Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:5][CH3:6]
Reactant: CC[C@H](COC)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](COC)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.7 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methoxymethyl-propyl)-amide (40 mg, 0.074 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (500 μl, 7.4 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (11:1:1 hot heptane/dichloromethane/EtOAc) to afford 21 mg (69%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methoxymethyl-propyl)-amide as an off-white solid. MS: [M+H]+=413; 1H NMR (DMSO-d6) δ: 12.84 (br. s., 1H), 9.12 (s, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.45 (s, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.7, 1.5 Hz, 1H), 4.16-4.27 (m, 1H), 4.18 (s, 3H), 3.57 (dd, J=9.6, 4.3 Hz, 1H), 3.47 (dd, J=9.6, 4.3 Hz, 1H), 3.27 (s, 3H), 1.71-1.89 (m, 1H), 1.47-1.71 (m, 1H), 0.96 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([C:37]2[C:38](C(O)=O)=NC=CC=2)=O)=[C:27]1[CH3:46])C.C1(NC2C=CC=CC=2)C=CC=CC=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:26]([C:27]3[CH:28]=[CH:35][CH:37]=[CH:38][CH:46]=3)[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:22])[O:21]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Reactant: CCn1c(C)c(C(=O)c2cccnc2C(=O)O)c2ccccc21
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OC(=O)c3cccnc32)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g. of an isomer mixture comprising 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid and 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyridinecarboxylic acid, 2.5 g. of diphenylamine and 30 ml. of acetic anhydride was stirred 6.5 hours, then treated with one ml. of pyridine and allowed to stand overnight. The reaction mixture was poured into 750 ml. of water and the resulting solid product was purified by column chromatography affording 7-(1-ethyl-2-methyl-3-indolyl)-7-(diphenylamino)furo[3,4-b]-pyridine-5(7H)-one as a light orange solid, m.p. 132.5°-136° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:42]([F:43])=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[O:33])=[CH:30][C:29]=3[F:44])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:42]([F:43])=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][C:29]=3[F:44])=[N:14][CH:13]=2)([CH3:10])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCNC(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)NCCC(=O)O)cc2F)ccc1F
Reaction time: 1.67 h
Yield: 39.7 %

Procedure:
A solution of methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate (0.85 mmol from previous step) in MeOH (10 mL) was treated with a solution of NaOH (0.6 mL of a 5M aqueous solution, 3 mmol) at ambient temperature. After stirring for 100 min, the reaction mixture was added dropwise to 1N HCl. The addition afforded a thick, white oil that separated from the aqueous acid. The aqueous mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude product. This material was purified by flash chromatography (silica gel, MeOH/DCM, 0:100 to 10:90) to afford the title compound (220 mg, 40% yield over three steps) as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.29 (dt, J=9.4, 6.0 Hz, 5H), 7.07 (d, J=2.2 Hz, 1H), 6.95 (dd, J=10.5, 8.6 Hz, 1H), 6.82 (dd, J=8.4, 2.2 Hz, 1H), 6.34-6.25 (m, 1H), 5.94 (dd, J=7.4, 2.4 Hz, 1H), 3.96 (s, 2H), 3.76-3.67 (m, 2H), 3.53 (s, 3H), 2.65 (s, 2H), 1.54 (s, 3H), 1.48 (s, 3H); MS (EI) m/z 652 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O)=CC=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COc1ccc(O)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OCC(F)(F)F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 51.9 %

