Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH:26]1[CH2:28][CH2:27]1)[C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([NH2:20])[N:18]=[CH:19][C:14]=3[S:13][C:12]2=[O:21])[C@@H:8](CC([O-])=O)[CH2:7]1)(=[O:3])[CH3:2].C(OC([C@H]1O[C@@H](N2C3N=C(N)N=CC=3SC2=O)[C@@H](CC([O-])=O)C1)CC)(=[O:31])C>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]2[S:13][C:12](=[O:21])[N:11]([C@@H:9]3[O:10][C@H:6]([C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]4[CH2:27][CH2:28]4)[CH2:7][C@H:8]3[OH:31])[C:15]=2[N:16]=1
Reactant: CC(=O)OC(C1CC1)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Product: CC(=O)O[C@@H](C1CC1)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3cnc(N)nc32)O1

Procedure:
The title compound was prepared in analogy to Example 4, by using [(2R,3R,5S)-5-[acetoxy(cyclopropyl)methyl]-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl] acetate (compound 16a) instead of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 2a). Example 16 was purified and separated by preparative HPLC to afford Example 16-A and Example 16-B as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21][NH:20][CH2:19]2)[CH:13]=[C:14]([Cl:17])[C:15]=1[Cl:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][C:18]([C:12]3[CH:13]=[C:14]([Cl:17])[C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=3)([C:23]([F:24])([F:25])[F:26])[CH2:19]2)[N:3]=1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Reactant: Cc1cccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
2-Chloro-6-methylpyridine (1.6 g), 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-pyrrolidine (4.0 g), sodium t-butoxide (1.5 g), tris(dibenzylidenacetone)dipalladium (0)-chloroform adduct (0.2 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.25 g) were added to toluene (15 ml), and heated for 1 hour at 120° C. using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). Upon the completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the precipitate was filtered off through a short silica gel layer. The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccc(Br)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-4-bromomethyl-benzene using the conditions described in Example 10C to provide 4-(4-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[NH:6]2.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[N:6]2[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCOC(=O)c1nc2ccc(OC)cc2n(C)c1=O

Procedure:
3,4-Dihydro-6-methoxy-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1.9 g), methyl iodide (2 ml) and anhydrous potassium carbonate (6 g) in 2-butanone (100 ml) were stirred and heated under reflux for 1.5 hours. The solid was filtered off and the filtrate was evaporated. The residue was crystallised from aqueous methanol, m.p. 166° (80%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH2:16]Cl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:16][C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]=3[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Yield: 33.7 %

Procedure:
A mixture of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine (1.2 g, 7.41 mmol), 2,6-dimethylbenzylchloride (1.145, 7.41 mmol), sodium iodide (0.3 g), sodium carbonate (2.0 g) and acetone (50 ml) was refluxed for 3 h. After the addition of methylene chloride the reaction mixture was filtered. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2—MeOH (100:5) to give 0.70 g of the desired product (from ethyl acetate-ether).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:23]1CCC(N)CC1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:5][CH2:4][O:23][CH2:3][CH2:2]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCOCC1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCOCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using tetrahydro-2H-pyran-4-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (bs, 2H), 1.52 (bs, 2H), 1.79 (d, J=16.39 Hz, 3H), 2.06 (d, J=8.87 Hz, 3H), 3.17 (d, J=11.01 Hz, 2H), 3.74 (d, 2H), 3.85 (bs, 1H), 4.44 (d, J=6.18 Hz, 2H), 5.81 (d, J=7.52 Hz, 1H), 6.73 (s, 1H), 7.12-7.16 (m, 1H), 7.23 (d, J=7.79 Hz, 1H), 7.65 (t, J=7.66 Hz, 1H), 8.45 (d, J=4.84 Hz, 1H); MS (ESI) m/z 314.4 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[CH:14][C:3]=12.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>O>[CH:25]1([NH:31][C:2]2[C:3]3[CH:14]=[CH:13][NH:12][C:4]=3[N:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:9])=[O:10])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(S(C)(=O)=O)cnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
4-Chloro-5-(methylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (61 mg, 0.16 mmol) in cyclohexylamine (200 μL, 1.74 mmol) was stirred with N,N-diisopropylethylamine (40 μL, 0.23 mmol) at 120° C. for 30 minutes The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1→5/1 (v/v)) to give the title compound as a colorless solid (7.0 mg, yield 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: c1c[nH]cn1
Product: CCOC(=O)c1cccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (163.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (63.5 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH:21][CH:22]=[O:23])[C:18]([F:24])=[CH:17][C:16]=1[F:25].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:32]([NH:39][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH:21][CH:22]=[O:23])[C:18]([F:24])=[CH:17][C:16]=1[F:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
To 30 ml of toluene were added 800 mg of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluoro-5-formylaminophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.21 ml of benzylamine, and 240 mg of anhydrous potassium carbonate. The solution was heated at reflux overnight. The reaction solution was allowed to cool down and concentrated in vacua. The residue was combined with chloroform and washed with water. The solution was dried over magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the residue. The solid was collected by filtration and washed with diethyl ether to give 600 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.I[CH3:21]>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH3:21])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: CI
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: Cn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro2-(4-formylphenyl)-1-methylbenzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and iodomethane by following General Procedure 3.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18]N=N[C:15]=2[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:8](=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:9][C:15]=2[CH:19]=1
Reactant: Clc1ccc2snnc2c1
Reactant: S=C=Nc1ccccc1
Product: Clc1ccc2sc(=Nc3ccccc3)sc2c1
Temperature: 220 °C
Yield: 24.6 %

