Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[C:12][CH:14]2[CH2:16][CH2:15]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(C#CC2CC2)c2occc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (0.30 g, 1.6 mmol, ArkPharm), PPh3 (0.008 g, 0.03 mmol) in THF (1.2 mL) and TEA (1.764 mL). The mixture was placed under vacuum and purged with N2 three times, then Pd(PPh3)2Cl2 (0.011 g, 0.016 mmol) and CuI (0.006 g, 0.03 mmol) were added. The mixture was placed under vacuum and purged with N2 three times and then ethynylcyclopropane (0.161 mL, 1.905 mmol) was added. The mixture was placed under vacuum and purged with N2 and then the mixture was stirred at rt for about 18 h. The mixture was filtered and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure and the residue was deposited on silica gel and purified by column chromatography (12 g silica gel, 0 to 30% EtOAc/heptane) to give 2-chloro-4-(cyclopropylethynyl)furo[3,2-d]pyrimidine (0.090 g, 26%): LC/MS (Table 2, Method c) Rt=2.11 min; MS m/z 219 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][CH:7]=1)=[O:2].[I:12]I>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][C:7]=1[I:12])=[O:2]
Reactant: II
Reactant: COC(=O)c1cc(C=O)c[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C=O)c(I)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3 (3.40 g, 22.2 mmol) in CHCl3 (20 mL) at 0° C. was added CF3CO2Ag (5.40 g, 24.4 mmol) followed by I2 (3.10 g, 24.4 mmol). The resulting mixture was stirred for 16 hours in the dark at room temperature. The reaction mixture was filtered through Celite and the filtrate was washed with saturated aqueous solution of Na2S2O3 (2×20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. MPLC purification (CH2Cl2:Et2O/95:5) of the residue gave 4 as a white solid (0.72 g, 32% based on the recovered starting material). Along with 4, two minor compounds methyl 4-formyl-5-iodo-1H-pyrrole-2-carboxylate, methyl 4-formyl-3,5-diiodo-1H-pyrrole-2-carboxylate and the starting material 3 were also isolated. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.52 (s, 1H), 7.04 (s, 1H), and 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 187.13, 160.36, 128.78, 127.79, 115.58, 87.40, and 52.42.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH3:40][C:41]1([CH:47]=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:40][C:41]1([CH:47]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)[OH:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CC1(C=O)CCCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCCC4)c3n2)cc(OC)c1OC
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (247 mg, 0.435 mmol) in anhydrous tetrahydrofuran (5 ml) was cooled to −78° C. and treated with iPrMgCl—LiCl (1M in tetrahydrofuran, 0.87 ml, 0.87 mmol) dropwise. The reaction mixture was allowed to stir for 20 minutes, and then 1-methyl-cyclohexanecarbaldehyde (219 mg, 1.74 mmol) was added rapidly. The reaction mixture was allowed to stir at −78° C. for 1 hour and then room temperature for 1 hour. The reaction mixture was partitioned between EtOAc/saturated aqueous. NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 15-100% EtOAc in hexanes as eluant to provide 81 mg (45%) of (1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanol as a pale yellow solid. M+H=412.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[C:15]([C:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)#[N:16].ClCCl>O>[C:15]([C:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][CH:24]=2)[CH2:18][CH2:19][N:20]([S:10](=[O:12])(=[O:11])[N:9]([CH3:14])[CH3:8])[CH2:21][CH2:22]1)#[N:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)N(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (48 μl) and dimethylsulfamoyl chloride (37 μl) were added to a mixture of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (150 mg) described in Reference Example 169 and dichloromethane (6.6 ml) and stirred at room temperature for two days. Water was added to the reaction solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (135 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 mL) was treated with 4-chlorophenyl-isocyanate (13.3 μL, 0.105 mmol) then reaction mixture stirred at room temperature overnight and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) to afford Compound 127 as a white solid in 69.8% yield. LCMS m/z (%)=414 (M+H35Cl, 100), 416 (M+H37Cl, 36). