Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:42][N:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccnc1CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.11 mmol), 2-(chloromethyl)-1-methyl-1H-imidazole (22 mg, 0.13 mmol), KI (22 mg, 0.13 mmol), K2CO3 (76 mg, 0.55 mmol) in anhydrous DMF (1.2 mL) was heated at 50° C. for 100 minutes. Added 1.2 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI and heated for another 35 minutes. Added 2.4 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI along with 2.0 equivalents of K2CO3 and heated for 1 h. The solution was diluted with CH2Cl2 and washed with aqueous saturated NaCl (2×). The organic phase was dried under Na2SO4 and concentrated in vacuo to afford tert-butyl 5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Reactant: CCCc1n[nH]c(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1nn(CC(=O)N2CCN(c3ccc(Cl)c(OC)c3)CC2)c(C(F)(F)F)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7, Rf=0.78) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.22-7.24 (d, 2H), 6.42-6.48 (m, 2H), 5.7 (s, 2H), 3.8 (s, 3H), 3.72-3.78 (m, 4H), 3.22-3.42 (m, 4H), 2.66-2.72 (t, 2H), 1.58-1.68 (m, 2H), 0.98-1.02 (t, 3H). 13C NMR (400 MHz, CDCl3): 164, 154.8, 150.5, 130, 109.8, 102.2, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26, 21.8, 14.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[CH2:34](Br)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][CH2:14][CH:13]2[C:11]([N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=2)[C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)=[O:12])=[CH:18][CH:19]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Reactant: CCCCBr
Product: CCCCOc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 110 using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and butyl bromide (0.18 mL) as starting materials, 7-butoxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.C(O[CH:11]=[NH:12])C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH2:25])[NH:23][N:24]=1.[C:26]([OH:29])(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([OH:29])(=[O:28])[CH3:27].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH:25][CH:11]=[NH:12])[NH:23][N:24]=1
Reactant: CCOC=N
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N=CNc1cc(-c2ccccc2Cl)n[nH]1

Procedure:
To a vigorously stirred solution of saturated aqueous Na2CO3 (50 mL) and methylene chloride (50 ml) was added solid ethylformimidate hydrochloride salt (8.98 g, 82 mol). After stirring for several minutes the aqueous layer was separated and extracted with additional methylene chloride (3×50 ml). The combined organic layers were dried (MgSO4) and filtered. To the stirred solution was added 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-9a; 5.27 g, 27 mmol) in methylene chloride (50 mL) and then glacial acetic acid (2.67 ml, 46.6 mmol), dropwise. A cloudy precipitate began to form as the acetic acid was added. After stirring overnight, the solids were collected by vacuum filtration, washed with methylene chloride, and then dried, in vacuo, to give intermediate I-3A-9b, contaminated with ˜25% of the corresponding dimer (MW=396; 2 pyrazoles+1 formamidine), as a solid (5.7 g, 75%): +APcI MS (M+1) 221.1; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.62-7.30 (m, 4H), 6.48 (s, 1H), 1.92 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:13])[N:7]([NH2:12])[C:8]([SH:11])=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14]I>[OH-].[Na+].CO>[C:1]([C:5]1[C:6](=[O:13])[N:7]([NH2:12])[C:8]([S:11][CH3:14])=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 20 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
4 parts by weight of 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one are dissolved in a mixture of 11 parts by weight of 2-normal sodium hydroxide and 4 parts by weight of methanol and the solution is treated at 0° C with 3.2 parts by weight of methyl iodide. The reaction mixture is then stirred for a further 4 hours at 20° C. The reaction product crystallizes out and is filtered off, dried and recrystallized from benzene. 3.52 parts by weight of 6-tert.-butyl-3-methylthio-4-amino-1,2,4-triazin-5(4H)-one of melting point 126°-127° C are obtained Yield: 82% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38](O)=[O:39])[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:60]1([NH:63][C:64]([C@@H:66]2[CH2:70][CH2:69][CH2:68][NH:67]2)=[O:65])[CH2:62][CH2:61]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C:64](=[O:65])[NH:63][CH:60]3[CH2:61][CH2:62]3)=[O:39])[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccc(C)cc3n2)CC1
Temperature: 50 °C

Procedure:
To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 12 ml of DMF, 392 mg of EDC, 376 mg of pentafluorophenol and 392 mg of NEM was added and the reaction mixture was warmed to 50° C. for 2 h. Then, after cooling to RT, 334 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 201 mg of NEM in 5 ml of DMF was added. After 1 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 1.2 g.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][CH:2]2[CH3:10].[OH:11]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(#N)C>[CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10]
Reactant: CC1CCC2CC1C2(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC#N
Product: CC1(O)CCC2CC1C2(C)C
Yield: 82 %

