Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][C:19]=1[Cl:33])([CH2:11][CH:12](OC)[O:13]C)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)=O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:20][C:19]=1[Cl:33])([CH2:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)(CC(OC)OC)C(=O)OCC
Solvent: O=CO
Solvent: CC(C)=O
Product: CCOC(=O)C(CC=O)(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)OCC
Reaction time: 24 h

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2,2-dimethoxy-ethyl)-malonic acid diethyl ester (10.0 g, 18.5 mmol) (Preparation 9) in 95 mL of acetone, add 10 ml of formic acid. After 24 h, concentrate the reaction to 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester as yellow oil product (6.7 g, 80%).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][C:16]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:15][CH2:14][CH2:13]2)=[O:11])[N:9]=1)([CH3:4])[CH3:3].Br[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][C:16]2([O:15][CH2:14][CH2:13][N:12]([C:10]([C:8]3[N:9]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:6][CH:7]=3)=[O:11])[CH2:17]2)[CH2:22][CH2:21]1
Reactant: OCCc1cccc(CCBr)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 60 °C

Procedure:
A mixture of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Example 27, step a] (13.6 g) and 2-(3-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (13.51 g) and potassium carbonate (21.7 g) in acetonitrile (700 mL) and water (13 mL) was heated at 60° C. for 36 hours. The solvent was decanted off and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography, using 5% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound.
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([C@@H:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O)[C@H]1SC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of methyl 2-[(3S,4R)-3-{(1S)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (376 mg) and 4-dimethylaminopyridine (336 mg) in dichloromethane (3 ml) was added p-nitrobenzyl chloroformate (358 mg) at -30° C. under a nitrogen atmosphere. After stirring for one hour at 0° C., the mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and the removal of the solvent left an oil (635 mg), which was chromatographed on silica gel (25 g) eluting with 10-25% ethyl acetate in hexane to afford methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (566 mg) as an oil.
Reaction SMILES: CO[C:3]1([CH:9]([CH3:11])[CH3:10])[O:8][CH2:7][CH2:6][CH2:5][O:4]1.[Al].[O-]CCCC>>[C:9](=[C:3]1[O:8][CH2:7][CH2:6][CH2:5][O:4]1)([CH3:11])[CH3:10]
Reactant: COC1(C(C)C)OCCCO1
Agent: CCCC[O-]
Agent: [Al]
Product: CC(C)=C1OCCCO1
Yield: 47.8 %

Procedure:
2-isopropylidene-1,3-dioxane was prepared from 2-methoxy-2-isopropyl-1,3-dioxane (17.1 g; 0.106 mol) and aluminum tri-t-. butoxide (26.2 g; 0.106 mol) according to a procedure similar to that described in preparation 3(e). The product was purified by distillation to afford 6.5 g (47.4%) of 2-isopropylidene-1,3-dioxane, (Formula V: R3 =R4 =CH3 ; R5 and R6 together=--O(CH2)3O--) as an oil, b.p. 70°-72° C./30 mm.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[NH:13]([C:19]([O:21][CH3:22])=[O:20])[NH:14][C:15](OC)=[O:16]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[NH:13]([C:19]([O:21][CH:22]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:20])[NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: COC(=O)NNC(=O)OC
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 38.6 %

Procedure:
The procedure of Example 1 is repeated using 33.9 g of 1,2,2,6,6-pentamethyl-piperidin-4-ol, 13.3 g of dimethyl hydrazine-1,2-dicarboxylate and 0.31 g of tetrabutyl titanate to afford 14.8 g of the title compound as a white solid; mp 189°-191° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:8][C:7]1[C:2]([O:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: COC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1nc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
A reaction vessel was charged with 43.4 g (0.2 mole) of 2,3,5,6-tetrachloropyridine, 108 g (1.2 mole) of methyl glycolate, and 26.6 g (0.25 mole) of anhydrous sodium carbonate. The resulting mixture was stirred and heated to 110° C. at atmospheric pressure with methanol distillate being removed, as it formed, through a distillation head. After 3.5 hours, 6.5 g of methanol distillate was collected. This distillate, along with 64.0 g of additional methanol was added to the reaction mixture and reflux was continued for 1 hour. The solution was cooled to room temperature and anhydrous hydrogen chloride was sparged in slowly, until the solution was acidic to thereby minimize hydrolysis. The solution was refluxed at 70° C. for two more hours, and volatiles were removed in a vacuum. One hundred and eighteen grams of methanol and methyl glycolate were recovered. Perchloroethylene (150 g) was used to extract the ester. After washing the resulting perchloroethylene solution with water and cooling to 20° C., crystals of the product precipitated. These crystals were filtered and dried to give 41.2 g (0.15 mole) of methyl 3,5,6-trichloro-2-pyridinyloxyacetate, m.p. 99°-103° C. The ester product was analyzed by gas-liquid chromatography and was shown to be about 98% pure. Further recrystallization from methanol gave the pure ester, m.p. 104.5°-106° C. In the filtrate from the original crystallization there was another 8.2 g (0.03 mole) of product, and therefore, the total amount of product was 49.4 g (0.18 mole), which represented a 90% yield based on the tetrachloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].C[O-].[Na+]>CO.C(Cl)Cl>[NH2:31][C:30]1[N:32]=[CH:18][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=3[C:6]=2[N:29]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 8 h

