Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([O:36]C)=[O:35]>>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[C:22]([O:28][C@H:33]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34]([OH:36])=[O:35])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O[C@H](Cc1ccccc1)C(=O)O

Procedure:
Prepared from of 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diisopropyl-phenol (Example 40) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO-d6); δ13.08 (broad s, 1 H), 8.27 (d, J=8 Hz, 1 H), 8.00 (d, J=8 Hz, 1 H), 7.76 (ddd, J=8, 8, 1, 1H), 7.66-7.58 (m, 2 H), 7.43 (ddd, J=8, 8, 1 Hz, 1 H), 7.40-7.34 (m, 4 H), 7.31-7.25 (m, 1 H), 7.12 (s, 2 H), 7.08 (ddd, J=8, 8, 1, 1H), 6.36 (d, J=8 Hz, 1 H), 4.55 (t, J=7 Hz, 1 H), 3.45 (septuplet, J=7 Hz, 2 H), 3.32 (d, J=7 Hz, 2 H), 1.14 (d, J=7 Hz, 3 H), 1.09 (d, J=7 Hz, 3 H), 1.05 (d, J=7 Hz, 3 H), 1.03 (d, J=7 Hz, 3 H); MS (+FAB): [M+] 636 (95%), 638 (100%); Anal. Calc. for C37H33BrO3S: C, 69.70, H, 5.11, N, 0.00. Found: C, 69.48, H, 5.11, N,0.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[C:12]4[N:11]([C:23](=[S:24])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: CC1=C(c2ccc(Cl)cc2)n2ncc(C(N)=O)c2NC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(c2ccc(Cl)cc2)n2ncc3c(=O)[nH]c(=S)n(c32)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 5.0 g of 7-(4-chlorophenyl)-4,5-dihydro-6-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 35) and 0.2 liters of dry tetrahydrofuran is stirred and cooled to -78° C. in a dry ice-acetone bath, then 1.43 g of sodium hydride (60 percent dispersion in mineral oil) is added in one portion. This mixture is stirred for 0.5 hours, then 3.19 g of 1,1 '-thiocarbonyldiimidazole is added and stirring is continued at -78° C. for 2 hours. The mixture is allowed to warm to room temperature and is stirred for 48 hours and then the reaction is quenched with 0.5 liters of water and neutralized with 5 percent aqueous hydrochloric acid. The crystalline solid that forms is collected, washed with ether and dried to give 4.2 g of the desired product as cream colored crystals, mp. 283-285° C.
Reaction SMILES: C[O-].[Na+].C([N:7]1[C:15]2[C:10](=[C:11]([CH3:30])[C:12]([O:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([N:23]4[C:27](=O)[CH2:26][CH2:25][C:24]4=O)[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1)(=O)C.[Cl-].[NH4+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:30][C:11]1[C:12]([O:16][C@H:17]2[CH2:18][CH2:19][C@@H:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][NH:7]2
Reactant: CC(=O)n1ncc2c(C)c(O[C@H]3CC[C@@H](N4C(=O)CCC4=O)CC3)ccc21
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(O[C@H]2CC[C@@H](N3CCCC3)CC2)ccc2[nH]ncc12
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Under a nitrogen atmosphere, 28%-sodium methoxide (64 μl, 0.311 mmol) was added at 0° C. to a suspension of cis-1-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pyrrolidine-2,5-dione (500 mg, 0.311 mmol) in a mixture of methanol (3 ml) and tetrahydrofuran (3 ml). After 10 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution and the resulting mixture was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure, and to a solution of the resulting residue in tetrahydrofuran (4 ml) was added lithium aluminum hydride (47 mg, 1.25 mmol) and the resulting mixture was refluxed. After 4 hours, water, a 2M-aqueous sodium hydroxide solution and water were added thereto in that order, and the resulting mixture was filtered by the use of Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain cis-4-methyl-5-[(4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole (59.6 mg, 64%) and cis-4({4-methyl-1H-indazol-5-yl}oxy)cyclohexyl}amino)butan-1-ol (15.4 mg, 16%).
Reaction SMILES: [C:1]([C:3](=[C:6](O)[C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]#[N:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].S(=O)=O>C(Cl)Cl>[Cl:13][C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[C:3]([C:4]#[N:5])[C:1]#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)C(O)=C(C#N)C#N
Agent: O=S=O
Solvent: ClCCl
Product: CC(C)(C)C(Cl)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 22 h
Yield: 88 %

Procedure:
To a solution of 69.6 g of 2-cyano-3-hydroxy-4,4-dimethyl- 2-pentenenitrile in 600 ml of methylene chloride was added in small portions 104.1 g of phosphorus pentachloride. The mixture was stirred for 22 hours at room temperature. Sulfur dioxide was passed through the mixture for 20 minutes and the mixture stirred for an additional hour. The mixture was concentrated and poured into 500 ml of ice. After stirring for 1 hour, the cold mixture was filtered, the solid was washed with cold water and dried in a vacuum oven at room temperature for 60 hours to give 68.8 g of 3-chloro-2-cyano-4,4-dimethyl- 2-pentenenitrile, mp 52°-53°.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[C:16]([O:34][CH3:35])=[C:17]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[ClH:36].O1CCOCC1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([CH3:22])=[C:17]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:16]=3[O:34][CH3:35])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[ClH:36]
Reactant: COc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1

