Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1B(O)O>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2,4-dimethoxyphenylboronic acid and making non-critical variations provided the title compound as an off-white foam. IR (diffuse reflectance) 2966, 2934, 1610, 1567, 1483, 1391, 1303, 1280, 1253, 1208, 1159, 1128, 1046, 1034, 741 cm−1; OAMS supporting ions at: ESI+ 420.1; MS (EI) m/z 419 (M+); HRMS (FAB) calcd for C25H29N3O3+H1 420.2287, found 420.2278.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:12][CH2:13][CH:14]=[CH2:15].[BH4-].[Na+]>>[CH2:15]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCBr
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Product: C=CCCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine (3.9 g, 0.03 mol) and 4-bromo-1-butene (4.9 g, 0.036 mol) was heated at 70°-80° C. for 5 hours. The reaction mixture was washed with a small quantity of ether, dissolved in methanol (200 ml) and water (60 ml). To the mixture, sodium borohydride (5.7 g, 0.15 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The resulting residue was purified by alumina column chromatography (eluted successively with petroleum ether, benzene and chloroform) and distilled, bp. 100°-103° C./0.9 mmHg, to afford the Compound No. 14 (1.6 g, 28.4%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][N:13]([CH3:14])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: -70 °C

Procedure:
Dissolve 50 g (0.26 mol) of 4,6-dichloro-5-nitropyrimidine in 500 mL of CH2Cl2 and cool to -70° C. Add a solution of 24 mL (0.28 mol) dimethylamine, 70 mL (0.40 mol) of diisopropylethylamine, and 100 mL of CH2Cl2 over 30 minutes. Warm to ambient temperature and wash the reaction mixture with 500 mL of 20% K2CO3. Dry the CH2Cl2 portion over MgSO4, treat with charcoal filter, and remove the filtrate under vacuum. Crystallize the residue with ether to provide 4-dimethylamino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:26]>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([Cl:26])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The carboxylic acid of example 2 (0.550 g, 1.8 mmol) was dissolved in SOCl2(20 mL) and DMF (˜0.1 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated to dryness and co-evaporate with EtOAc to give a 1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carbonyl chloride as a brown solid (580 mg). The acid chloride (0.050 g, 0.16 mmol) was dissolved in DMF (1 mL) and reacted with I-carnosine (0.036 g, 0.159 mmol) in the presence of DIEA (82 μL, 0.476 mmol). The reaction mixture was stirred for 3 days at room temperature before it was acidified with AcOH (1 mL) and purified by reversed phase C18 preparative HPLC. The title compound of example 145 was obtained as a white solid.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[S:25][C:26]([CH3:29])=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was allowed to react with 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) in a similar manner to that of Example 1 to give the captioned compound (2.2 g.), pale yellow powder, mp. 160° to 165° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([NH2:35])[CH:31]=[CH:30]3)[N:21]=[CH:20][N:19]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([NH2:35])[CH:31]=[CH:30]3)[CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3ccc(N)nc23)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)c2n1
Reaction time: 16 h

Procedure:
To {2-[6-(2-amino-quinolin-8-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester, (Example 148), (0.10 g, 0.20 mmol) was added 4 M HCl in dioxane (15 mL). The reaction mixture was stirred for 16 h and then concentrated in vacuum. The residue was dissolved in EtOAc (20 mL) and washed with NaHCO3 (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (2:1, EtOAc: hexanes) afforded the title compound as thick yellow oil. Mp: 233–234° C. MS (ESI, pos. ion) m/z: 398 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:3].Cl.[OH-].[Na+].O=[C:19]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([BH3-])#N.[Na+]>C(O)C>[C:20]([C@@H:19]([NH:1][C@H:2]([C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:3])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1CC(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1CC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of L-alanyl-(S)-2-pyrrolidineacetic acid (390 mg; 2.0 mmol) (from the hydrochloride neutralized with 2.5N NaOH) and ethyl 2-oxo-4-phenylbutyrate (1.00 g) in 5 ml of ethanol is added 1 g of ground 4A molecular sieves. The mixture is stirred for 30 minutes and sodium cyanoborohydride (310 mg) is added in portions over 2 hours. The mixture is stirred overnight, filtered, and the filtrate concentrated under reduced pressure to near dryness. The mixture is taken up in methylene chloride and washed with water. The methylene chloride layer is extracted with 5% aqueous potassium bicarbonate, the latter extract is acidified to pH 2 and extracted with methylene chloride. The organic extract is dried over sodium sulfate and concentrated to dryness under reduced pressure to give the desired product. The S,S,S and R,S,S diastereomers are separated using reverse phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+].Cl.CO>C(Cl)(Cl)Cl.O.CO>[CH2:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:36][CH:37]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc(NCc3ccccc3)cc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.7 %