Procedure:
To 25 milliliters of acetonitrile were added 1.38 grams (10 millimoles) of pinane, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide and 0.015 gram (0.06 millimole) of Co(AA)2, and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 100° C. for six hours. Pinane was transformed into 2-pinanol (selectivity for pinane 91%, yield 82%) with a transformation rate of 90%.
Reaction SMILES: [CH3:1]NCCN(C)C.C([Li])CCC.[CH:13]([Si:16]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([CH3:15])[CH3:14].CI>C1COCC1>[CH3:1][C:24]1[CH:25]=[C:18]([O:17][Si:16]([CH:13]([CH3:15])[CH3:14])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])[CH:19]=[CH:20][C:21]=1[CH:22]=[O:23]
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Reactant: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1C=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of trimethylethylenediamine (0.45 mL, 3.48 mmol) in THF (9 mL) at −20° C. was added Butyllithium 1.6M in hexanes (2.11 mL, 3.8 mmol). The solution was stirred at −20° C. for 15 min. A solution of 4-Triisopropylsilanyloxy-benzaldehyde (0.922 g, 3.31 mmol) was added dropwise and the solution stirred for 15 min at −20° C. Bu 16M in hexanes (6.21 ml, 9.93 mmol) was added dropwise and the solution kept in the freezer at −20° C. for 26 hours. The solution was cooled to 40° C. and methyl iodide (3.71 mL, 59.60 mmol) was added. The solution was allowed to reach room temperature and further stirred 30 ml. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were dried (MgSO4), concentrated under vacuum and purified by column chromatography (silica gel, hexanes/Ethyl acetate 20:1, Rf0.085) (49%). 1H-NMR (CDCl3, 200.15 MHz): δ 10.1 (s, 1H), 7.69 (d, 1H, J=8.3), 6.80 (dd, 1H,J=8.6, 2.4), 6.72 (s, 1H), 0.61 (s, 3H), 1.33–1.19 (m, 3H), 1.12 (s,18H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][C:3]=1[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[N:26]4[C:22]([O:23][CH:24]=[CH:25]4)=[N:21][C:20]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.[NH4+].[OH-:35].[OH-:36].[Na+].N>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:36])=[O:35])=[CH:4][C:3]=1[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[N:26]4[C:22]([O:23][CH:24]=[CH:25]4)=[N:21][C:20]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: N#Cc1ccc(F)c(-c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)c1
Reactant: [OH-]
Agent: N
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(F)c(-c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a suspension of 4-fluoro-3-{6-[6-(4-fluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}-benzonitrile (0.15 g, 0.34 mmol; Example #K.1.19) in water (1 mL) and then was added NH4OH (28-30% in water, 2.0 mL, 51 mmol) and 1M NaOH (1 mL, 1.0 mmol). The reaction mixture was stirred at about 65° C. for about 8 h. Ammonia (0.5 M in 1,4-dioxane, 10 mL) was added and the reaction mixture was stirred about 72 h at about 65° C. The organic solvent was removed under reduced pressure and aqueous layer was buffered with ammonium acetate aqueous solution. The crude material was purified by reverse phase preparative chromatography (Table 1, Method e). The resulting material was purified by trituration with hot MeOH to afford the title compound (0.038 g, 23%) LC/MS (Table 1, Method a) Rt, =1.84 min; MS m/z: 458.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([O:26]C)=[O:25])=[N:16]1.[OH-].[Na+].Cl>CCO>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([OH:26])=[O:25])=[N:16]1
Reactant: COC(=O)c1nn(-c2ccc(N3CCOCC3)c(F)c2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)O)c1=O
Yield: 94.1 %

Procedure:
A solution of methyl 1-(2,3-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 11 mmol) and 2 M NaOH aqueous solution (11 mL, 22 mmol) in EtOH (20 mL) was stirred at room temperature for 16 h. To the mixture was added 1 M HCl aqueous solution (21 mL). The precipitate was collected by filtration and dried over under reduced pressure to give the title compound (3.8 g, 98% yield) as a white solid: NMR (300 MHz, DMSO-d6): δ ppm 3.06-3.23 (4H, m), 3.66-3.82 (4H, m), 3.88 (3H, s), 6.84-7.27 (1H, m), 7.36-7.74 (1H, m), 8.86 (1H, d, J=1.1 Hz), 14.95 (1H, brs). LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])([CH3:28])[CH3:27])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
Sodium hydride (0.664 g, 26.28 mmol) was added to a solution of 4-hydroxy-benzoic acid benzyl ester (5.0 g, 21.90 mmol) and 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) in DMF (50 mL). The resulting mixture was warmed up to 80° C. and stirred for 1 h before additional 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) and sodium hydride (0.664 g, 26.28 mmol) was added. After 18 h at 80° C. about 50% product could be detected by LC-MS. The reaction mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (Mg504) and evaporated and the desired product was isolated from the remaining mixture by HPLC. The title compound was obtained as an oil (2.5 g, 30.8%). 1H NMR (500 MHz, CDCl3): δ 7.96 (d, 2H), 7.43 (d, 2H), 7.37 (t, 2H), 7.33 (d, 1H), 6.82 (d, 2H), 5.32 (s, 2H), 1.60 (s, 6H), 1.40 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[CH:11]([C:9]1[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=1)=[O:12]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Reactant: Cc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C=O)cc(C(=O)O)c2)cc1
Yield: 57.2 %

