Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.[CH3:29][S-:30].[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:22][C:8]1[C:6]2[N:7]=[C:2]([S:30][CH3:29])[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1c(CN2CCN(S(C)(=O)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)c(C)c2n1

Procedure:
2-Chloro-7-methyl-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (2.38 mM) was added to sodium thiomethoxide dissolved in 50 mL toluene under N2 and heated to reflux. The reaction was stirred at reflux 24 hours and there was very little product by LCMS. To this reaction mixture was added 50 mL DMF to dissolve the starting material and again heated to reflux for two hours. Complete product formation was confirmed by LCMS. The reaction was poured onto ice water, extracted with ether, dried over MgSO4, and concentrated in vacuo. This crude product was purified by flash chromatography (MeOH/DCM) giving 7-methyl-2-(methylthio)-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. MS (Q1) 445 (M+)
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]>C1COCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 78.3 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. The suspension is added to the aqueous solution of 1.5 g of L-glutamic acid and 2.0 g of triethylamine, and treated in the same manner as Example 2 to give 1.9 g (80%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44]CC2C=CC=CC=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]CC2C=CC=CC=2)=[CH:11][CH:10]=1>[Pd].O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:11][CH:10]=1
Reactant: Fc1cccc(-c2ccc(OCCCCCC=CC(CCCCCCOCc3ccccc3)CCCCCCOCc3ccccc3)cc2)c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCCCCCC(CCCCCCO)CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.6 %

Procedure:
First, 3.3 g of 2,3-difluoro-4'-[8,8-bis(6-benzyloxyhexyl)-6-octene-1-yl]oxybiphenyl, 1 g of 10% Pd-C, and 100 ml of tetrahydrofuran were placed in a 200 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/2) to obtain 2.3 g of 2,3-difluoro-4'-[8,8-bis(6-hydroxyhexyl)octyl]oxybiphenyl (Y: 93.6%). The compound thus obtained had a purity of 98.8% by HPLC.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:41])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NCc5ccc(F)cc5)c(F)cc43)c(C)c2C1=O
Yield: 62.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 3 (61 mg, yield 62.2%) as a henna solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:22][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4cccc(Cl)c4)c3c2s1
Yield: 74 %

Procedure:
Prepared from VII and 3-chloroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 74%; pale yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2849, 2226, 1643, 1611, 1577, 1461, 1377, 1354, 1306, 1218, 1161, 1128, 1070, 974, 875, 833; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.40-7.35 (m, 2H), 7.19-7.11 (m, 2H); HRMS calcd for C16H9N5SCl (M+H+): 338.0267, found 338.0259.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][C@@H:26]([CH2:30][C:31]1[NH:35][CH:34]=[N:33][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[OH:25][C@@H:26]([CH2:30][C:31]1[NH:35][CH:34]=[N:33][CH:32]=1)[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: O=C(O)[C@@H](O)Cc1cnc[nH]1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@@H](O)Cc4cnc[nH]4)CC3)nc(-c3ccccc3O)nc2c1

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol), (S)-2-hydroxy-3-(1H-imidazol-5-yl)propanoic acid (64 mg, 0.41 mmol), triethylamine (76 μL, 0.54 mmol), and BOP (180 mg, 0.41 mmol) in 1 mL of CH2Cl2 were stirred at room temperature for 1.5 h. The reaction mixture was diluted with H2O and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification using 1-15% MeOH in CH2Cl2 gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one. LC/MS: m/z 459.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[CH2:28][CH2:27][C:26]([C:37](O)=[O:38])=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:45][N:46]([CH2:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>ClCCl.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[CH2:28][CH2:27][C:26]([C:37]([NH:58][C:57]4[CH:59]=[CH:60][C:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:55][CH:56]=4)=[O:38])=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C)c2)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cnn(C)c2)cc1
Reaction time: 1 h
Yield: 62.4 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(1-methypyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (380 mg) in dichloromethane (20 ml). Then, thionyl chloride (124 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this solution was added to a solution of 4-[[N-methyl N-(tetrahydropyran-4-yl)amino]methyl]aniline (229 mg) and triethylamine (2.1 g) in dichloromethane (30 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 69) (338 mg) as yellow crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([OH:22])=[O:21])[CH2:3]1.Cl.[CH3:24]O>>[CH3:24][O:21][C:20]([C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])=[O:22]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
38.97 g (121.4 mmol) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid were dissolved in 97 ml MeOH and 64.5 ml 1.75 M (112.8 mmol) HCl in MeOH were added and the solution heated to reflux for 3 h and concentrated. Trituration with hexane yielded 41.4 g (quant.) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown solid, MS: 335 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[C:10]([C:13](OCC)=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:10]([C:13]([OH:14])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[N:18]3[CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[N:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCC1=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 5-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}pyridine-2-carboxylate and ethyl 3-chloro-3-oxopropionate in a manner similar to that described in Example 1, Steps 10-11 and was obtained as a white solid: 1H NMR (CDCl3) δ 8.50 (1H, d, J=1.4 Hz), 8.11 (1H, s), 7.26 (2H, m), 7.00 (2H, ddd, J˜9, 9, 2 Hz), 4.52 (2H, q, J=7 Hz), 4.33 (2H, br t, J˜7 Hz), 4.14 (2H, s), 3.52-3.44 (4H, m), 2.35 (2H, t, J=8 Hz), 2.00 (2H, m), 1.48 (3H, t, J=7 Hz); HRMS calcd for C24H24FN3O5+H+: 454.1778. Found: 454.1787.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH:30][C:31]([NH2:33])=[NH:32]>>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:33]=[C:31]([NH:30][C:22]3[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=3[CH3:20])[N:32]=2)[CH:8]=[N:9][CH:10]=1
Reactant: COc1cncc(C(=O)C=CN(C)C)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: O=[N+]([O-])O
Product: COc1cncc(-c2ccnc(Nc3cc([N+](=O)[O-])ccc3C)n2)c1

