Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH:3]([C:8]1[CH:14]=[C:13]([C:15](F)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[NH2:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:25][OH:26]>>[CH3:2][CH:3]([C:8]1[CH:14]=[C:13]([C:15]([O:26][CH3:25])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[NH2:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CO
Reactant: CC(C)CC(C)c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: [Na]
Product: COC(c1ccc(N)c(C(C)CC(C)C)c1)(C(F)(F)F)C(F)(F)F
Yield: 87 %

Procedure:
Sodium (533 mg, 23 mmol) was dissolved in methanol (40 ml), followed by adding thereto 2-(1,3-dimethylbutyl)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (2 g, 5.8 mmol), and the resulting mixture was stirred at reflux temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain 1.8 g of the desired compound.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].C1COCC1.[CH3:18][C:19]([CH3:29])([CH2:25][CH2:26][CH2:27][CH3:28])[C:20](OCC)=[O:21]>C(O)(=O)C>[O:21]=[C:20]([C:19]([CH3:29])([CH3:18])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithium (400 ml.) is added slowly to a solution of dimethyl methylphosphonate (73.7 g.) in 1.3 l. of THF at about -66° C. To the mixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in 150 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 46 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 41.6 g., b.p. 117°-120° C./1 mm.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1.[N+](C1C=CC=CC=1S([O:26][C:27]1[C:28]([O:36][CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2)(=O)=O)([O-])=O.O>CN(C)C=O>[CH3:37][O:36][C:28]1[C:27]([OH:26])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[N:31][NH:32]2
Reactant: COc1c(OS(=O)(=O)c2ccccc2[N+](=O)[O-])ccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(O)ccc2[nH]ncc12
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
Cesium carbonate (45 mg, 0.137 mmol) and thiophenol (24 ml, 0.229 mmol) were added to a solution of 4-methoxy-1H-indazol-5-yl 2-nitrobenzenesulfonate (40 mg, 0.115 mmol) in N,N-dimethylformamide (1 ml) at 0° C. After 30 minutes, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-methoxy-1H-indazol-5-ol (19 mg, 100%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[N:8]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1)=O.CO>C(N(CC)CC)C>[F:24][C:20]1[CH:19]=[C:18]([S:15]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:7]=[C:6]3[NH2:5])(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12

Procedure:
The crude 2,2,2-Trifluoro-N-[5-(3-fluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-acetamide (46.33 mmol) was treated with methanol (250 mL) and triethylamine (20 mL) and heated to reflux for 36 hours. The volatiles were partially evaporated, cooled and filtered. The solid was washed with a small volume of methanol then with water. After drying under vacuum at 70° C. and further purification by recrystallization from ethyl acetate the title compound was obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:32][CH3:33])[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)C.[Li+].[OH-].Cl>CO>[CH2:13]([O:12][C:9]1[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:21]=2[CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:32][CH3:33])=[CH:7][C:6]([CH2:5][C:4]([OH:44])=[O:3])=[CH:11][CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of {6-benzyloxy-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.050 g, 0.08 mmol) in MeOH (3 mL) was added 1N aqueous LiOH (1 mL), and the reaction was stirred at 65° C. overnight. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 578.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26]>CN1CCCC1=O.CO>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: CC(C)CN
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)CNc1cc(NC2CC2)n2ncc(C=C3SC(=O)NC3=O)c2n1
Temperature: 130 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (30 mg, 0.09 mmol) in N-methylpyrrolidinone (NMP) was added 2-methylpropan-1-amine (20 mg, 0.268 mmol). The reaction was heated at 130° C. overnight. Mixture was diluted with methanol and prepared by HPLC to yield 5-((7-(cyclopropylamino)-5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=373)
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](OC/C=C\C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 84.8 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene (67.9 mg, 0.0880 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a white solid (32.0 mg, 85%).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[CH3:14]O>>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CO
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: Cl
Product: COC(=O)C(O)Cc1ccccc1
Reaction time: 7 h
Yield: 98 %