Procedure:
To a mixture of 3-bromo-5-formylbenzoic acid (8.0 g, 34.9 mmol), p-tolylboronic acid (9.5 g, 70 mmol), toluene (300 mL), cesium carbonate (28 g, 87 mmol), and water (25 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.7 mmol). The mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried, and concentrated. The residue was purified by column chromatography using methylene chloride:methanol gradient (0-5%) to afford the title compound (4.8 g, 51%). LC-MS: 239.0 [M−1]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].[OH-].[Na+].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl.C>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20]([NH:21][C:33]([NH:32][CH3:31])=[O:38])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: COc1ccc(F)cc1C(=O)NC1COc2cc(OC)c(S(N)(=O)=O)cc2C1
Reactant: CNC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 0 °C

Procedure:
1.64 g (4 mmol) of 3-(5-fluoro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman were heated at 80° C. for 30 minutes in 10 ml of dry DMSO after addition of 0.4 g (10 mmol) of freshly powdered sodium hydroxide and 1.05 g (6 mmol) of N-methyltrichloroacetamide. The cooled reaction mixture was introduced into ice-water, clarified with active charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. The product had a melting point of 260° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].[F:14][C:15]1[C:16]([C:34](O)=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:14][C:15]1[C:16]([C:34]([NH:1][CH2:2][C:3]([OH:7])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6])=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: O=C(O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
1-Amino-2-phenylpentan-2-ol (0.099 g, 0.45 mmol, 1.5 eq) was dissolved in NMP (3 mL) and to this solution was added 3-fluoro-4-(2-(pyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (0.101 g, 0.30 mmol), EDAC (0.089 g, 0.45 mmol, 1.5 eq), HOBt (0.042 g, 0.30 mmol, 1 eq) and diisopropylethylamine (0.16 mL, 0903 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 2 h. The mixture was then purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound (0.0552 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.84-0.96 (1H, m), 1.19-1.30 (1H, m), 1.68-1.79 (2H, m), 3.63 (2H, d, J=5.81 Hz), 5.29 (1H, s), 7.01 (1H, dd, J=6.82 and 5.56 Hz), 7.05 (1H, t, J=5.18 Hz), 7.12 (1H, d, J=8.34 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.42-7.46 (2H, m), 7.78 (1H, td, J=7.77 and 1.89 Hz), 7.82 (1H, s), 8.22-8.26 (2H, m), 8.31 (1H, dd, J=5.05 and 1.01 Hz), 11.88 (1H, s). LC/MS (M+H)+: 510. HPLC ret. time (Condition J): 6.095 min. HRMS calcd: 510.1434; found: 510.1412.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C(N(CC)CC)C.O([Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][CH:16]([O:23][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(O[Si](C)(C)C(C)(C)C)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 87.4 %

Procedure:
To a solution of 17β-acetyloxy-5α-estran-3-one (1.595 g, 5 mmol) in dry dichloromethane (30 mL) was added with stirring at ice-water bath temperature, triethyl amine (2 mL) followed by t-butyldimethylsilyl triflate (2.64 g, 10 mmol). The solution was stirred for 25 min, then diluted with dichloromethane (20 mL) and washed with satd.aq. NaHCO3 (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed to yield a solid, which was purified by chromatography (silica gel, dichloromethane, pretreated with 1% triethyl amine in hexanes) to get 1.9 g (87%) of pure product as colorless crystals, m.p. 89°-90° C.
Reaction SMILES: OCC1COC(=O)O1.CN(C)C1CCCCC1.[N-:18]=[C:19]=[O:20].[N-:21]=[C:22]=[O:23].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:30][C:24]1[C:25](=[CH:26][C:27](=[CH:28][CH:29]=1)[N:21]=[C:22]=[O:23])[N:18]=[C:19]=[O:20]
Reactant: [N-]=C=O
Reactant: Cc1ccccc1
Agent: O=C1OCC(CO)O1
Solvent: CN(C)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 25 °C

Procedure:
To a one-liter, round bottom 3-necked flask, fitted with a mechanical stirrer, thermometer and dropping funnel, was added 118 g of glycerin carbonate (I) (1.0 moles) and 200 ml. of dry tetrahydofuran (THF). After addition of 1.0 g dimethylcyclohexylamine (DMCHA), the resulting solution was stirred under nitrogen at ambient temperature. Then, 87 g (1.0 equiv.) of Rubinate® 80/20 (Huntsman Corp.) toluenediisocyanate (TDI) (II) was then added dropwise while controlling the exothermic reaction so that the temperature did not exceed 60° C. After the addition of compound II was complete the reaction product was maintained at 50° C. for one hour. The resulting product was primarily a solution of III in THF, a light yellow mobile liquid. The reaction is shown diagrammatically below.