Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[OH:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[O:3][C:4]([C:7]3[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:5][N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Reactant: Nc1cccc(O)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 73.9 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.23 g, 0.723 mmol) and commercially available 3-aminophenol 8 (0.079 g, 0.724 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 22 (0.209 g, 74% yield) as solid. MS (ES) m/z 392 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24](O)[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([O:19][CH:24]([CH3:25])[CH3:23])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)O
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)C

Procedure:
The ester can be prepared by acid catalysed esterification of 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoic acid with/in 2-propanol. Isocratic HPLC method 2 (4.96 min.): 98.4%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=1>>[CH3:28][S:27][C:23]1[N:24]=[C:25]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)[CH:26]=[CH:21][N:22]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Product: CSc1nccc(NCC2CCN(C(=O)OCc3ccc(C)cc3)CC2)n1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using 4-methylbenzyl 4-(aminomethyl)-1-piperidinecarboxylate (600 mg, 2.29 mmol), and 4-chloro-2-methylthiopyrimidine (386 mg, 2.40 mmol) as starting materials and gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:20][C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: COC(=O)NC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1ccc(S)cc1C
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)c1ccc(CSc2ccc(C)c(C)c2)cc1

Procedure:
A solution of 3,4-dimethylbenzenethiol (9.24 g) in DMF (30 ml) reacted with a solution of methyl N-[1-(4-bromomethylphenyl)-1-methylethyl]carbamate (19.15 g) in DMF (100 ml) by Method 6a) to give methyl N-{1-methyl-1-[4-(3,4-xylylthiomethyl)phenyl]ethyl}carbamate as a sticky solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.O1CCOCC1.O.C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:15])[CH3:25]
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 6-bromo-N-((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.37 g, 0.85 mmol) and 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) in dioxane/water mixture (3 mL+1 mL for 1 mmol), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.05 equiv.) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound. (38% yield). LCMS: 491.25 (M+1)+; HPLC: 95.01% (@ 254 nm) (Rt; 5.463); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.87 (s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 6.80 (s, 1H), 5.91 (s, 1H), 5.22-5.19 (m, 1H), 4.39 (d, 2H, J=4.0 Hz), 2.42-2.40 (m, 4H), 2.24 (s, 3H), 1.49 (d, 6H, J=6 Hz). 1.24 (s, 6H), 1.14 (s, 6H), 1.11 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:35])=[O:4].O[Li].O.Cl>CO.O>[CH:14]1([N:12]2[C:13]3[C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:35])[CH:7]=[CH:8][C:9]=3[N:10]=[C:11]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH3:18])[CH2:15][CH2:16]1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(C3CC3)c12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1C1CC1
Temperature: 80 °C
Yield: 21.5 %

