimeric fluorenone derivative, which was a yellow solid (5.0 g, 47% yield). The product had a melting point of 137° C. A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 3.88–4.00 (t, 4H); 4.56–4.65 (t, 4H); 7.15–7.34 (m, 4H); 7.40–7.49 (td, 2H); 7.61–7.68 (d, 2H); 7.71–7.77 (dd, 2H); 7.85–7.92 (dd, 2H); 8.20–8.27 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: COc1ncc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
A suspension of 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (140 mg, 0.38 mmol) in THF (2 mL) at 0° C. was treated with methylmagnesium bromide (1.9 mL of 1.4 M in toluene/THF=75/25, 2.65 mmol). The reaction mixture was stirred at 0° C. for 5 min followed by RT for 30 min and then quenched with sat. NH4Cl solution and extracted with EtOAc. The organic layer was concentrated and purified on a silica gel column eluting with 5-10% MeOH in DCM to give 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-2-ol (50 mg, 34%) as a yellow crystalline solid. m/z (ESI, +ve ion) 386.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (br., 1H); 8.95 (d, J=2.6 Hz, 1H); 8.43-8.37 (m, 3H); 7.89 (s, 1H); 7.73 (s, 1H); 5.15 (s, 1H); 3.93 (s, 3H); 2.45 (s, 3H); 1.47 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=O)[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:13][CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethylthiochroman (Compound 61) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 degrees C, 0.7 mm) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([Cl:30])=[C:22]([Cl:31])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:7][CH:6]=2)[CH2:2]1.C(N(CC)CC)C.[N:39]([CH3:42])=[C:40]=[O:41]>CN(C=O)C>[Cl:31][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH:3]4[CH2:4][N:1]([C:40]([NH:39][CH3:42])=[O:41])[CH2:2]4)=[CH:6][CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[Cl:30]
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CC(c3ccc(C4CNC4)cc3)=NO2)cc(Cl)c1Cl
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)N1CC(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(C(F)(F)F)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-(azetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.05 mmol) was dissolved in DMF (1 mL); triethylamine (0.20 mmol) was added, followed by a solution isocyanatomethane. The resulting solution was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the crude product purified by preparative HPLC to give 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-N-methylazetidine-1-carboxamide (11.2 mg) MH+ 540.1; retention time 6.14 minutes.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH3:32])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([CH:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]1[CH3:32])=[O:20]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)C1c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc2N(C)C1C

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carbyxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.41 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=3.20 Hz), 7.74 (1H, d, J=11.68 Hz), 7.30 (1H, s), 6.94 (1H, d, J=8.66 Hz), 6.62 (1H, d, J=5.5 Hz), 4.64–4.59 (2H, m), 4.20–4.15 (2H, m), 3.63 (3H, s), 2.85 (3H, s), 2.57 (3H, s), 2.44–2.36 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 435. found 435.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NCC2

Procedure:
A mixture of 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine (12 g, 0.063 m) and 10% palladium-on-carbon (1.2 g) in acetic acid (200 ml) was shaken in an atmosphere of hydrogen (60 psi), degassed, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and filtered to give 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]1[N:11]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[C:10]2[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=2[N:8]=1.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH:29]=[CH:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]1[N:11]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[C:10]2[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=2[N:8]=1)([OH:32])=[O:31]
Reactant: OC[C@H]1O[C@@H](n2c(NCc3cccc(Br)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 26.5 %

Procedure:
2-(3-Bromobenzylamino)-1-(β-D-ribofuranosyl)-1H-benzimidazole (200 mg), acrylic acid (112 mg), palladium acetate (10 mg) and tri-o-tolylphosphine (28 mg) were suspended in acetonitrile (2 mL). To the mixture was added triethylamine (0.3 mL), and the mixture was stirred at 100° C. for 10 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (52 mg).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([O:25][C:26](OC4C=CC=CC=4)=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:35])=[N:13]2)=[CH:8][CH:7]=1.C(OC(C)C)(C)C>C(#N)C>[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([O:25][C:26]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:35])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: NC1CC1
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: O=C(NC1CC1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 81.4 %

Procedure:
Cyclopropylamine (2.85 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (4.3 g.) in acetonitrile (43 cc.), and the suspension obtained is stirred for 20 hours at a temperature of about 20° C. Diisopropyl ether (85 cc.) is then added, after which the insoluble product is filtered off and washed with diisopropyl ether (2 × 10 cc.). Recrystallisation from acetonitrile (130 cc.) gives 2-(7-chloro-1,8-naphthyridin-2-yl)-3-cyclopropylaminocarbonyloxy-isoindolin-1-one (3.2 g.) melting at 220° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[N:6]=[CH:5][C:4]([C:3]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 79 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 79%) which was obtained as a white solid. MS: m/e=381.3 [M+H]+.