Procedure:
Phenylisothiocyanate (8.8g) and 5-chloro-1,2,3-benzothiadiazole (3.75g) are combined under an inert atmosphere and heated at 220° C until nitrogen evolution ceases. Initial purification of the product is accomplished by dry column chromatography (600g alumina column, benzene solvent). The product is further purified with a methylene chloride wash and recrystallization (twice) from pentane to yield 1.5g of the title compound, melting point 71°-73° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:1](=[O:3])[CH3:2])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Cl
Reactant: Fc1cccc(CC[C@@H]2CCCN2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.29 ml) was added to a solution of N,N-diisopropyl-N-ethylamine (0.71 ml) and (R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidine (Intermediate 233, 0.39 g) in DCM (30 ml) and the mixture was stirred for 1.5 hours. The mixture was washed with 1M HCl, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 1-{(R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidin-1-yl}ethanone (0.48 g) as an oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O)[CH3:3].C(O)C.[S-:18][C:19]#[N:20].[K+]>O>[CH2:2]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:20]=[C:19]1[SH:18])[CH3:3]
Reactant: N#C[S-]
Reactant: CCNCC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1cc(-c2ccc(O)cc2)nc1S
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred and refluxing mixture of 21.5 parts of 2-(ethylamino)-1-(4-hydroxyphenyl)ethanone hydrochloride, 60 parts of ethanol and 75 parts of water is added dropwise a solution of 12 parts of potassium thiocyanate in a small amount of water. Upon completion, stirring is continued overnight at reflux temperature. Another portion of 4 parts of potassium thiocyanate in a small amount of water is added and the whole is stirred for 8 hours at reflux temperature. The reaction mixture is concentrated. The product is filtered off and crystallized from a mixture of ethanol and water, yielding 10 parts (91%) of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol; mp. 251.7° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:27][N:13]3[C:14](=[O:26])[NH:15][C:16]4[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:21]=4[C:12]3=[N:11][CH2:10]2)=[CH:5][CH:4]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:27][N:13]3[C:14](=[O:26])[NH:15][C:16]4[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:21]=4[C:12]3=[N:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:41]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CNc1ccc(C2CN=C3c4ccc(C(=O)OC)cc4NC(=O)N3C2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)NC(=O)N1CC(c3ccc(N(C)C(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)CN=C21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
To a solution of methyl 3-[4-(methylamino)phenyl]-6-oxo-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline-9-carboxylate (5.1 mg, 0.014 mmol) in 0.7 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0024 mL, 0.017 mmol) and the reaction stirred at rt. After 15 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. At 1 hour the reaction was quenched with 1 mL MeOH and evaporated. The resulting solid was crystallized from EtOAc/hexane to give the title compound as an off-white solid (6.4 mg, 80%). 1H NMR (Acetone-d6) δ: 9.70 (br. s, 1H), 8.57 (dd, J=7.3, 2.3 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.69 (dd, J=8.4, 1.6 Hz, 1H), 7.50-7.59 (m, 4H), 7.25-7.39 (m, 2H), 7.06 (d, J=2.9 Hz, 1H), 4.39-4.47 (m, 1H), 3.88-3.97 (m, 4H), 3.62-3.79 (m, 2H), 3.34 (s, 3H), 3.15-3.27 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[S:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9]([NH2:11])=[S:10])=[O:14])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: NC(=S)NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)N(NC(N)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-phenylthiosemicarbazide (25 g), ethanol (180 ml) and ethyl chloroformate (17 ml) was heated under reflux with stirring for 30 minutes. The mixture was cooled to room temperature and the solid was filtered, washed with ethanol and then with ether to give 28.9 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[C:17](Cl)(Cl)=[O:18]>>[C:4]1([N:1]=[C:17]=[O:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1
Solvent: Nc1ccccc1
Product: O=C=Nc1ccccc1