Procedure:
Condensation of 12 with N-(2-methyl-5-nitro-phenyl)-guanidine nitrate 2 using a similar procedure for the preparation of 4 affords 4-(5-methoxypyridin-3-yl)-N-(2-methyl-5-nitrophenyl)pyrimidin-2-amine 13. 1H NMR (400 MHz, d6-DMSO) δ 9.23 (s, 1H), 8.93 (d, J=1.2 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.44 (d, J=2.8 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=2.0, 8.4 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.44 (s, 3H). MS (m/z) (M+1)+: 338.1
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:21]([O:20][C:19](=[O:25])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:4]2[C:3]([CH:2]=[O:1])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=2)[CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CSc1ncc(CO)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reaction time: 18 h
Yield: 43 %

Procedure:
At RT, manganese (IV) oxide (358 g, 4.1 mol) was added to a solution of tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50d) (140 g, 386.8 mmol) in CHCl3. After 18 h, the reaction mixture was filtered through a pad of Celite washing with 3×100 mL of CHCl3. The filtrate was concentrated and the residue was purified on a silica gel column (eluted with 15-65% EtOAc in hexanes) to give tert-butyl(3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (60 g, 43% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.61 (1H, br. s.), 9.77 (1H, s), 8.44 (1H, s), 7.99 (1H, br. s.), 7.33-7.39 (1H, m), 7.27-7.30 (1H, m), 7.00-7.06 (1H, m), 6.41-6.55 (1H, m), 2.59 (3H, s), 1.53 (9H, s). m/z (ESI, +ve ion) 361.1 (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=1[OH:29].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc([N+](=O)[O-])c1O
Yield: 67.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 590 mg of 2-amino-6-nitrophenol, and 734 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 6 ml of N,N-dimethylformamide. 976 mg of N-(2-hydroxy-3-nitrophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [O-]CC.[Na+].C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12]2)(=O)C>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (1.86 g) was added to a stirred solution of ethyl 5-acetoxy-N-(3,4-dichlorobenzyl)indole-2-carboxylate (5.55 g) in ethanol (50 ml) under an atmosphere of argon. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue acidified with aqueous hydrochloric acid (2 M) and extracted with dichloromethane. Combined organic extracts were washed with water, saturated aqueous sodium chloride solution and dried. The solvent was removed in vacuo and the residue was triturated with hexane/diethyl ether to yield the product as a white solid (3.17 g, 92%). NMR: δ 1.26 (t, 3H), 4.25 (q, 2H), 5.75 (s, 2H), 6.81-6.91 (m, 2H), 6.98 (d, 1H), 7.19 (s, 1H), 7.29 (d, 1H), 7.38 (d, 1H) 7.50 (d, 1H), 9.06 (s, 1H); m/z 364 (M+H+).
Reaction SMILES: [CH2:1]([C:5]([NH2:7])=[O:6])[C:2]([NH2:4])=[O:3].C[O-].[Na+].[CH3:11][N:12](C=NC=[N+](C)C)[CH3:13].[Cl-].CNC.Cl>O1CCCC1>[OH:3][C:2]1[C:1]([C:5]([NH2:7])=[O:6])=[CH:13][N:12]=[CH:11][N:4]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: NC(=O)CC(N)=O
Agent: CNC
Agent: C[O-]
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cncnc1O
Temperature: 25 °C

