Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH:28](O)=O>>[Cl:27][C:25]1[CH:26]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[C:9]([O:21][CH3:22])[CH:8]=3)[CH:28]=[N:1]2)=[CH:23][CH:24]=1
Reactant: O=CO
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2cnc3cc(Cl)ccc3c2=O)ccc1OCCN1CCCC1
Yield: 91 %

Procedure:
2-Amino-4-chloro-N-{3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl}benzamide (11.6 mmol, 4.5 g) was dissolved in 90 mL 88% formic acid and was heated to reflux for 3 h. The solvents were removed by rotary evaporation and the residue was purified by silica gel column chromatography affording the lo product (4.2 g, 91%). 1H NMR (DMSO-D6): δ 1.82 (4H, m), 2.65 (4H, m), 2.88 (2H, t, J=6.2 Hz), 3.88 (3H, s), 4.20 (2H, t, J=6.4 Hz), 6.89-6.91 (2H, overlapping), 7.01 (1H, d, J=10.1 Hz), 7.49 (1H, d, J=8.6 Hz), 7.76 (1H, s), 8.12 (1H, s), 8.29 (1H, d, 8.7 Hz). LCMS m/z=400 (m+H+).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6](=[C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl.O>O1CCCC1.[Cl-].[Na+].O>[CH:15]1([CH:12]2[CH2:13][CH2:14][C:9](=[C:6]3[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC1(OC)CCC(=C2CCC(C3CCCCC3)CC2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(=C2CCC(C3CCCCC3)CC2)CC1
Yield: 107.8 %

Procedure:
A solution of 4-(4'-cyclohexylcyclohexylidene)cyclohexanone dimethyl ketal (0.016 mol) and 1.0 N HCl (100 ml) in tetrahydrofuran (125 ml) was left at room temperature for 2.5 hours at which time TLC indicated hydrolysis to be complete. Water and brine were added to the reaction solution and the mixture was extracted with ether (4×). The pooled ether extracts were washed with brine, dried (Na2SO4), filter and concentrated to give 4.49 g of white solid. This solid was chromatographed (790 g of 40-63 μm silica gel, 4.5 1 of 5% ethyl acetate-hexane followed by 10% ethyl acetate-hexane)with4-(4'-cyclohexylcyclohexylidene)cyclohexanonedimethylketal(0.56 g, 10%) eluted first followed by the title compound. Recrystallization of the title compound from hexane gave colorless crystals, mp 81°-81.5° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32]>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:33][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC(C)CCC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCC(C)C

Procedure:
In 35 ml of acetone is dissolved 1.0 ml of 4-methylvaleric acid, and 4.6 ml of 2N-NaOH and then 1.9 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added to the above solution. The mixture is refluxed for 6 hours. The acetone is distilled off under reduced pressure and 10 ml of water is added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is subjected to column chromatography, elution being carried out with 600 ml of diisopropyl ether-n-hexane (1:1). The eluate is evaporated under reduced pressure to remove the solvent, giving 1.3 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccc(NC(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 56 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) was reacted with benzenesulfonyl chloride to yield 112 mg (56%) of the title compound as a white solid.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](C(O)=O)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CCOCC>[C:11]([O:10][C:6]([C@H:19]1[CH2:20][CH2:21][C@H:16]([OH:15])[CH2:17][CH2:18]1)=[O:5])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
N,N-Dimethylformamide di-tert-butyl acetal (7.4 ml, 31 mmol) was added to a solution of trans-4-hydroxy-cyclohexanecarboxylic acid (1.484 g, 10.29 mmol) in toluene (8.5 ml), and the mixture was stirred at 80° C. for 25 hours. The reaction mixture was diluted with ether, and the organic layer was sequentially washed with water, an aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give trans-4-hydroxy-cyclohexanecarboxylic acid tert-butyl ester as a colorless solid (838 m, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:19])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].COCC(O)=O.S(Cl)(Cl)=O>CC(N(C)C)=O>[OH:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:4]1[C:5]([I:12])=[C:6]([C:10]([I:11])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][O:21][CH3:20])[C:3]=1[I:19])[C:7]([OH:9])=[O:8]
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCCO)c1I
Reactant: COCC(=O)Cl
Agent: COCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCCO)c1I

Procedure:
Analogously to Example 1(c), 90.3 g. (150 mmol) of 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodoisophthalamic acid and methoxyacetyl chloride, freshly prepared from 45.5 ml. of methoxyacetic acid/43.5 ml. of thionyl chloride, are reacted in dimethylacetamide; yield: 84.7 g. (84%) m.p. 285° C., with decomposition.
Reaction SMILES: S1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH:25]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=3)=[O:15])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O[O:33][S:34]([O-:36])=O.[K+]>CO.O>[O:33]=[S:34]1(=[O:36])[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH:25]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=3)=[O:15])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=S([O-])OO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3sccc3c2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)C=CS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.7 %