Procedure:
A solution of tert-butyl 3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (27 mg, 0.053 mmol) in methylene chloride (0.25 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.13 mL, 0.50 mmol) at room temperature for 1 hour, then stripped to dryness to give 4-amino-8-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one as HCl salt.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>P(=O)(O)(O)O>[C:1]1([NH:7][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][C:14]3[NH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17](=[O:18])[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=P(O)(O)O
Product: O=C(O)c1cc2[nH]c3ccccc3c(=O)c2cc1Nc1ccccc1

Procedure:
A process is disclosed wherein 2,5-di(phenylamino) terephthalic acid is half-cyclized by dissolving it in a mixture of polyphosphoric acid and phosphoric acid and heating at 100°-120° C. to form 2-(phenyl)amino-3-carboxy-9(10H)acridone (ACA). The ACA is decarboxylated to form 2-(phenyl)amino-9(10H)acridone, also known as 2-anilinoacridone, by dissolving it in tetramethylene sulfone and heating in the presence of a basic cupric carbonate catalyst.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[C:12]1([CH3:26])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23].CCCCCC>N1C=CC=CC=1.C(OCC)C.C(OCC)(=O)C>[NH2:25][C:24]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:20]([C:13]2[C:12]([CH3:26])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[CH3:19])[C:21]=1[C:22]#[N:23]
Reactant: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)c1cnn2c(N)c(C#N)c(-c3c(C)cc(C)cc3C)nc12

Procedure:
In a variation of Example 8, Step A, a solution of 5.69 g (36.7 mmol) of 3-amino-4-carbethoxypyrazole and 6.00 g (30.6 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 34 mL of anhydrous pyridine was stirred at reflux under air for 6 days. The dark solution was cooled and concentrated in vacuo. The residue was flash chromatographed on silica gel (gradient elution with 20-50% ethyl acetate in hexane) to give the crude product as a dark solid contaminated with another regioisomer. This material was dissolved in diethyl ether containing a little ethyl acetate. Addition of hexane precipitated a dark, tacky solid. This semisolid was collected and redissolved in 9:1 dichloromethane:methanol. Addition of hexane resulted in precipitation. The precipitate was collected on a filter and dried to give the title compound as a yellow solid. LC-MS 350 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To 20.2 g (45 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide U.S. Pat. No. 4,156,007, column 7, line 17) in 75 ml of tetrahydrofuran (THF) that had been cooled under a nitrogen atmosphere to -75° C. was added 100 ml of 1.0M diisobutylaluminum hydride (DIBAL-H) in THF. The reaction mixture was warmed to 0° C. and stirred for 1 hour. An additional 50 ml of the 1.0M DIBAL-H solution was added and the reaction was warmed to 20° C. After 1 more hour yet another 50 ml of the 1.0M DIBAL-H solution was added. After stirring at 20° C. for an additional hour the mixture was cooled to 0° C. and carefully quenched with 40 ml of methanol. This mixture was poured onto a mixture of 300 g of ice and 75 ml of 12M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from 600 ml of ethanol to yield 10.4 g of product, mp 212°-214° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: BrCCCCCCOCCCCc1ccccc1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCCCCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7 mmol) in N,N-dimethylformamide (20 ml) was added dropwise to a suspension of sodium hydride (0.19 g of a 60% dispersion in mineral oil, 4.8 mmol) in N,N-dimethylformamide (10 ml). The reaction was maintained for 45 minutes followed by the dropwise addition of {4-[(6-bromohexyl)oxy]butyl}benzene (1.6 g, 5.1 mmol). The reaction was stirred overnight at room temperature and then partitioned between ethyl acetate and water. The two phases were separated and the aqueous fraction was extracted with additional ethyl acetate. The organic fractions were combined, washed with water, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.81 g of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J9) (306 mg. 1.0 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (246 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (333 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][N:25]([C:18]4[C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:15]=[CH:16][CH:17]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccnc3ccccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-quinolinyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 64% overall yield. mp 150°-151°. FDMS m/e=402 (M+ of free base). α[D]589 =-12.41 (c=0.76, methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][SH:30].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:30][CH2:29][C:28]([F:32])([F:31])[F:27])[CH:7]=1)[CH3:2]
Reactant: FC(F)(F)CS
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (2.0 g, 4.72 mmol) and 2,2,2-trifluoroethanethiol (0.46 mL, 5.18 mmol) in 1,4-dioxane (40 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.207 g, 5.18 mmol), and the reaction was stirred at 0° C. for 30 minutes. The mixture was partitioned between EtOAc and H2O. The aqueous layer was separated and acidified, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3nccs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=O.P(Cl)(Cl)([Cl:26])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[Cl:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(OC)c(CCc2ccc3nc[nH]c(=O)c3c2)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc(OC)c(CCc2ccc3ncnc(Cl)c3c2)c1