Procedure:
Hydrochloric acid gas was bubbled into a solution of 2-hydroxy-3-phenyl-propionic acid (6.0 g, 36.10 mmol) in MeOH (250 ml) at room temperature under CaSO4 tube for 20 minutes. The resulting colorless solution was stirred for 7 hours and concentrated in vacuo to afford 2-hydroxy-3-phenyl-propionic acid methyl ester as a brown syrup (6.36 g, 98% yield): MS (ESI) m/z 181.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([CH3:36])[CH2:35][O:34][CH2:33]4)=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([CH3:36])[CH2:35][O:34][CH2:33]4)=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C(O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from ((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(3-methyloxetan-3-yl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[CH3:28]>>[Cl:1][C:2]1[C:3]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:27][CH3:28])[CH:30]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCc1cccc(N)c1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: CCc1cccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)c1
Yield: 49 %

Procedure:
By a procedure similar to that of Example 219 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and 3-ethylaniline, the title compound was obtained in 49% yield.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH2:20]([OH:23])[CH2:21][OH:22].CC(C)([O-])C.[K+]>CN(C)C=O>[OH:22][CH2:21][CH2:20][O:23][CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: OCCO
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COCCO)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 11.7 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), ethylene glycol (0.031 mL, 0.56 mmol), and potassium tert-butoxide (0.10 g, 0.90 mmol) in dimethylformamide (5 m L) provided 2-(2-hydroxyethoxy)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.016 g) after reverse-phase HPLC purification. MS (ESI) m/z 304 ([M+H]+); MS (ESI) m/z 302 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24](O)=[O:25])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:18])([F:20])[F:19])[N:14]3[N:21]=[C:22]([C:24]([N:30]4[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]4)=[O:25])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(C(=O)O)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3N2)cc1OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
A 5 mL microwave vial was charged with 5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (50 mg, 0.135 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.404 mmol), HATU (205 mg, 0.539 mmol), N,N-diisopropylethylamine (0.059 mL, 0.337 mmol) and DMF (1.0 mL, 12.915 mmol). The vial was capped and the mixture was stirred for 6 hours at 40° C. The mixture was diluted with Ethyl acetate (5 mL), washed 2× with water (2 mL), washed with 0.1N aqueous HCl (2 mL), washed with saturated aqueous sodium bicarbonate (2 mL), washed with brine (2 mL), dried with sodium sulfate, filtered and concentrated. Compound was purified by chromatography on Biotage SP4 (Column Interchim 25 g, 30 μM) using 12-100% EtOAc/Heptane as eluent to afford intermediate tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carbonyl)piperazine-1-carboxylate (38 mg, 0.070 mmol, 52.3% yield).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2>[OH-].[NH4+]>[Cl:3][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c2ncccc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
To 150 ml of phosphorus oxychloride, at an internal temperature of 80°-85°, was added in portions, with vigorous stirring, during 0.5 hr, 40.5 g (0.184 mole) of 5-hydroxy-6-methoxy-8-nitroquinoline. After completion of addition, the mixture, which had turned from a red solution to a yellow suspension, was heated under reflux for 1.5 hr. The golden yellow solution was allowed to cool to room temperature and the resulting yellow mush was added to a vigorously stirred mixture of 700 ml of conc ammonium hydroxide and ice. The addition rate was regulated to keep the temperature from rising above 25° The pale yellow precipitate was washed with water and air dried to give 43 g (97%) of 5-chloro-6-methoxy-8-nitroquinoline mp 204°-206° (Mp 204° cited by R. C. Fuson et al., J. Org. Chem., 12, 799 (1947).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.O.[OH-].[Li+].C(O)C>C1COCC1.O>[Cl:1][C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2OCC)OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1c(Cl)ccc2c1C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 40 %

Procedure:
To the solution of ethyl 6-chloro-5-ethoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (300mg, 0.93 mmol) in 3 mL of THF was added a solution of lithium hydroxide hydrate (156 mg, 3.7 mmol) in 4 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to 80° C. for four hrs. After removing the solvent, the residue was acidified at 0° C. with ice-cold dilute hydrochloric acid. The product was extracted with EtOAc. After removing the solvents, the residue was purified on reverse phase HPLC. The product was obtained as white solid (120 mg). LC-MS (ES+) 323.2(M+1, 100). 1H NMR (CDCl3/400 MHz) 8.11(s, 1H), 7.32(d, J=8.8 Hz, 1H), 6.73(d, J=8.4 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 4.12(m, 2H), 1.44(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/400 MHz) −78.81(d, J=6.8 Hz). 13C NMR(CDCl3/400 MHz) 169.5, 153.5, 152.8, 134.9, 134.3, 123.4(q, J=285.8 Hz), 121.3, 115.8, 115.5, 112.8, 71.6, 70.2(q, J=33.4 Hz), 15.5. HRMS (EI+) m/z calc. For (C13H10ClF3O4) 322.0220 (M+), found:322.0223.
Reaction SMILES: [O-:1][CH2:2][CH2:3][CH3:4].[Na+].Cl[C:7]1[N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=2)[N:8]=1>O>[I:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:1][CH2:2][CH2:3][CH3:4])[N:16]([CH2:17][CH2:18][CH3:19])[C:15]2=[O:20]
Reactant: CCC[O-]
Reactant: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Agent: [Na+]
Solvent: O
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 1 °C
Reaction time: 2.5 h

