Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[F:34][C:35]([F:58])([F:57])[CH2:36][O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[C:49]([CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:54]1[CH2:55][CH2:56][CH:51]([C:49]([C:41]2[N:40]([CH2:39][CH2:38][O:37][CH2:36][C:35]([F:58])([F:34])[F:57])[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=2)=[O:50])[CH2:52][CH2:53]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: O=C(c1nc2ccccc2n1CCOCC(F)(F)F)C1CCNCC1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(F)cc1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1)c1ccc(F)cc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-fluorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[N:2]1.[Br:16]Br>ClCCl.C(O)(=O)C>[Br:16][C:4]1[C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[N:2][S:1][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)Nc1ccsn1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)Nc1nscc1Br
Reaction time: 0.75 h
Yield: 102.3 %

Procedure:
To a solution of methyl N-isothiazol-3-yl-L-leucinate (160 mg, 0.70 mmol) in dichloromethane (3 mL) and acetic acid (0.5 mL) was added bromine (0.04 mL, 0.78 mmol). The solution was stirred for 45 min, then diluted with dichloromethane and washed with saturated aqueous NaHCO3 and brine, filtered through cotton and evaporated to give 220 mg of methyl N-(4-bromoisothiazol-3-yl)-L-leucinate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27](=[O:29])[CH3:28])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1)c1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N-[4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178° C.; Anal. Calc'd for C22H18FN5: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].[BH4-].[Na+].[OH2:28]>O1CCCC1.[OH-].[Na+]>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:28])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(C)=O
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-acetyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.4 g. of ethyl 8-acetyl-12-hydroxy-12-methylheptadecanoate as a yellowish oil used in the next step without further purification; pmr (CDCl3)δ 0.88 (3H,t), 1.13 (3H,s, CH3COH), 1.25 (3H,t, CH3CH2OCO--), 2.12 (3H,s, CH3CO), 4.12 (2H,q).
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.Br.[NH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:9])[C:3]=1[NH:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: NCCn1oc(=O)[nH]c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(NCCn2oc(=O)[nH]c2=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (0.56 g, 4.0 mmol) in ethanol (20 mL) was added to 2-(2-aminoethyl)-1,2,4-oxadiazolidine-3,5-dione hydrobromide (0.90 g, 4.0 mmol) in ethanol (100 mL). The reaction mixture was treated with 1N sodium hydroxide solution (8 mL, 8 mmol) and allowed to stir for 24 hours at room temperature. The resulting precipitate was filtered, dissolved in water and passed through an ion exchange column (AG 50W-X2, 100-200 mesh, H+ form), eluting with water. The eluent was freeze dried yielding the title compound as a cream colored solid, partial hydrate (0.45 g, 45%, mp 225° C. (dec)); IR (KBr, cm-1) 3300, 3140, 1820, 1740, 1720, 1640; MS (+FAB) 241 (MH+); 1H NMR (DMSO, 400 MHz): δ12.4 (br s, NH), 7.5 (br s, 3 NH), 4.0-3.5 (m, 4H); 13C NMR (DMSO, 400 MHz): ppm 183.72, 183.63, 170.06, 168.96, 158.17, 152.72, 50.41, 41.68.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:21][NH2:22]>CO>[NH2:15][C:14]1[NH:22][N:21]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:13]=1[C:16]#[N:17]
Reactant: CSC(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1n[nH]c(N)c1C#N

Procedure:
A mixture of 80.81 g (286.4 mol) of 3-[2-(Boc-amino)-ethylamino]-2-cyano-3-methylmercapto-acrylonitrile, 14.9 ml (300.7 mmol) of hydrazine hydrate and 500 ml of methanol is heated under reflux for 4 hours and then concentrated by evaporation in vacuo at about 50° C., yielding 5-amino-3-[2-(Boc-amino)-ethylamino]-4-cyano-pyrazole; TLC-Rf=0.27 (methylene chloride/methanol [9:1]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:38](O)=[O:39])[CH:31]=[CH:30]1>>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:38]([N:17]2[CH2:18][CH:19]([CH:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[OH:21])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:39])[CH:31]=[CH:30]1
Reactant: OC(c1ccccc1)C1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: Cn1ccc2cccc(C(=O)O)c21
Product: Cn1ccc2cccc(C(=O)N3CC(CN4CCC(c5ccc(F)cc5)CC4)C(C(O)c4ccccc4)C3)c21