Procedure:
150 mg of 6-[2-(2,5-dimethoxyphenyl)ethyl]-3H-quinazolin-4-one are heated together with 5 ml of phosphorus oxychloride and 100 mg of phosphorus pentachloride at reflux for 30 minutes. The mixture is concentrated in vacuo and then partitioned between ice-cold 2 M aqueous pH 7 buffer and ethyl acetate. The organic layer is separated, dried and evaporated in vacuo to yield crude 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-chloroquinazoline, which can be directly used in the following step or purified by chromatography (silica gel, cyclohexane/ethyl acetate=1/1). The crude intermediate is added to a solution of sodium isopropoxide (prepared from 8.3 mg of sodium in 20 ml of isopropanol) in isopropanol. The mixture is refluxed for 1 hour, concentrated in vacuo and poured onto water. Extraction with ethyl acetate yields the crude title compound, which is purified by chromatography on silica gel (cyclohexane/ethyl acetate=2/1) to give a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)=[C:47]([C:58]([F:61])([F:60])[F:59])[CH:46]=1>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:57][C:54]1[CH:55]=[CH:56][N:52]([CH2:51][C:48]2[CH:49]=[CH:50][C:45]([I:44])=[CH:46][C:47]=2[C:58]([F:61])([F:59])[F:60])[N:53]=1)=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-fluorobenzoic acid (22 mg, 0.157 mmol, Aldrich) was added a solution of HATU (58 mg, 0.153 mmol, Advanced asymmetrics) in DMF (0.5 ml), DIPEA (0.062 ml, 0.355 mmol) and then a solution of 1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 39)(43 mg, 0.117 mmol) in DMF (0.5 ml). The resulting yellow solution was stirred at ambient temperature overnight. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (40 mg); LCMS: (System 4) MH+=490, tRET=3.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].[Br:27]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[C:12]([Br:27])[C:13](=[O:23])[C:14]=1[OH:15])=[O:8]
Reactant: BrBr
Reactant: O=C(NCc1cccc(Cl)c1)c1occc(=O)c1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1O

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (5.13 g) obtained in Example 10, Step 1 in chloroform (100 ml) was added a solution of bromine (1.5 ml) in chloroform (50 ml) and the mixture was stirred with heating under reflux for 2 hr. A solution of bromine in chloroform (1.0 ml) was added, and after stirring with heating for 16 hr, the solvent was evaporated. Toluene was added to the residue and the mixture was concentrated, which operations were performed twice to give a crude product of 5-bromo-3-hydroxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide. The obtained crude product was dissolved in dimethylformamide (50 ml), and potassium carbonate (3.87 g) and benzyl bromide (2.75 ml) were added thereto. The reaction mixture was stirred at room temperature for 1 hr. Water (100 ml) and 1N aqueous hydrochloric acid (50 ml) were added to the reaction mixture and the mixture was extracted twice with ethyl acetate (200 ml each). The ethyl acetate layer was washed, dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (3.31 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][C:9](=[CH2:8])[CH2:11][O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COCC(F)(F)F
Reaction time: 15 h

Procedure:
In 100 ml DMF is placed 2,2,2-trifluoroethanol (20 g), 3-chloro-2-methyl-1-propene (18.1 g) and potassium carbonate (33.15 g). The mixture is heated to 50°, with stirring, for 15 hr. The solution is cooled and extracted with pentane. The pentane layer is washed with water (3X) and dried over sodium sulfate. The pentane is fractionally distilled off and the product is distilled in vacuo to give 2,2,2-trifluoroethyl 2-methyl-2-propenyl ether.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([CH:29]4[CH:33]=[CH:32][C:31](=[C:34]=[O:35])[O:30]4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:37]Cl=O.[Na+].CC#N>O>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[O:30][C:31]([C:34]([OH:37])=[O:35])=[CH:32][CH:33]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cnc(C2C=CC(=C=O)O2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cnc(-c2ccc(C(=O)O)o2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.5 %

Procedure:
A mixture of the compound of Example 85 (19 mg), NaClO2 (9.2 mg) in a mixed solution of CH3CN (3 mL) and water (0.5 mL) was stirred at room temperature for 24 hours. After the reaction was quenched by 1N NaOH solution (1 ml), the mixture was extracted with diethyl ether (3×10 mL). The aqueous phase was acidified with 1N HCl to give a yellow solid precipitate (5 mg) which was the product shown. MS m/z: (M+H)+ Calc'd for C26H23N6O7: 503.16; found 503.19. HPLC retention time: 1.37 minutes (column A).