Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13](=[O:20])[C:14]4[C:19]([C:10]=3[O:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22]NC.O1CCOCC1>>[CH3:22][N:8]=[C:7]([C:11]1[C:10](=[O:9])[C:19]2[C:14]([C:13](=[O:20])[C:12]=1[OH:21])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C1C(=O)c2c(-c3ccccc3)noc2-c2ccccc21
Solvent: C1COCCO1
Product: CN=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
A solution of 3-phenyl-4,5-dihydronaphtho[2,1-d]-isoxazole-4,5-dione (500 mg) in 8 % dimethylamine-dioxane solution (100 ml) is irradiated by light of a high-pressure mercury lamp (1 KW) through a pyrex filter at room temperature (20- 30°C) in argon atmosphere for about 1.5 hours. After removal of the solvent, the residue is dissolved in methylene chloride, washed with water, dried with anhydrous sodium sulfate, and evaporated. The residue is washed with benzene to give 2-(N-methylbenzimidoyl)-3-hydroxy-1,4-naphthoquinone (158 mg), which is identical with the product of Example 16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH:10]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)=[O:12]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1nc(Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A 250 ml. three necked flask was fitted with a mechanical stirrer, a thermometer, and a reflux condenser with drying tube. To the flask was charged 70 ml. of a 98% formic acid and 3.85 g (0.025 mole) of 2-amino-4,6-dichloropyrimidine as prepared in example 1. Acetic anhydride, 30 ml. was added slowly with stirring to maintain temperature below 50° C. When the addition of acetic anhydride was complete, the mixture was heated for 6 more hours at 50° C and then allowed to stand overnight at room temperature. Excess formic acid and acetic anhydride were evaporated under vacuum. The solid residue was crystallized from 15 ml. of ethyl alcohol. There was obtained 3.7 g of 2-formamido-4,6-dichloropyrimidine (PY-24) in the form of white crystals, melting point, 142°-144° C, yield 77%.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: OCCNCCO
Reactant: ClCc1ccc(Cl)cc1
Product: OCCN(CCO)Cc1ccc(Cl)cc1

Procedure:
2-[(4-chlorobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (14.3 g, 95 mmol). and 4-chlorobenzyl chloride (10.2 g, 63 mmol). Yield 12.1 g, (84%); yellow oil; MS: 230 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C@@H:10]2[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:35](=O)([O-])[O-:36].[K+].[K+].S(=O)(=O)(O)O>CO>[OH:12][CH2:11][C:10]1([O:13][C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:35][OH:36]
Reactant: O=C([O-])[O-]
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 1.18 g portion of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose was dissolved in 8.5 ml of methanol, treated with 5.11 ml of 37% formalin and 480 mg of potassium carbonate and the mixture immersed in an 85° C. bath. After 4 hours the mixture was cooled, neutralized with 3.5 ml of 10% sulfuric acid and the volatiles removed. The residue was extracted with chloroform, giving 0.86 g of the desired compound after chromatography.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:21](Cl)=[O:22])[CH2:18][CH2:19][CH3:20]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:21](=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 83° C. and MS: m/e=296.3 (M+H+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and butanecarboxylic acid chloride.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46](C(=O)C2C=CC=CC=2)[CH:45]=1)(=O)C1C=CC=CC=1.Cl>C(OCC)(=O)C>[C:1]([O:9][C:10]1([CH2:43][C:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 43 %

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added 5-chloro-2-oxo-1-propylindolin-3-yl benzoate (0.08 grams, 0.24 mmol, 0.2 M in toluene). While stirring at 0° C. KHMDS (0.3 mL, 0.26 mmol, 0.87 M, purchased from Fisher Scientific) was added. After approximately fifteen minutes a solution of (1-benzoyl-1H-indol-3-yl)methyl benzoate (0.02 grams, 0.06 mmol, 0.3 M in anhydrous DMF (purchased from Fisher Scientific)) was added. The reaction continued to stir overnight. The next day the reaction was acidified with 0.1M HCl, diluted with ethyl acetate and the two layers were separated. The aqueous layer was salted out and washed twice more with ethyl acetate. The combined organic solution was dried with sodium sulfate, filtered and concentrated. Purification was done on a Teledyne ISCO with silica gel using a hexanes ethyl acetate gradient. This was followed by a subsequent reverse phase purification using Teledyne ISCO with a C18 column and a water with 0.1% formic acid, acetonitrile gradient. 43% yield. 1H-NMR δ 8.05 (bs, NH), 8.00 (d, 2H), 7.57 (t, 1H), 7.50 (d, 1H), 7.42 (t, 2H), 7.30 (d, 1H), 7.18 (m, 2H), 7.08 (m, 2H), 6.78 (d, 1H), 6.61 (d, 1H), 3.71 (d, 1H), 3.60 (m, 1H), 3.51 (d, 1H), 3.40 (m, 1H), 1.35 (m, 2H), 0.74 (t, 3H). Calculated mass for C27H23ClN2O3, 458.14. Observed 481.1 (M+Na).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:34]([O:36][CH2:37][Cl:38])=[O:35])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)OCCl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of aripiprazole (2 g, 4.46 mmol) in 2-methyltetrahydrofuran (40 mL) was added NaH (357 mg, 8.92 mmol). After 20 minutes, further 2-methyltetrahydrofuran (20 mL) was added to aid stirring. Chloromethyl chloroformate (1.19 mL, 13.38 mmol) was then added and the reaction stirred for 2 days. The reactions were combined for work up. The reaction was cooled to 0° C., diluted with ethyl acetate (50 mL) and quenched with aqueous saturated NaHCO3 solution (50 mL). The reaction was extracted with ethyl acetate (3×50 mL) and the combined organics washed with brine (100 mL), then dried (MgSO4) and concentrated to give chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 2.59 g) as 3:2 mixture of product/aripiprazole. The product was not purified due to instability during silica chromatography and so taken onto the next step crude.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:30][C:31]1[CH:32]=[C:33]([F:51])[C:34]([F:50])=[C:35]([C@:37]2([CH2:48][F:49])[CH2:42][C@@H:41]([C:43]([F:46])([F:45])[F:44])[O:40][C:39]([NH2:47])=[N:38]2)[CH:36]=1>CO>[NH2:47][C:39]1[O:40][C@H:41]([C:43]([F:44])([F:46])[F:45])[CH2:42][C@:37]([C:35]2[CH:36]=[C:31]([NH:30][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:32]=[C:33]([F:51])[C:34]=2[F:50])([CH2:48][F:49])[N:38]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)O1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: N#Cc1ccc(C(=O)Nc2cc(F)c(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a cooled (ice bath) solution of 5-cyanopicolinic acid (0.043 g, 0.293 mmol) in MeOH (10.0 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.094 g, 0.318 mmol). After stirred for 30 min, (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.080 g, 0.244 mmol) in MeOH (10.0 mL) was added dropwise. The reaction was then stirred at room temperature for 17 h. LCMS showed about 30% remaining starting material. The reaction was quenched with saturated sodium bicarbonate solution. MeOH was removed by rotary evaporation. The aqueous residue was extracted with EtOAc (2×). The organic extracts were combined, concentrated and purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-cyanopicolinamide (0.041 g, 0.090 mmol, 36.7% yield) as white solid. MS m/z=458.1 [M+H]+. Calculated for C19H13F6N5O2: 457.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([O:26]C)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].Cl>O.C1COCC1>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:28]([F:30])([F:31])[F:29])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Yield: 35.9 %