Procedure:
A stirred mixture of 2.83 g of Compound 4A, 6.05 g of cesium carbonate and 2.95 g of 2,2,2-trifluoroethyl p-toluenesulphonate in 60 mL of acetonitrile was refluxed for 16 hours. The solvent was evaporated at reduced pressure. 90 mL of brine was added to the residue and the mixture was extracted with 3×40 mL of ethyl acetate. The organic layer was washed with 3×20 mL of water and 20 mL of brine, and dried over sodium sulphate. The solvent was removed at reduced pressure and the residue purified by flash chromatography (petroleum ether/ethyl acetate gradient 95:5 to 80:20). The solvents were removed in vacuo to give 1.86 g (52%) of Compound 4B as a white solid. M.p. (98) 102-105° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.[NH2:38][C:39]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[N:42]=[CH:41][C:40]=1[C:51]([NH:53][CH2:54][C:55]([CH2:61][NH:62][CH2:63][CH3:64])([OH:60])[C:56]([F:59])([F:58])[F:57])=[O:52]>CN(C)C=O>[NH2:38][C:39]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[N:42]=[CH:41][C:40]=1[C:51]([NH:53][CH2:54][C:55]([CH2:61][N:62]([CH2:63][CH3:64])[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])([OH:60])[C:56]([F:59])([F:58])[F:57])=[O:52]
Reactant: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1ccccc1S(C)(=O)=O
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
2-(Methylsulphonyl)benzoic acid (0.204 g, 1.017 mmol) was dissolved in dry dimethylformamide before diisopropylethylamine (0.531 ml, 3.05 mmol) was added. O-7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.464 g, 1.22 mmol) was added and the reaction stirred for 10 minutes. The reaction mixture was cooled in ice and then 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.46 g, 1.118 mmol, 1.1 equiv) was added (washed in with dimethylformamide) (total volume of dimethylformamide used 2.5 ml). The reaction was then stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The product was extracted into dichloromethane and concentrated under reduced pressure. The crude product was purified on silica (50 g) with a 0-100% ethyl acetate:dichloromethane over 40 minutes as gradient to give the title compound (0.53 g).
Reaction SMILES: C1(NC(C2(C)CCC3C(C)=C(OC(=O)C)C(C)=C(C)C=3O2)=S)C=CC=CC=1.[CH3:28][C:29]1([CH3:57])[O:34][CH2:33][C:32]([NH:36][C:37]([C:39]2([CH3:56])[CH2:44][CH2:43][C:42]3[C:45]([CH3:55])=[C:46]([O:51]C(=O)C)[C:47]([CH3:50])=[C:48]([CH3:49])[C:41]=3[O:40]2)=[S:38])([CH3:35])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:57])[O:34][CH2:33][C:32]([NH:36][C:37]([C:39]2([CH3:56])[CH2:44][CH2:43][C:42]3[C:45]([CH3:55])=[C:46]([OH:51])[C:47]([CH3:50])=[C:48]([CH3:49])[C:41]=3[O:40]2)=[S:38])([CH3:35])[CH2:31][O:30]1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)NC1(C)COC(C)(C)OC1)O2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)Nc1ccccc1)O2
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=S)NC1(C)COC(C)(C)OC1)O2

Procedure:
By carrying out the reaction as in Example 2 (2nd process), but replacing the compound of Example 1 with the compound of Example 64, the title product is obtained.
Reaction SMILES: O.[BH4-].[Na+].Cl[CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])=[CH:12][CH:13]=1)=[O:7]>O1CCOCC1.O1CCCC1>[CH3:20][C:15]1[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:6]3[CH2:5][O:7]3)=[CH:9][N:10]=2)[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Water (1.08 Kg) was added dropwise to a suspension of sodium borohydride (0.17 Kg, 4.36 mol) in 1,4-dioxane (6.49 L) at 16° C. and the resulting solution stirred at room temperature. A solution of 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone (1.08 Kg, 4.35 mol) in tetrahydrofuran (2.16 L) was added over 1 hour and the resulting solution stirred for 45 minutes at room temperature. When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture was cooled to 19° C. and treated with concentrated HCl (36% w/w) (1.08 L) over 40 minutes. The mixture was cooled to 11° C. and NaOH (32% w/w) (1.64 L) was added over 45 minutes maintaining the temperature below 25° C. The mixture was then allowed to granulate at room temperature overnight. When all the chloroalcohol intermediate was consumed, DCM (5.0 L) and water (5.0 L) were added and the mixture was stirred before allowing the phases to separate. The aqueous phase was extracted with DCM (2.50 L) and the combined organic phases were washed with water (2×1.0 L) and concentrated in vacuo. Yield 98% (0.92 Kg) δH (CDCl3, 300 MHz) 2.10 (6H, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) ppm. MS m/z 215 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]1[N:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C>[C:1]([O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[F:15])[CH2:25][CH2:24]2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccnc(OC(C)(C)C)n1
Reactant: Fc1ccccc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccc(CCN2CCC(COc3ccccc3F)CC2)n1
Yield: 92.9 %