Procedure:
To a solution of 3-(1-benzothien-5-yloxy)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (178 mg, 0.41 mmol) in methanol (3 mL) at 0° C. was added dropwise a solution of oxone (752 mg, 1.22 mmol) in water (3 mL). The resultant cloudy slurry was allowed to warm to RT and stir for 16 hours. Water (20 mL) was added and the mixture extracted with DCM (3×20 mL). The combined extracts were dried (MgSO4), filtered and evaporated. The material was chromatographed on silica, eluting with 0-3% methanol in DCM, to give the desired compound as yellow oil (113 mg). m/z 470 (M+H)+
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br-:19].[Li+]>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6]([Br:19])=[O:7])(=[O:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
2,3,4-Triacetoxybutanoyl chloride (39.9 g, 0.142 mol), prepared according to the liteature procedure Glattfeld, J. and Kribben, B., J.Am. Chem. Soc. 61 (1939) 1720) was mixed with lithium bromide (30.9 g, 0.356 mol) in methylene chloride (400 ml) and stirred at ambient temperature for 24 h. The mixture was filtered, the solid was washed with additional methylene chloride (50 ml) and the filtrate was evaporated at ambient temperature to give 45 g (97%) of the crude product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Cl>CC(N(C)C)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCCCc2ccccc2O)cc(OC)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCC1CO1
Solvent: CC(=O)N(C)C
Product: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Yield: 79.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), 1.9 g of 2-[4-(3,5-dimethoxyphenyl)butyl]phenol (prepared as described in Preparation 9), 0.75 g of potassium t-butoxide and 0.91 g of epichlorohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified to give 1.81 g (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10].O>C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: CCn1c(=O)c2cc(C=O)cn2c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c2cc(C=NO)cn2c2ccccc21
Yield: 80.6 %

Procedure:
A mixture of 1.5 g (21.6 mmole) of hydroxylamine hydrochloride, 2 g (24.4 mmole) of sodium acetate, 3.4 g (14.1 mmole) of the product of Example 25, 20 ml of water and 40 ml of ethanol was warmed on a water bath for one hour and the mixture was evaporated to a volume of 20 ml. The mixture was filtered and the recovered product was rinsed with water and dried over P2O5 under vacuum to obtain 2.9 g of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime in the form of colorless needles melting at 262°-264° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:33])[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH3:24])=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=1)[CH2:38][N:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[N:40]1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:33])[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:20]([CH3:24])=[C:21]([NH:23][C:44]([C:42]2[CH:41]=[N:40][N:39]([CH2:38][C:37]3[CH:47]=[CH:48][CH:49]=[C:35]([F:34])[CH:36]=3)[CH:43]=2)=[O:45])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N)cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n1COCC[Si](C)(C)C
Reactant: O=C(O)c1cnn(Cc2cccc(F)c2)c1
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Product: Cc1c(NC(=O)c2cnn(Cc3cccc(F)c3)c2)cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n1COCC[Si](C)(C)C

Procedure:
The title compound was prepared according to the experimental used in Example 20, Step 4 with intermediate (7d), 2-[5-amino-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydropyridin-3-yl]indole-1-carboxylic acid tert-butyl ester, and 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, which was synthesised according to the protocol described for intermediate (6e) in Example 21. The resultant crude product was purified by flash chromatography on SiO2 with hexane—50% ethyl acetate/hexane (gradient) to afford the title compound as a yellow oil, 80 mg, 70%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 19.3 %

Procedure:
3-Morpholinobenzoyl chloride (6.22 g) was added to a solution of 4-methyl-3-nitroaniline (4.20 g) and triethylamine (11.0 ml) in methylene chloride (150 ml) at ambient temperature under argon. The reaction mixture was stirred for 18 hours then diluted to 250 ml with methylene chloride. The mixture was washed with water (3×150 ml) and saturated sodium bicarbonate solution (2×100 ml), dried and evaporated to give a dark brown oil. The oil was triturated with diethyl ether and the solid collected and dried to yield N-(4-methyl-3-nitrophenyl)-3-morpholinobenzamide (1.82g); NMR: (CDCl3) 2.53 (s, 3H), 3.22 (t, 4H), 3.83 (t, 4H), 7.06 (dd, 1H), 7.23 (d, 1H), 7.37 (m, 2H), 7.42 (d, 1H), 7.88 (dd, 1H), 7.97 (s, 1H), 8.21 (d, 1H); m/z 340 (MH+); m.p. 149-150° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][C:12]=2[NH2:21])[O:6][CH2:5][CH2:4][O:3]1.[C:22](OCC)(OCC)(OCC)[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:22][C:23]1[N:10]([CH2:9][CH2:8][CH2:7][C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC1(CCCNc2c(N)cnc3ccccc23)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3ccccc3c2n1CCCC1(C)OCCO1
Yield: 99.6 %