Procedure:
The title compound was prepared from 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(phenylhydroxymethyl)pyrrolidine and 1-methyl-7-indolecarboxylic acid according to procedures described in Example 39. The crude product was purified by chromatography (silica, acetone:hexane=1:2) to give the separate diastereomers of the title compound.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([C@@:32]1([CH2:46][C:47](=C)[CH2:48]O)[CH2:36][C:35](=[O:37])[N:34]([C@@H:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:39])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([C@@:32]1([CH2:46][C:47](=[CH2:48])[CH2:1][Br:5])[CH2:36][C:35](=[O:37])[N:34]([C@@H:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH3:39])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: C=C(CO)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(CBr)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1

Procedure:
Carbon tetrabromide (3.24 g, 9.77 mmol) and triphenylphosphine (2.57 g, 9.80 mmol) were added to a solution of (3S)-3-(3-hydroxy-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester in dichloromethane (113 ml) under ice water-cooling in a nitrogen atmosphere. The mixture was stirred under ice water-cooling for 15 minutes and then concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25→66:34) to give 3.22 g of the title compound as white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[C:14]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1nn(-c2ccccc2)c2ccccc12
Temperature: 30 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a mixture of methyl 1H-indazole-3-carboxylate (3.44 g), phenylboronic acid (4.76 g), pyridine (2.84 mL) and N,N-dimethylformamide (70 mL) was added copper (II) acetate (5.32 g), and the mixture was stirred at 30° C. overnight. The insoluble material was filtered off, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.58 g, 32%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C=CCn1c2ccccc2c2ccccc21

Procedure:
Into a 500-mL, three-necked, round-bottomed flask, equipped with a magnetic stirrer, a thermometer, and a condenser connected to a nitrogen bubbler, were placed carbazole (8.4 g, 50 mmole), allyl bromide (10 mL, 115 mmole), powdered anhydrous potassium carbonate (41 g, 300 mmole), and anhydrous acetonitrile (300 mL). The resultant mixture was stirred and heated under reflux with a heating mantle for 18 hours. Dichloromethane (300 mL) was then added, and the mixture was filtered through a pad of Celite. The clear filtrate was evaporated, and the residue was recrystallized from methanol to yield the desired product as amber-colored crystals. The product had melting point 56°-57° C., and sublimation (100° C./0.1 mm Hg) yielded white crystals (8.65 g, 83%), melting point 57°-58° C. The proton NMR spectrum in carbon tetrachloride was
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:34])([F:33])[CH:30]1[O:32][CH2:31]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:31][CH:30]([OH:32])[C:29]([F:34])([F:33])[F:28])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CN(Cc1cccc(OCC(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 20.4 %

Procedure:
The N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine (0.50 g, 1.35 mmol) product from EX-659B and 1,1,1-trifluoro-2,3-epoxy-propane (1.0 ml, 11 mmol) were heated to 90° C. in a sealed container under argon for 2 d. The resulting mixture was eluted from silica gel with 4% ethyl acetate in hexane, and fractions were pooled based on TLC analysis to give 134 mg (21%) of the desired 3[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil. 1H NMR (C6D6) δ6.80-7.08 (m, 7H), 6.64 (d, 1H), 6.53 (bt, 1H), 6.49 (t, 1H), 6.44 (dd, 1H), 6.34 (dt, 2H), 4.23 (s, 2H), 3.84 (m, 1H), 3.61 (m, 2H), 3.53 (dd, 1H), 3.20 (m, 1H), 2.03 (d, 1H). 19F NMR (C6D6) δ−74.20 (t, 3F), −78.95 (d, 3F). HRMS calcd. for C24H21F6NO3: 486.1504 [M+H]+, found: 486.1498.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 2,5-dimethoxyphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 372.0 (M+H)+, retention time 1.44 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:15][CH2:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:16].[BH4-].[Na+]>CO.O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:15][CH2:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]2[OH:16]
Reactant: O=C1c2ccccc2CCC12CCCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2CCC12CCCCN2
Reaction time: 0.5 h
Yield: 31 %