Procedure:
To a suspension of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (198 mg, 0.4 mmol) in chloroform (2 mL)-methanol (2 mL) was added benzaldehyde (49 μL, 0.48 mmol) and the mixture was stirred at room temperature for 40 minutes. To the resulting solution was added bromocresol green as well as sodium cyanoborohydride (30 mg, 0.48 mmol). Then, 10% HCl/methanol was added dropwise until the color of the mixture had ceased to change. This reaction mixture was stirred at room temperature for 15 minutes, at the end of which time it was diluted with water and extracted with 3 portions of chloroform. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 163 mg (Yield 70%) of the title compound. m.p. 178°-182° C.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:17](OCCCC)=O.[ClH:24]>CCOCC>[ClH:24].[NH2:17][CH:9]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH:10]1[OH:12]
Reactant: CCCCON=O
Reactant: O=C1Cc2ccccc2-c2ccccc2C1
Agent: Cl
Solvent: CCOCC
Product: NC1c2ccccc2-c2ccccc2CC1O
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol)(CAS# 1139-82-8, prepared as described in Tetrahedron Letters, Vol. 28, No. 23, (1987). pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et2O. The solution was cooled to 0° C. and treated drop-wise with a saturated solution of HCl(g)/Et2O. After 5 h at 0° C. the resulting precipitate was filtered, rinsed with cold Et2O and vacuum dried to give the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].O(CC)C([S-])=[S:23].[K+].[OH-].[K+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([SH:23])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Sc1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Benzyloxyaniline (2.06 g, 10.3 mmol) was dissolved in water (40 ml) and concentrated HCl (8 ml). The solution was cooled to 0° C. and solution of sodium nitrite (778 mg, 11.3 mmol) in water (10 ml) was added. After 15 min stirring at 0° C., the mixture was added to a solution of potassium ethyl xanthate (3.1 g, 20 mmol) in water (10 ml), and heated to 65° C. for 30 min. After cooling to room temperature, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 1N NaOH and water, and dried over MgSO4. The solvent was evaporated and the residue was dissolved in ethanol (50 ml). Potassium hydroxide (2 g, 40 mmol) was added and the mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated, and partitioned between diethylether and water. The aqueous layer was acidified to pH 1 with concentrated HCl, and then extracted twice with methylene chloride. The combined organic layers were dried over MgSO4 and the solvent was evaporated. The product was used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:36][NH2:37])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH:28]=1)([CH3:22])([CH3:21])[CH3:20].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:36][NH:37][C:15](=[O:17])[CH:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH3:18])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cccc(-c2cc(C(C)(C)C)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cc(C(C)(C)C)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 121.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (66 mg, 0.18 mmol) and (5-tert-butyl-3′-methylbiphenyl-2-yl)methanamine (113 mg, 0.119 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (52 mg, 0.270 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and triethylamine (0.063 mL, 0.45 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography. N-((5-tert-Butyl-3′-methylbiphenyl-2-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (example 21) (74 mg) was obtained as 81% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])OC)=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1)=[O:14].[CH:38]([NH:40][NH2:41])=O.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:41][N:40]=[CH:38][N:11]=2)=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:19][CH:20]=1
Reactant: NNC=O
Reactant: COC(=N)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2ncn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 150 °C
Yield: 21.9 %

Procedure:
A mixture of methyl 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzenecarboximidoate (50 mg, 0.10 mmol), formylhydrazine (30 mg, 0.5 mmol) and Hunig's base (17 μL, 0.20 mmol) in ethanol (2 mL) was heated to 150° C. in a sealed tube overnight. The reaction was cooled to rt and concentrated on a rotary evaporator. The residue was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(1H-1,2,4-triazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (10.9 mg, 22%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.84-9.82 (m, 2H), 8.62 (s, 1H), 8.19 (d, 2H), 8.06-7.99 (m, 3H), 7.90-7.78 (m, 5H), 7.66-7.63 (m, 3H), 7.42 (ddd, 1H), 7.36 (d, 1H), 2.36 (s, 3H). MS (EI) for C30H23N7O: 498.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH3:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1C)COC2=O