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.36 (s, 1H), 7.62-7.59 (m, 3H), 7.50 (s, 1H), 7.42 (s, 1H), 7.31 (d, J=8.90 Hz, 2H), 7.12 (d, J=8.92 Hz, 1H), 6.24 (s, 1H), 4.11 (t, J=5.86 Hz, 2H), 3.77 (s, 3H), 2.61 (t, J=5.85 Hz, 2H), 2.20 (s, 6H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH:12]1([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13]1>C1COCC1>[CH:12]1([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:8][O:16]2)[CH2:13][CH2:14]1
Reactant: C[S+](C)C
Reactant: O=C(c1ccc(F)cc1)C1CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C2(C3CC3)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of cyclopropyl (4-fluorophenyl)methanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:14][CH2:13]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: N#Cc1ccc(C2CCCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a 4-mL vial was added 3-amino-4-methylbenzoic acid (27 mg, 0.18 mmol, 1.0 equiv), 4-(azepan-4-yl)benzonitrile (compound 40.4, 40 mg, 0.2 mmol, 1.1 equiv), hydroxybenzotriazole (39 mg of 20 wt % H2O, 0.23 mmol, 1.3 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (44 mg, 0.23 mmol, 1.3 equiv), DMF (1 mL) and N,N-diisopropylethylamine (93 μL, 0.54 mmol, 3.0 equiv). The mixture was stirred at room temperature for 4 hours then diluted into ethyl acetate (10 mL) and washed with brine (10 mL). The aqueous was extracted with ethyl acetate (3 mL) and the combined organics were washed with brine (10 mL), 1 M NaH2PO4 (5 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a brown solid (45 mg, 74%). m/z (ES+) 334 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]([O:16][C:17](C1C=CC=CC=1)(Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1C=CC=C[CH:11]=1)[C:4]1C=CC=[CH:6][CH:5]=1.[CH:31]12[O:37][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36]2>C1COCC1.C(OCC)(=O)C.[Cu]Cl>[CH2:17]([O:16][C:3]1[CH:4]=[CH:5][CH:6]=[CH:11][C:10]=1[C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(OC(Br)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCC2OC2C1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A 1 L round bottom flask equipped with a mechanical stirrer, addition funnel, condenser, and nitrogen inlet is charged with 6.6 g (0.27 mol) of magnesium turnings and 25 ml of dry tetrahydrofuran. To this stirred mixture a solution of 50 g (0.27 mol) of bromophenyl benzylether in 50 ml of dry THF is added dropwise. The reaction needs to be heated (30°-40° C.) at first to initiate it but then the heating mantel is removed and the temperature maintained by the rate of addition. Once the addition is complete the reaction is held at 45°-50° C. for 2 hours, then 300 ml of dry THF is added. The solution is cooled to -30° C. and 1.2 g (0.012 mol) of copper (I) chloride is added. The resulting mixture is stirred for 10 minutes and then a solution of 26 g (0.265 mol) of cyclohexene oxide in 30 ml of THF is added dropwise over 1 hour. Upon completion of the addition the reaction is allowed to warm to 0° C. and stirred for 2 hours, then diluted with 300 ml of ethyl acetate and quenched by addition of 150 ml of saturated aqueous ammonium sulfate solution. The organic phase is separated and washed with another 75 ml of ammonium sulfate solution. The combined aqueous phases are extracted with 100 ml of ethyl acetate. The organic phases are combined, dried with magnesium sulfate, and evaporated under reduced pressure to yield 65 g of trans-2-(2'-benzyloxyphenyl)cyclohexanol as an amber oil, which is used directly in the next step.
Reaction SMILES: CS[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1>[Ni]>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[CH:4]1
Reactant: CSc1c[nH]c2ccccc12
Agent: [Ni]
Product: c1ccc2[nH]ccc2c1