Procedure:
In 20 ml of methanol was dissolved 0.80 g of 3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one. Then, 0.15 g of sodium borohydride was added portionwise. The mixture was stirred for 30 minutes, after which it was diluted with water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was then distilled off. The solid residue was recrystallized from methylene chloride-ether to provide 0.25 g of white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:30]=[C:29]5[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2nccn3nc(N)nc23)cc1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)nccn4n3)ccc21

Procedure:
8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine, synthesized as described earlier, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[N:3]=1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N1c1ccccc1
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-phenyl-7,8-dihydropteridin-6(5H)-one (1.59 g, 5.78 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and phenylboronic acid (1.41 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The resulting mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (750 mg, 37%). 1HNMR (300 MHz, CDCl3): δ 1.65 (d, J=6.9 Hz, 3H), 4.82 (q, J=6.9 Hz, 1H) and 7.36-7.65 (m, 11H).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)[CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1csc(C2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2CC2)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.13 g) was added to a solution of ethyl 2-cyclopropylthiazole-4-carboxylate (example 57, step b) (0.15 g) in a mixture of THF (8 mL) and water (2 mL) and the resulting mixture was stirred overnight. The reaction was acidified with aqueous HCl (2M, 3 mL) and the solvent evaporated. The residue was partitioned between brine (20 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as an off white solid. Yield 0.12 g.
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:21][CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:3]=1.C1COCC1>[Pt].CO>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([O:21][CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:3]=1
Reactant: Nc1cc(OC2CCOC2)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(OC2CCOC2)c(C(=O)OCc2ccccc2)cc1N
Reaction time: 5 h

Procedure:
Platinum on charcoal (100 mg 5%) was added to the product obtained at (659b) (160 mg, 0.45 mmol) in 10 mL methanol with 5 mL THF and the mixture was hydrogenated at 4 bar H2 pressure at ambient temperature for 5 h. The mixture was filtered, washed with methanol and the filtrate concentrated i. vac. The product was reacted without further purification.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1([CH3:48])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[C:29]2[CH:28]=[C:27]([O:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[C:42]([CH2:46][OH:47])=[CH:41][CH:40]=[CH:39]4)[CH:26]=[CH:25][C:24]1=2>ClCCl>[CH3:22][C:23]1([CH3:48])[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[C:29]2[CH:28]=[C:27]([O:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[C:42]([CH:46]=[O:47])=[CH:41][CH:40]=[CH:39]4)[CH:26]=[CH:25][C:24]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(CO)cccc4c3)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C=O)cccc4c3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
100 ml of dichloromethane and 1.7 g (4.5 mmol) of pyridinium dichromate were introduced into a round-bottomed flask. The mixture was cooled to 0° C. and a solution of 1.2 g (3.3 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthalene methanol in 20 ml of dichloromethane was added dropwise. The mixture was stirred at room temperature for one hour, the reaction medium was filtered over silica, the filtrate was evaporated to dryness and the solid was triturated in heptane and filtered off. 1.07 g (90%) of the expected aldehyde was recovered, having a melting point of 123°-4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Product: Cc1cc(C)c(C(=O)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 328 mg of 2,4,6-trimethylbenzoic acid and 3 mL of thionyl chloride was stirred at room temperature for 2 hours. The volatile components were evaporate in vacuo, the residue was redissolved in 5 mL of CH2Cl2, and the volatile components were again evaporated in vacuo to give 2,4,6trimethylbenzoyl chloride.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.