Procedure:
At room temperature, malonodiamide (10.75 g, 0.10 mol) was added to a sodium methoxide solution (55.88 g, 0.30 mol., 29% in methanol.), and the mixture was diluted with tetrahydrofuran. At room temperature, the Gold's reagent prepared as in Example 1 (18.0 g, 0.11 mol) was added, and argon was passed through for 24 hours in order to drive off the dimethylamine liberated. The pH was then adjusted to 7.4 using an aqueous hydrochloric acid solution, and most of the tetrahydrofuran was removed on a rotary evaporator. The resulting suspension was adjusted to pH=5.5 using eq. HCl and heated to reflux temperature. Water was then added again in order to bring everything into solution, then activated carbon was added and the mixture was stirred under reflux for a further 15 min. After slow cooling to room temperature, pale yellow crystals precipitated out, which, after filtration, were dried under reduced pressure at 40° C. to give the title product in a yield of 5.58 g (80%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:12]3)[CH:7]=1.C(O)C.Cl.[H][H]>C(Cl)Cl.O=[Si]=O.[OH-].[Pd+2].[OH-]>[NH2:18][C@@H:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([CH2:8][N:6]3[CH:7]=[C:3]([CH2:2][OH:1])[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5]3)[CH:10]=2)[CH2:14]1
Reactant: [H][H]
Reactant: O=C(N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=[Si]=O
Solvent: CCO
Solvent: ClCCl
Product: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Yield: 70.5 %

Procedure:
Palladium hydroxide (20% on carbon, 6.38 mmol, 0.895 g) was wetted in a hydrogenation vessel before addition of (S)-benzyl 5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate (6.38 mmol, 2.84 g) and ethanol (50 mL) followed by aqueous 5N HCl solution (5.00 mL). The mixture was stirred under 2 bar of hydrogen for 1 hour before diluting with DCM (100 mL) and filtration through a dicalite pad which was then washed with 10% MeOH/DCM (200 mL). Combined organics were concentrated and partitioned between ethylacetate and saturated sodium carbonate solution. The organic layer was concentrated to give a light yellow oil which was purified on silica eluting with 5.5% 2M NH3-MeOH/DCM to give (S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (1.40 g, 70.7%). 1H NMR (400 MHz, CDCl3) δ 2.65 (m, 2H) 3.16 (m, 2H) 3.82 (m, 1H) 4.59 (s, 2H) 5.23 (s, 2H) 7.06 (d, 1H) 7.10 (s, 1H) 7.18 (d, 1H) 7.38 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17]
Reactant: CCn1c2ccccc2c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COc1cccc(-c2ccccc2Br)c1
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: Cc1ccccc1
Product: CCn1c2ccccc2c2ccc(-c3ccccc3-c3cccc(OC)c3)cc21
Reaction time: 5 h
Yield: 68.9 %

Procedure:
3.93 g (15.00 mmol) of 2-bromo-3′-methoxybiphenyl, 5.3 g (16.50 mmol) of 9-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)carbazole, and 0.35 g (0.30 mmol) of Pd(PPh3)4 were dissolved in 50 ml of toluene, and 4.77 g (45.00 mmol) of Na2CO3 was put into 25 ml of distilled water and then refluxed and agitated for 5 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=7:3 (v/v) to obtain 3.90 g of 9-ethyl-2-(3′-methoxybiphenyl-2-yl)carbazole (yield 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:12]([N:15](C(C)C)CC)([CH3:14])[CH3:13].C(N)(C)C>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH:12]([CH3:14])[CH3:13])=[O:9]
Reactant: Nc1ccc(F)c(C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)c1cc(N)ccc1F
Yield: 619.6 %

Procedure:
A solution of 5-amino-2-fluorobenzoic acid (300 mg, 1.9 mmol), diisopropylethylamine (1 ml, 5.8 mmol), and isopropylamine (0.3 ml, 3.9 mmol) in acetonitrile was heated to 110° C. in microwave for 45 min. This reaction was repeated 5 times and the crude products combined then concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/dichloromethane (0% to 10% v/v) to afford the title compound as a yellow solid (2.31 g). HPLC retention time 3.93 min. Mass spectrum (ES+) m/z 197 (M+H).
Reaction SMILES: FC1C=C(CCC(O)=O)C=CC=1OC.C([O:18][C:19]1[CH:20]=[C:21]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH:22]=[C:23]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[C:24]=1[O:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)(=O)C.[OH-].[Na+]>>[CH:26]1([O:25][C:24]2[C:23]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)=[CH:22][C:21]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:20][C:19]=2[OH:18])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)CCc1cc(OC(C)=O)c(OC2CCCC2)c(-c2ccc3ccccc3c2)c1
Agent: COc1ccc(CCC(=O)O)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1cc(O)c(OC2CCCC2)c(-c2ccc3ccccc3c2)c1
Reaction time: 2 h
Yield: 109.7 %

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 2 hours, Intermediate 58 (146 mg) and 2 N aqueous sodium hydroxide (0.35 ml) were reacted and treated to obtain the title compound (Compound No. T-2, 135 mg).