Procedure:
A solution of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (607 mg, 1.27 mmol) and LiOH.H2O (266 mg, 6.33 mmol) in MeOH (20 mL) and water (2 mL) was heated at 80° C. for 22 h. Additional LiOH.H2O (266 mg) was added and the mixture heated at 80° C. for 5 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1M aqueous HCl. The organic solvent was removed under reduced pressure and the aqueous phase extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) to afford the title compound (127 mg, 21% over 2 steps) as a white solid. LCMS (Method C): RT 2.17 min [M+H]+ 466.22.
Reaction SMILES: [N+](C1C=C(S(O[C@@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)(=O)=O)C=CC=1)([O-])=O.C(#N)CC.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41].C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC#N
Product: COC(=O)[C@@H]1C[C@@H](Sc2ccccc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-(3-nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylate (8.5 g, 19.7 mmol, Eq: 1.00) was combined with propionitrile (82.0 ml) to give a light brown solution. Then 2-chlorobenzenethiol (4.28 g, 3.38 ml, 29.6 mmol, Eq: 1.50) and triethylamine (4.00 g, 5.5 ml, 39.5 mmol, Eq: 2.00) were added dropwise. The reaction was stirred overnight at reflux (100° C.). The reaction was cooled to room temperature, and poured in 50 ml Na2CO3 solution (10%), and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 50 ml HCl 0.1M and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 80% heptane in ethyl acetate). The title compound was obtained as a yellow oil (5.7 g, 77.6%, MS (m/e)=372.1 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][S:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[NH:9]2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)-c1ccccc1SC2
Solvent: CC(=O)O
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1)-c1ccccc1S(=O)C2
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a 50 ml. round bottom flask under nitrogen was placed 2-(p-chlorophenyl)-1,2,3,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazole-3-one (0.5 g., 0.0016 mole) 8.33 ml. of glacial acetic acid and 3 ml. of 30% hydrogen peroxide. After stirring at 0° C., for 3.5 hours, the resulting solid was removed by filtration, washed with glacial acetic acid and dried in vacuo over phosphorous pentoxide to afford product, m.p. 193° C. (dec.). Weight 0.42 g. (80%). A second crop (0.4 g., 8%) was obtained from mother liquors.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=O)=[O:8])[CH:3]=1.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.BrBr.[C:36]([O-:39])(=[S:38])[CH3:37].[Na+]>C(O)(=O)C.C(#N)C>[C:36]([S:38][CH:9]([C:7](=[O:8])[C:4]1[CH:3]=[C:2]([Cl:1])[S:6][CH:5]=1)[CH2:10][C:11]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])(=[O:39])[CH3:37]
Reactant: O=C(O)CCC(=O)c1csc(Cl)c1
Reactant: CC([O-])=S
Reactant: O=C(O)[C@@H]1CCCN1
Agent: BrBr
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1csc(Cl)c1

Procedure:
As for Example 8, 3-(5-chloro-3-thenoyl)propionic acid is coupled to L-proline with 1,1'-carbonyldiimidazole. The coupled product is reacted with bromine in acetic acid and the brominated derivative is reacted with sodium thioacetate in acetonitrile to give the product of the Example as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])C(O)=O.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)cc(Cl)c1OC
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(Cl)c1OC