Procedure:
A stirred suspension of 16 g (0.047 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 12.5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room temperature, under argon, with 7.5 g (0.14 mol) of sodium methylate in one portion. Methylene chloride (290 ml) was added after 10 min. and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 460 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from ethanol/methylene chloride solution gave off-white crystals: mp 245°-248° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[C:37]1[C:45]2[C:41](=[N:42][S:43][N:44]=2)[CH:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[N:42]1[S:43][N:44]=[C:45]2[C:37]([O:35][CH2:34][CH2:33][O:32][C:27]3[C:26]([N:23]4[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]4)=[N:31][CH:30]=[CH:29][N:28]=3)=[CH:38][CH:39]=[CH:40][C:41]=12
Reactant: Oc1cccc2nsnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc3nsnc23)CC1
Yield: 12 %

Procedure:
DEAD (0.52 mL, 3.3 mmol) was added to a slurry of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 4-hydroxy-2,1,3-benzothiadiazole*(0.46 g, 3.0 mmol) and resin bound PPh3 (1.1 g, 3.3 mmol) and shaken until HPLC showed no starting material. The mixture was filtered to remove the resin, concentrated and purified by column chromatography on silica to give 0.163 g (12%) of the title compound. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C21H26N6O4S (M)+458.1736, found 458.1716.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11]2[N:16]=[C:15]([N:17]([CH:27]3[CH2:29][CH2:28]3)CC3C=CC(OC)=CC=3)[C:14]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:13]3[N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:3]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH:27]3[CH2:28][CH2:29]3)[C:14]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:13]3[N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1ccc(CN(c2nc(Nc3nc(C#N)ncc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: N#Cc1ncc(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was dissolved in DCE. Anisole (50 μL) was added followed by TFA (200 μL) and the reaction was stirred at 50° C. overnight. The reaction was concentrated and dried under vacuum. The crude product was purified by preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 0-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions concentrated and dried via centrifugal evaporation to afford 3.6 mg of 2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC.C1C(CCCCC(N)=O)SSC1>[C:15]([O:12][CH2:11][C@H:9]1[O:10][CH:2]([O:1][CH2:13][CH3:14])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)O
Reactant: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCCCCC
Product: CCCCCCCC(=O)OC[C@H]1OC(OCC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 98.4 %

Procedure:
To a suspension of ethyl D-glucopyranoside (500 g, 2.4 mol prepared according to example 10) and octanoic acid (520 g, 3.6 mol) in hexane (1000 ml) in a stirred batch reactor at 70° C. (reflux) was added immobilized lipase (5 g Lipozyme™, commercial available NOVO lipase prepared from a Mucor Miehei). Stirring was continued and the produced water was removed by azeotropic distillation. The progress of the reaction was followed by HPLC. As the product was being formed, the suspension gradually became a homogeneous solution (after 12 hours). After 52 hours the enzyme was removed by filtration and the solvent removed in vacuo. Excess fatty acid was removed by repeated molecular distillation giving a crude product (790 g, 91% monoester, 8% diester and 1% ethyl D-glucopyranoside). H1 and 13C NMR-spectra of the purified product were in accordance with the spectra for the pure α- and β-anomers given in tables 4 a/4 b.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1