Procedure:
After dissolving 221 mg of 2-tert-butoxy-4-vinylpyrimidine and 200 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride in 5 ml of ethanol, 123 mg of anhydrous potassium carbonate was added and the mixture was heated to reflux for 50 minutes. Ethyl acetate was added to the reaction mixture, the insoluble portion was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (293 mg, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][OH:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2, 800 mg, 1.96 mmol, 1 equiv) and MnO2 (850 mg, 9.8 mmol, 5.00 equiv) in dichloromethane (100 mL) was heated at reflux for 1.5 hours. Additional NbO2 (700 mg, 8.05 mmol, 4.10 equiv) was added and heating was continued for 1 hour. The catalyst was filtered and washed with dichloromethane (100 mL). The combined filtrate was concentrated to give tert-butyl 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1) as a white foam. 1H NMR (500 MHz, CDCl3) δ 10.11 (s, 1H), 8.47 (d, 1H, J=8.8 Hz), 8.22 (s, 1H), 8.16 (d, 1H, J=1.0 Hz), 8.09 (d, 1H, J=8.6 Hz), 7.95 (dd, 1H, J=8.8, 1.7 Hz), 7.89 (d, 1H, J=8.1 Hz), 7.81 (br t, 1H, J=7.6 Hz), 7.64 (br t, 1H, J=7.5 Hz), 6.80 (s, 1H), 1.27 (s, 9H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22](C)=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)C1C=CC=CC=1.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[OH:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[CH:28]=[C:23]([CH:22]=[CH:21][C:20]=2[CH3:30])[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:16])([F:18])[F:17])[N:14]=1
Reactant: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(CO)nc2C(F)(F)F)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 219.4, except methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:13]N)[CH:6]=[C:7]([CH3:12])[C:8]=1[O:9][CH2:10][CH3:11].[CH3:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=O.[OH-].[Na+]>C(O)(=O)C.O>[CH2:10]([O:9][C:8]1[C:3]([CH3:2])=[CH:4][C:5]2[N:13]=[C:17]3[C:18]4[C:23]([CH2:24][C:16]3([CH3:15])[C:6]=2[C:7]=1[CH3:12])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:11]
Reactant: CC1Cc2ccccc2C1=O
Reactant: CCOc1c(C)cc(NN)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c(C)cc2c(c1C)C1(C)Cc3ccccc3C1=N2
Yield: 96.1 %

Procedure:
A solution of 2.16 g (0.01 mol) of 3,5-dimethyl-4-ethoxyphenylhydrazine hydrochloride and 1.46 g (0.01 mol) of 2-methyl-1-indanone in 20 ml of acetic acid was stirred overnight at room temperature and then refluxed for 3 hours. The mixture was diluted with water, alkalinized with 10N sodium hydroxide solution and extracted three times with methylene chloride. The combined organic phase was washed with water, dried (Na2SO4) and evaporated giving 2.8 g of crude product which was recrystallized from light petroleum/ethyl acetate (5/1). Yield 2.1 g (72%). M.p. 164° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][C:12]#[N:13])[O:3]1.[N:14]([Sn](CCCC)(CCCC)CCCC)=[N+:15]=[N-:16]>O1CCOCC1.C(Cl)(Cl)Cl.CCCCCC>[NH:14]1[C:12]([CH2:11][CH:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2](=[O:1])[O:3]2)=[N:13][N:16]=[N:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCC1OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1OC(Cc2nnn[nH]2)c2ccccc21