Procedure:
from 2-chloro-N-(3-methoxyphenyl)-4-pyrimidineamine (0.50 g, 2.13 mmol) [see Example 92] and 3-chloro-4,5-dimethoxyaniline (0.40 g, 2.13 mmol) to give the title compound (0.55 g) as a white soid m.p. 204-205°. δH (d6DMSO) 11.19 (1H, br s),10.85 (1H, brs), 8.00 (1H, d, J 7.1 Hz), 7.23 (4H, m), 7.12 (1H, d, J 4.4 Hz), 6.75 (1H, m), 6.59 (1H, d, J 7.1 Hz), 3.74 (3H, s), 3.69 (3H, s) and 3.65 (3H, s). MS m/z 387 (M+H)+. The aniline starting material was prepared in a similar manner to the analogous aniline of Example 113, from 1-chloro-2,3-dimethoxy-5-nitrobenzene (1.08 g, 5.82 mmol), to give the desired product (0.85 g) as a white solid m.p. 66-68°. MS m/z 188 (M+H)+. The 1-chloro-2,3-dimethoxy-5-nitrobenzene was prepared by heating a solution of 3-chloro-4,5-dimethoxybenzoic acid (3.50 g, 16.2 mmol) in glacial acetic acid (15 ml) and 70% nitric acid (15 ml) at 600 for 1 h. The reaction was poured onto ice-water and the white precipitate which formed was filtered off, washed with water and dried in vacuo and washed thoroughly with hexane. The hexane washings were evaporated and the residue subjected to column chromatography [silica 20% ethyl acetate-hexane] to give the desired product (1.03 g) as a white solid m.p. 104-105°. MS m/z 217 (M+H)+. The acid used as starting material was prepared according to the method of Y. Ohtani et al. Acta. Chem. Scand., Ser B. B36, 613 (1982).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:34][CH2:26][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:23])[N:12]([CH3:24])[C:11]=2[S:25][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)c2c(CBr)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (25 mg, 0.0636 mmol) in CCl4 (1 mL) was added NBS (11.3 mg, 0.0636 mmol) followed by benzoyl peroxide (2 mg). The reaction was heated at reflux for 4 h, cooled to RT then diluted with DCM (10 mL). The mixture was washed with aq. NaHCO3 (5 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated to give methyl 3-(5-(bromomethyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (30 mg, 100% yield). LCMS: MH+ 473 and TR=1.907 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26](=[O:25])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(Nc2ccnc(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine (2.70 g, 10.82 mmol) in THF (45 mL) was added Et3N (6.32 mL, 45.3 mmol). The mixture was cooled to 0° C., and DMAP (0.0135 g, 0.110 mmol) and BOC2O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt and stirred for 18 h. The mixture was quenched with ice and diluted with water. Extracted with EtOAc (3×200 mL), washed with brine and water, dried (MgSO4), and concentrated. A dark oil was afforded, which was passed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes. Concentrated and dried under high vacuum to afford tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2[C:54](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:53][C:35]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C.C[OH:82]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:20][N:19]=[CH:18][N:17]=1)[S:12]([C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([C:35]([O:53][CH3:54])=[O:82])=[CH:11][CH:10]=[CH:9]2)(=[O:13])=[O:14]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)ccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 500-mL two-neck flask was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D, 10 g, 19.22 mmol), palladium (ii) acetate (0.216 g, 0.961 mmol), and Xantphos (1.112 g, 1.922 mmol). Triethylamine (77 ml, 19.22 mmol), toluene (48.0 ml), and methanol (15.55 ml, 384 mmol) were added, and the reaction was fitted with a reflux condenser. The reaction was evacuated and back-filled with carbon monoxide three times, and then the reaction was heated to 70° C. and stirred for four hours under an atmosphere of carbon monoxide. The reaction was filtered through a pad of diatomaceous earth, which was thoroughly washed with ethyl acetate. The filtrate was concentrated, triturated in ethyl acetate and filtered. The solid was collected and the filtrate was concentrated. The trituration procedure was repeated twice, and the solids resulting from each trituration were combined with the previously isolated material. After the third trituration, the mother liquor was purified via column chromatography (RediSep Gold 80 g silica gel column, gradient elution 0-50% EtOAc:Heptane). The clean product fractions were combined with the previously isolated material and the resulting slurry was concentrated to afford methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate as a light yellow solid. m/z (ESI) 500.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1O)=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].O=P(Cl)(Cl)[Cl:27]>>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[Cl:27])=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: Cc1cccc2c1c(O)c(C(=O)N(C)c1ccccc1)c(=O)n2C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c1c(Cl)c(C(=O)N(C)c1ccccc1)c(=O)n2C

Procedure:
N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (3.5 g) was heated in phosphorus oxytrichloride (7 ml) at 100° C. for 2 hours. The mixture was concentrated, dissolved in dichloromethane and washed with water. The organic phase was dried (Na2SO4) and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C.C([O-])(=O)C.[NH4+:25].N>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:25]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1nc(Cl)ccc1N(C=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(Cl)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (4.71 g), acetic acid (11.1 mL) and ammonium acetate (7.48 g) was stirred at 130° C. for one hour. The reaction solution was left to cool to room temperature. Ice water, ethyl acetate and aqueous ammonia were added and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.42 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1Cc1nc(/C=C/C(=O)O)cs1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound 72 (980 mg) in dimethylformamide (3.00 mL) was added n-butyl iodide (570 μL) at room temperature and then thereto was added potassium carbonate (691 mg) at 0° C. The solution was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated. The organic residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=78:22→50:50) to give the title compound (960 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([CH:29]=[CH2:30])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
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: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C3CCCC3)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.5 g, 3.386 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.625 g, 4.063 mmol) and Pd(PPh3)4 (0.392 g, 0.034 mmol) in 1,4-dioxane (15 mL) and purged with argon for 10 min. A solution of 2M Na2CO3 (1.29 g, 12.18 mmol) was then added to it before a further argon purge for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-vinyl-1H-indazole-4-carboxamide (0.9 g, 68.2%).