Procedure:
The process of claim 18 in which the nitrobenzene is converted to an aniline compound and then reacted with phosgene to form a phenyl isocyanate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[CH:4]=1.[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38](O)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([O:1][CH2:2][C:3]3[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]4[N:11]=[C:12]([C:16]5[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=5)[O:13][C:14]=4[CH3:15])[CH:4]=3)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(CO)on3)c(C)o2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)on3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A mixture of ethyl {4-[4-({[5-(hydroxymethyl)isoxazol-3-yl]oxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (500 mg), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (389 mg), 1,1′-(azodicarbonyl)dipiperidine (440 mg), tributylphosphine (0.501 mL) and tetrahydrofuran (20 mL) was stirred at 50° C. for 1 hr. After cooling, the resulting precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v). The obtained eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (257 mg, yield 30%) as pale-yellow amorphous form.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]2[N:16]([CH:2]=[C:3]([CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[N:20]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Reactant: Nc1ncccc1Cl
Product: C[Si](C)(C)C#CCCc1cn2cccc(Cl)c2n1
Yield: 72.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (4.96 g, 20.1 mmol, Example 223(C)) and 3-chloropyridin-2-amine (1.29 g, 10.0 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 2.00 g (7.22 mmol, 72%) of 8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:3]1[CH3:19].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:19])=[C:4]2[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:25])[CH3:21]
Reactant: Cc1ccc(-c2c(C)n(C)c3ccc(O)cc23)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(C)cc1)c(C)n2C

Procedure:
The above compound was prepared from 1,2-dimethyl-3-(4-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2ccc(C(F)(F)F)cc2)ccc1O
Yield: 30.6 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-(trifluoromethyl)benzyl chloride (760 mg, 3.92 mmole), 310 mg (50% yield) of 5-(4-(trifluoromethyl)benzyl)aminosalicylic acid was obtained as a white solid.: mp>188° C. (decompose).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.CCN(C(C)C)C(C)C.[N:21]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>C(Cl)Cl>[CH:24]1([NH:21][C:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1cccc2cnccc12
Reactant: O=C=NC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cnccc12)NC1CCCC1
Reaction time: 24 h

Procedure:
To isoquinolin-5-amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added DIEA (0.557 mL, 3.19 mmol) and isocyanatocyclopentane (0.180 mL, 1.595 mmol). After 24 h, the reaction was quenched with H2O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). An impure yellow solid was collected and was carried onto the next step. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:41][CH2:42][F:43])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]([CH2:41][CH2:42][F:43])[C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)n(CCF)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 3.7 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (24 mg, 0.06 mmol) and potassium carbonate (33 mg, 0.24 mmol) were stirred in DMF (0.5 mL) at room temperature, then 2-fluoroethyl tosylate (40 mg, 0.18 mmol) was dropwise added thereto and stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (1.0 mg, 4%) as a pale yellow solid.