Procedure:
A solution of N4-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (6.20 g, 21.6 mmol), triethyl orthoacetate (3.10 g, 25.8 mmol) and pyridinium p-toluenesulfonate (0.18 g, 0.71 mmol) in toluene (250 mL) was heated at reflux under a Dean-Stark trap for 2 hours, periodically draining off the distillate and adding fresh toluene to the reaction mixture. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (150 mL), washed successively with a saturated aqueous sodium bicarbonate solution and water (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (6.70 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[C:28]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:33][C:30]4[CH:31]=[CH:32][C:27]5[N:26]=[CH:25][N:24]([CH3:23])[C:28]=5[CH:29]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: Cn1cnc2ccc(N)cc21
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (57 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 12 mg (10%) of brown powder. LC/MS: 419 (M+H); HPLC: 95% pure, RT=2.21 min; mp: lyophilyte; 1H NMR: (DMSO, δ) 10.11 (s, 1H), 9.33 (s, 1H), 9.14 (s, 1H), 8.43 (d, J=8.6, 2H), 8.40 (s, 1H), 8.11 (d, J=8.6, 2H), 7.81 (d, J=9.0, 1H), 7.70 (d, J=9.0, 1H), 7.34 (d, J=4.9, 1H), 7.08 (d, J=4.9, 1H), 3.85 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.Br[CH2:27][C:28]#[C:29][CH3:30]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)([CH2:27][C:28]#[C:29][CH3:30])[C:6]([OH:5])=[O:25])(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)C(Cc1cccnc1)S(=O)(=O)c1ccc(F)cc1
Product: CC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 g of the product was isolated. Yield 100%; yellowish gum; MS: 419.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)(=[O:7])=[O:6].Br[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[NH:33][N:32]=2)[C:27]([C:39]#[C:40][Si](C)(C)C)=[CH:26][N:25]=1.C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1>[Pd]>[CH:36]1([C:34]2[CH:35]=[C:31]([NH:30][C:28]3[C:27]([C:39]#[CH:40])=[CH:26][N:25]=[C:24]([C:10]4[CH:9]=[C:8]([S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=4)[N:29]=3)[NH:32][N:33]=2)[CH2:38][CH2:37]1
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)NCCO)c2)OC1(C)C
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Pd]
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2cccc(S(=O)(=O)NCCO)c2)nc1Nc1cc(C2CC2)n[nH]1
Yield: 22 %

Procedure:
3-(4-(3-Cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl)-N-(2-hydroxyethyl)benzene sulfonamide (Compound 122) (100 mg, 22%) was prepared from N-(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 2-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine using the same Pd cataliysed condition as described in Compound 110. LC-MS (m/z)=425.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.81-0.83 (m, 2H), 0.96-0.98 (m, 2H), 1.91-1.98 (m, 1H), 2.83 (q, J=6.0 Hz, 2H), 3.37 (q, J=6.0 Hz, 2H), 4.70 (t, J=5.6 Hz, 1H), 4.91 (s, 1H), 6.46 (s, 1H), 7.71 (t, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 8.52 (d, J=7.6 Hz, 1H), 8.62 (s, 1H), 8.73 (s, 1H), 8.76 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[O:32])[NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)OCC1(CO)CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (424 mg, 1.78 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.27 ml, 1.96 mmol) and cyclohexyl isocyanate (1.0 ml, 7.84 mmol). The mixture was stirred at 80° C. for 18 hours, concentrated and purified by column chromatography on silica (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 366 mg (57%).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[O:17])[CH:15]=[CH2:16]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH:1]1([C:4](=[O:5])[CH2:16][CH2:15][C:14](=[O:17])[CH3:13])[CH2:3][CH2:2]1
Reactant: C=CC(C)=O
Reactant: O=CC1CC1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)C1CC1
Temperature: 85 °C

Procedure:
To a solution of cyclopropanecarbaldehyde (3.20 ml, 42.8 mmol) in ethanol (15.3 mL) was added triethylamine (11.9 mL, 86.0 mmol), but-3-en-2-one (3.54 mL, 42.8 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (2.16 g, 8.56 mmol). The reaction mixture was heated at 85° C. for 18.5 h. The reaction was then concentrated and the resulting residue was extracted with ethyl acetate (3×50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to an orange residue which was purified on silica gel on an automated system (ISCO 120 g, 20 mL/min) using 0 to 75% ethyl acetate in hexanes over 60 minutes. The product, 1-cyclopropylpentane-1,4-dione, was isolated as a yellow oil (2.21 g, 15.8 mmol, 37% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 2.86 (t, 2H), 2.72 (t, 2H), 2.19 (s, 3H), 1.90-1.99 (m, 1H), 1.01 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: N1C=CC([C:7]2[CH:15]=[C:14]3[C:10]([C:11](C=O)=[N:12][N:13]3[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=2)=CC=1.NN1C=CC=C1.C(O)(=O)C>C(O)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:17][CH2:16][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][CH:15]=2)[CH:11]=[N:12]1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccc(-c3ccncc3)cc21
Agent: Nn1cccc1
Solvent: CC(=O)O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc2ccccc21
Yield: 95.5 %

Procedure:
A solution of 6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde (208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid (5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution was then evaporated under reduced pressure, and purified by silica gel chromatography to give 6-pyrid-4-yl-3-E-N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as an oil (140 mg, 57%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.71 (d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=8.5 Hz), 8.34 (s, 1H), 7.85 (d, 2H, J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=2.3 Hz), 6.25 (t, 2H, J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz), 0.86 (t, 2H, J=7.9 Hz), 0.00 (s, 9H).