Procedure:
A portion of the sodium propoxide solution prepared above (87 g) was cooled to 1° C. and treated dropwise with the solution of 2-chloro-6-iodo-3-n-propyl-4(3H)-quinazolinone prepared in Step 2B above. The temperature was maintained at or below 0° C. and the addition took 2.5 h. After stirring at 0° C. for an additional 1.5 h, the reaction mixture was poured into 250 mL water. The phases were separated and the organic phase was washed two times each with 250 mL water. The organic phase was then evaporated under reduced pressure to give 53.4 g of a light yellow oil which solidified upon standing to a white solid. mp 60-62° C.; 1H NMR (CDCl3): δ8.49 (d,1H), 7.87 (dd,1H), 7.19 (d,1H), 4.43 (t,2H), 4.05 (m,2H), 1.85 (m,2H), 1.70 (m,2H), 1.05 (t,3H), 0.96 (t,3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OC3COC3)[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1.BrC1C(OC(F)F)=NC=C(CBr)C=1.[Cl:37]C1C=C(B(O)O)C=CC=1>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:37])[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(OC2COC2)c1
Agent: FC(F)Oc1ncc(CBr)cc1Br
Product: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1, followed by bromination according to Step 3. [M+H]=348.17350.15
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.Cl>CCOCC>[OH:11][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C1CCc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: OC1(c2ccccc2)CCc2ccccc2C1

Procedure:
2-Tetralone (8.76 g) in dry ether (100 ml) was added dropwise to phenyl magnesium bromide (generated from bromobenzene 19.16 g) in dry ether (300 ml). The mixture was refluxed for 1 hr. The reaction mixture was decomposed by careful addition of water. The resulting emulsion was clarified by addition 2M-hydrochloric acid (250 ml) and ether (500 ml). The ether layer was separated and washed with water (100 ml), dilute sodium hydrogen carbonate solution solution (200 ml) and water (100 ml) and dried (magnesium sulphate and evaporated in vacuo to afford 2-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene as an oil. (8.8 g), characterised by its nmr spectrum
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4[C:26](O)=[O:27])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:36][NH:37][C:26]([C:22]1[N:21]=[CH:20][N:19]=[C:18]2[C:23]=1[N:24]=[CH:25][N:17]2[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:32])([F:31])[F:33])[CH:4]=2)=[O:29])=[CH:16][CH:15]=1)=[O:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(Nc1ccc(-n2cnc3c(C(=O)O)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CNC(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
In 3 mL of dimethylformamide, 30 mg (0.063 mmol) of 9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purine-6-carboxylic acid was dissolved, and 10 μL of 40% methylamine, 17 mg (0.13 mmol) of HATU and HOAt (0.13 mmol) were added thereto and the mixture solution was stirred at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water and the organic layer was washed with water and a saturated sodium chloride solution in the order named, and then concentrated under reduced pressure. The coarse product was recrystallized from ethyl acetate to obtain 16 mg (52%) of a target product as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23]>>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: NC(CO)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Product: Nc1nc2nc(SCc3ccccc3)nc(NC(CO)CO)c2s1

Procedure:
Prepared by the method of example 12 step a) using the product of example 1 step c) and 2-amino-1,3-propanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:29]([N:31]([CH2:41][C:42]1[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[S:45][CH:46]=1)[C@@H:32]([CH3:40])[CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[S:45]1[CH:46]=[C:42]([CH2:41][N:31]([C@@H:32]([CH3:40])[CH:33]([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[C:29](=[O:30])[C@@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:11]([CH3:12])[NH:10][C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 88 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)-((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate IV-18) 100 mg (0.22 mmol) to obtain the title compound.