Procedure:
Conversion of the dimethyl acetal from part A to 3-methylthioindole was accomplished by stirring 0.50 g (2.20 mmol) of the dimethylacetal dissolved in 25 ml of ethyl ether for 2 hr. with 10 ml of 0.5 N aqueous hydrogen chloride. The ethereal layer was separated, treated with a saturated sodium bicarbonate solution, dried, filtered and evaporated to yield 0.35 g (2.14 mmol, 97%) of the oily 3-methylthioindole. This 3-methylthioindole was treated with Raney nickel as described to form indole, identified by comparison with an authentic sample.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4]
Reactant: COCCN
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Product: COCCNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 94.1 %

Procedure:
Prepared from 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (Example 38 step A) (150 mg, 0.406 mmol, HPLC 1.185 min) and 2-methoxyethylamine (700 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white solid (156 mg, 94%, HPLC 0.576 min), MS (ISP) m/e=409.3 [(M+H)+].
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Br[C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>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>[CH3:38][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[N:42][CH:43]=[N:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Brc1cncnc1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cncnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 5-bromopyrimidine (243 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain a colorless solid (313 mg). The obtained partially purified product was dissolved in 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) and methanol (4 mL), and the mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (241 mg, 61%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C=O.[C:20]([O-])(=[O:22])C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:20][OH:22])[N:4]=[C:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(CO)nc(-c2ccc(C(F)(F)F)cc2)n1C
Yield: 59.3 %

Procedure:
A mixture of 1,5-dimethyl-2-(4-trifluoromethylphenyl)imidazole (0.6 g), aqueous formaldehyde (3.5 ml of 36%), sodium acetate (0.6 g), and acetic acid (0.5 ml) was refluxed for 24 hours. The mixture was cooled, and concentrated sodium hydroxide added until the mixture was just basic, keeping the temperature at about 10° C. The mixture was extracted with methylene chloride, and solvent removed from the organic layer under reduced pressure. The residue was flash-chromatographed on silica gel, eluting with methylene chloride containing methanol (97/3), to yield 0.4 g of 1,5-dimethyl-4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)imidazole, m.p. 152° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][NH:3]1.Br[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:20])([F:22])[F:21])[CH:5]=[CH:4][N:3]1[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}isophthalonitrile (0.076 g, 0.249 mmol), tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.078 g, 0.249 mmol) and potassium carbonate (0.034 g, 0.249 mmol) were combined and diluted with dimethylformamide (1 mL) and stirred at room temperature. After 16 hours, water (10 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting solid was dissolved in TFA. After 30 minutes, the solution was concentrated. The resulting solid was suspended in methanol and filtered to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.6 Hz, 1H), 8.17-8.17 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.98 (m, 2H), 7.18 (dd, J=8.2 Hz, J=4.7 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.52 (s, 2H). HRMS (M+1)=437.0981.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:14]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[N:15]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:2]1([CH2:1][NH:8][C:9](=[O:10])[O:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([N:14]([CH2:11][CH2:12][CH3:13])[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:16]=[CH:17]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 101.1 %

Procedure:
Benzyl isocyanate (2 g) was added to a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (3.3 g) in 75 mL tetrahydrofuran containing potassium carbonate (milled, 3 g). After stirring twenty hours at ambient temperature, the mixture was filtered and the filtrate was concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield 5 g of the product as a solid, m.p. 156°-158° C. The product was recrystallized from acetonitrile to yield 3.8 g of crystals, m.p. 162°-164° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1.[Li+].C[Si]([N-:31][Si](C)(C)C)(C)C>>[NH2:31][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Yield: 37.2 %

Procedure:
The intermediate methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate was prepared from methyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (45 mg, 0.1 mmol) and LiHMDS (1M in THF, 120 μL, 0.12 mmol) according to the General Procedure 4, described in Example 45, using a modified reaction time (130° C., 300 s, microwave reactor). The experiment was repeated four times giving 14 mg of methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.ClC(N(C)C)=C(C)C.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:34])([CH3:33])[C:25](=[O:32])[N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH:29]1([N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)[CH:28]=3)[C:24]([CH3:33])([CH3:34])[C:25]2=[O:32])[CH2:31][CH2:30]1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C2CC2)C(=O)C3(C)C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylisonicotinic acid (95.1 mg, 694 μmol) in dry dichloromethane (3.64 ml) under an argon atmosphere at 0° C. was added a solution of 1-chloro-N,N,2-trimethylpropenylamine (104 mg, 763 μmol) in dry dichloromethane (1 ml). After 2 hours 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c, 150 mg, 694 μmol) and triethyl amine (140 mg, 193 μl, 1.39 mmol) were added at 0° C. The reaction mixture was warmed to room temperature, kept at this temperature for 16 hours, then diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as light yellow oil (207 mg).