Procedure:
To a flask charged with 5-bromo-4-methyl-2-benzofuran-1(3H)-one (320 mg, 1.409 mmol) and a stir bar was added allyl tri-n-butyltin (0.655 mL, 2.11 mmol), Pd(PPh3)4 (244 mg, 0.211 mmol), lithium chloride (179 mg, 4.23 mmol), and toluene (15 mL). The reaction was purged with nitrogen 2 times then was heated at reflux for 4 hours. The reaction mixture was diluted with DCM, adsorbed onto silica gel, and purified by silica gel chromatography to give 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.OS(O)(=O)=O.C(Cl)Cl.CO.[CH3:19][CH2:20]O>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[N:2]1
Reactant: CCO
Reactant: O=C(O)c1cc[nH]n1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc[nH]n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H2SO4 the colorless reaction mixture was heated to reflux (100° C.) and stirred at this temperature for 4 h. TLC analysis (DCM/MeOH 95:5) indicated full conversion of the starting material. After cooling to rt the mixture was transferred to a flask to remove the solvent at a rotary evaporator. The colorless residue was diluted in 20 mL water and neutralized with 17 mL saturated aqueous NaHCO3 solution. Thereby a white solid precipitated. The aqueous layer was extracted with EtOAc (4×50 mL), dried over MgSO4 and the solvent was evaporated under reduced pressure to yield the pure title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][N:28]=[CH:29][C:22]=34)=[CH:16][CH:15]=2)=[O:12])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31].[H-].[Na+].I[CH3:37].[Cl-].[NH4+]>CN(C=O)C>[F:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[N:27]([CH3:37])[N:28]=[CH:29][C:22]=34)=[CH:18][CH:19]=2)=[O:12])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CI
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(CCF)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(NC(=O)Nc4ccc(CCF)c(C(F)(F)F)c4)cc3)ccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
1-[4-(2-Fluoroethyl)-3-(trifluoromethyl)phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (92 mg, 0.2 mmol) was dissolved in DMF (1 mL), and sodium hydride (60%, 8 mg) was added thereto. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 0.5 hours, and then iodomethane (18 μL) was added thereto. The mixture was further stirred overnight, and a saturated ammonium chloride aqueous solution was added thereto to quench the reaction. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane:methanol=20:1) to give 1-[4-(2-fluoro-ethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (47 mg, 50%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1>C1COCC1.CC(C)=O>[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reaction time: 0.08 h
Yield: 36.3 %

Procedure:
A 250 mL round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (2.291 g, 9.12 mmol) and THF (45.6 mL). The resulting mixture was cooled in a dry ice and acetone bath for 10 min. To this solution was added lithium bis(trimethylsilyl)amide (13.68 mL, 13.68 mmol) dropwise over 30 seconds. The ice bath was removed for 10 minutes and then the flask was returned to the bath for an additional 5 minutes. A solution of 1-chloroisoquinoline-6-sulfonyl chloride (2.39 g, 9.12 mmol) in 7 mL of THF was then added dropwise over 5 minutes. The ice bath was removed and the resulting mixture stirred for 30 minutes. LC/MS indicated that the desired product was generated. The reaction mixture was concentrated, taken up in minimal DCM, loaded onto a cartridge and purified by silica gel chromatography (330 g), using 0 to 30% Heptane: EtOAc. Fractions containing the product were combined and concentrated to afford (1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (1.58 g, 3.31 mmol) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18](O)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+].[N:48]1C=CC=CC=1>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:48])=[O:19])(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(N)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100160.7 %

Procedure:
To a suspension of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Step H, 200 mg, 0.51 mmol) and di-tert-butyl dicarbonate (145 mg, 0.66 mmol) in acetonitrile (3 mL) were added ammonium bicarbonate (48 mg, 0.61 mmol) and pyridine (48 mg, 0.61 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and dichloromethane (30 mL). The aqueous layer was separated and extracted with dichloromethane (30 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:3 as eluent) to afford the title compound (200 g, quant.) as a white solid.