Procedure:
A 332 mg (1.2 mmol) sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and 240 mg (1.38 mmol) of 5-bromo-3-hydroxypyridine, prepared as in step b above, were reacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THF at room temperature for 16 hours, to give 355 mg of the title compound. MS (CI/NH3) m/z 357/359 (M+H)+, 374/376 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H), 2.10-1.80 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([O:30]CC)=[O:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>C1COCC1.O>[C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH:27]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]([OH:30])=[O:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3cc(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A mixture of ethyl 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (4.10 g, 7.88 mmol), potassium hydroxide (1.35 g, 24.1 mmol) in THF (66 mL) and water (66 mL) was stirred for 2 hours at room temperature. The mixture was poured into excess water and washed with diethyl ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with hexane and the formed solid was crystallized from acetonitrile. Drying at 82° C. for 16 hours afforded the title compound as a light yellow solid (2.87 g), mp 144-145° C. Mass spectrum (+ESI, [M+H]+) m/z 493. 1HNMR (500 MHz, DMSO-d6): δ13.1-13.5 (br s, 1H), 8.35 (s, 1H), 7.95-8.05 (m, 2H), 7.9 (d, 1H, J=8.6 Hz), 7.8 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.7 (dd, 1H, J=7.4 Hz and 0.84 Hz), 7.2-7.45 (m, 9H), 5.2 (q, 2H, J=4.2 Hz), 3.2-3.25 (m, 1H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.15 (m, 2H), and 0.7 and ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C32H28O5: Calculated: C, 78.03; H, 5.73; N, 0.00. Found: C, 77.83; H, 5.55; N, 0.02.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[N:8][CH:7]=1
Reactant: Oc1cnnc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: FC(F)(F)c1ccc2nncc(Cl)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 6-(trifluoromethyl)cinnolin-4-ol (as prepared in the previous step, 1.8 g, 8.41 mmol, 1.00 equiv) in acetonitrile (30 mL) and phosphoryl trichloride (12.78 g, 84.08 mmol, 10.00 equiv). The reaction mixture was stirred for 2 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20-1:10). The title compound was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:31][C@@H:30]2[C@@H:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN1CCCC1=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][C@@H:26]2[C@@H:30]([CH2:29][N:28]([C:2]3[NH:3][C:4]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Clc1nc2ccc(-c3ccccc3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@@H]2C1
Temperature: 150 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
2-Chloro-5-phenylbenzimidazole (34 mg) was added to the N-methylpyrrolidone solution (0.2 mL) containing 3-tert-butoxycarbonyl-cis-3,7-diazabicyclo[3.3.0]octane (62 mg), followed by stirring at 150° C. for 4 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified on a silica-gel column chromatograph (C-300, chloroform:THF=4:1) to give the title compound (29 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])([O-:3])=[O:2].[H-].[Na+].ClC(Cl)(Cl)[C:29](Cl)=[O:30]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10](=[O:11])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:29]2=[O:30])[CH:22]=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: O=C(NCC(F)(F)F)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC(F)(F)F
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 3.4 g of 2-(m-nitroanilino)-N-(2,2,2-trifluoroethyl) benzamide and 25 ml of dry tetrahydrofuran was added 0.5 g of approximately 55 % sodium hydride, and stirring was continued for one hour at room temperature. To this was added dropwise under cooling 5.5 g of trichloroacetyl chloride and the mixture was allowed to stand for one hour at room temperature, and then refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue was added water to precipitate a crude product. This product was recrystallized from ethanol to give 3.2 g of 1-(m-nitrophenyl)-3-(2,2,2-trifluoroethyl) quinazoline-2,4(1H, 3H)-dione as pale yellow prisms, melting at 182°-184° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Br:11]Br>C(O)(=O)C>[Br:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: O=C(O)c1cccc(O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19199.7 %

Procedure:
To a solution of 3-hydroxybenzoic acid 5 (18.2 g, 0.132 mol) in 180 ml of glacial acetic acid cooled in a water bath was slowly added over a period of 2 h bromine (21.1 g, 0.132 mmol) in 70 ml of acetic acid. The solution was stirred overnight. After removing bromine and 160 ml of acetic acid under reduced pressure, the mixture was cooled to 0° C., filtered, washed (50 ml of cold water), and dried under vacuum to give a white solid. Crystallization (H2O) gave 4-bromo-3-hydroxybenzoic acid as white crystals (5.5 g, 19%).
Reaction SMILES: [C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([CH:23]=[CH2:24])=[O:22]>C(O)C>[C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][N:13]([CH2:24][CH2:23][C:21](=[O:22])[CH3:20])[CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C)=O
Reactant: c1ccc(C2c3ccccc3CC3CNCC32)cc1
Solvent: CCO
Product: CC(=O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1

Procedure:
A solution of 7.4 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline in 60 cc of ethanol is heated to the boil at reflux for 11/2 hours after the addition of 3 cc of methylvinylketone, and is subsequently concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate. After concentrating by evaporation, the filtrate yields the title compound as oily residue. Hydrogen maleate salt form: M.P. 121°-124° (after crystallization from ethanol).