Procedure:
A solution of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetonitrile (890 mg, 5.14 mmol) and azidotributyltin (1.97 ml, 7.20 mmol) in dioxane (4.0 ml) was heated at 95° C. for 17 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 aqueous solution, and then washed with saturated NaHCO3 aqueous solution. The aqueous layers were combined, washed with EtOAc, then acidified with 10% HCl aqueous solution. The acidic aqueous layer was extracted with EtOAc. The combined organic layers were then washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to obtain a yellow oil. The oil was dissolved in CHCl3/Hexane and allowed to crystallize, leading to 3-(1 H-tetrazol-5-ylmethyl)-2-benzofuran-1(3 H)-one as a white solid (913 mg, 82%).
Reaction SMILES: N(C1C=C(S(N=C=O)(=O)=O)C=CC=1)=C=O.NC1N=C(OC)C=C(C)N=1.[N:26]([C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([NH:41][C:42]2[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([CH3:50])[N:43]=2)=[O:40])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)=[C:27]=[O:28].[CH3:51][CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:49][O:48][C:46]1[CH:45]=[C:44]([CH3:50])[N:43]=[C:42]([NH:41][C:39]([NH:38][S:35]([C:31]2[CH:30]=[C:29]([NH:26][C:27](=[O:28])[O:54][CH:52]([CH3:53])[CH3:51])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])=[O:40])[N:47]=1
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(N=C=O)c2)n1
Reactant: CC(C)O
Agent: COc1cc(C)nc(N)n1
Agent: O=C=Nc1cccc(S(=O)(=O)N=C=O)c1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(NC(=O)OC(C)C)c2)n1

Procedure:
To an anhydrous solution of 2.3 g of m-isocyanatobenzenesulfonyl isocyanate in 50 ml of methylene chloride was added in small portions 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine. Efficient stirring was maintained during the addition and for three additional hours. The intermediate thus obtained, 3-isocyanato-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, was reacted further by adding one gram of 2-propanol and stirring the resultant mixture for an additional sixteen hours. Filtration of the reaction mixture and evaporation of the filtrate yielded the desired product melting at 173°-180°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]#[CH:22].C(NCC)C.C(OCC)(=O)C>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#Cc1c(C)cccc1C
Reactant: COC(=O)c1ccc(I)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#Cc2c(C)cccc2C)c(N)c1

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (920 mg, 3.32 mmol), 2,6-dimethylphenylacetylene (540 mg, 4.15 mmol),), bis-(triphenylphosphine) palladium (II) chloride (47 mg, 67 μmol), diethylamine (486 mg, 66 mmol), and copper (I) iodide (19 mg, 100 μmol) in DMF (10 mL) was heated at 120° C. in a microwave apparatus for 10 min. The mixture was poured into ethyl acetate and extracted six times with brine. The organic phase was dried, filtered, and the solvent was removed under reduced pressure to leave a residue that was chromatographed using a gradient of 0-30% heptane/ethyl acetate to afford methyl 3-amino-4-(2,6-dimethylphenylethynyl)-benzoate.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:15]3)=[CH:9][CH:8]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Fc1ccc(Oc2ccc(COCC3CCCNC3)cc2)cc1
Product: COC(=O)c1cccc(N2CCCC(COCc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Yield: 57.3 %

Procedure:
Using 3-[4-(4-fluorophenoxy)benzyloxymethyl]piperidine (35.7 mg, 0.113 mmol) and 3-(methoxycarbonyl)phenylboric acid (40.7 mg, 0.226 mmol), the same procedure was followed as in Example 2 to give 29.1 mg (57%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:13])[CH3:12].Cl>C(O)CCC>[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=2)=[CH:17][CH:16]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: Clc1ncc2cc[nH]c2n1
Agent: Cl
Solvent: CCCCO
Product: CC(C)Oc1ccc(Nc2ncc3cc[nH]c3n2)cc1
Temperature: 140 °C

Procedure:
To a suspension of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (700 mg, 4.33 mmol) in BuOH (10 mL) is added 4-isopropoxyaniline (1.31 g, 8.66 mmol) and concentrated aqueous HCl (37%, 1.28 mL, 13.0 mmol). The reaction mixture is heated to 140° C. for 24 h, cooled to rt, and concentrated under reduce pressure. The residue is dissolved in EtOAc and the organic layer is washed with saturated aqueous Na2CO3 solution (2×). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid residue is triturated with hexane to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.ClC1C=CC([N:34]=[C:35]=[O:36])=CC=1C(F)(F)F.O>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH2:34])=[O:36]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(N)=O)c(C)c2)ccn1
Reaction time: 144 h
Yield: 48.9 %

Procedure:
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl urea as a brown oil (0.11 g, 0.22 mmol): 1H NMR (DMSO-d6) δ2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).