Procedure:
A solution of methyl 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylate (70 mg, 0.14 mmol) and NaOH (30 mg, 0.75 mmol) in H2O-THF (1:1, 10 mL) was stirred at rt for 3 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 5-(5-(3,4,5-trichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (24 mg, yield 35%) as a yellow solid. MS: m/z=477.0 (M+1, ESI+).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[NH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][N:33]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11].[CH3:39][Si:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][O:43][CH2:44]Cl>O>[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[N:33]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:47])([CH3:46])[CH3:39])[CH:32]=[C:31]([C:34]([F:35])([F:37])[F:36])[N:30]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3ncc(C(F)(F)F)[nH]3)cn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60%, 35 mg) was added to an N,N-dimethylformamide (3 mL) solution containing methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate (320 mg) at 0° C., and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (195 μL), a temperature of the mixture was raised to room temperature and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain a mixture (324 mg) of methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate and methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-pyrazin-2-yl}pyridin-2-yl)oxy]propanoate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[N:13][CH:14]=2)O1.Br[C:24]1[C:25]([Cl:34])=[C:26]2[C:31](=[N:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2>>[Cl:34][C:25]1[C:26]2[CH2:27][CH2:28][CH2:29][NH:30][C:31]=2[N:32]=[CH:33][C:24]=1[C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[N:13][CH:14]=1
Reactant: Clc1c(Br)cnc2c1CCCN2
Reactant: CC1(C)OB(c2cncc(C3(O)CCOCC3)c2)OC1(C)C
Product: OC1(c2cncc(-c3cnc4c(c3Cl)CCCN4)c2)CCOCC1

Procedure:
4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol is coupled with 6-bromo-5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine to give 4-[5-(4-chloro-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol using Suzuki Coupling Method VI.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N(C)CC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) and sarcosine tert-butyl ester hydrochloride 122 mg (0.67 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (4:1 hexanes:ethyl acetate), 200 mg (74%), mp 102-105° C.; 1H NMR (CDCl3): δ 8.29 (s, 1H), 4.27 (br s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.35 (br s, 3H), 2.54 (s, 3H), 1.41 (s, 9H); MS (APCI): m/z 421 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>C(Cl)Cl>[O:15]1[CH2:16][CH2:11][CH2:12][CH2:13][CH:14]1[O:6][CH:4]1[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]2[O:1][CH2:5]1
Reactant: OC1COC2C(O)COC12
Reactant: C1=COCCC1
Solvent: ClCCl
Product: OC1COC2C(OC3CCCCO3)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of hexahydrofuro[3,2-b]furan-3,6-diol (10.0 g, 68.50 mmol) in DCM (150 mL) was added PPTs (1.7 g, 6.85 mmol) at rt followed by DHP (6.0 g, 71.90 mmol) slowly in 2 h, and then the mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (150 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (300 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a white solid (7.1 g, 45%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[I-].[Na+]>C(#N)C>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH2:1])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ccc(C(C)=O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Under nitrogen, 11.0 g (66.2 mmol) of 4-(methylthio)acetophenone (prepared in Step 1 of Example 1) and 13.8 mL (99 mmol) of triethylamine in 50 mL of acetonitrile was treated with 12.6 mL (99.3 mmol) of chlorotrimethylsilane at ambient temperature and allowed to stir for 20 minutes prior to the slow addition of a suspension of 14.9 g (99.4 mmol) of sodium iodide in 60 mL of acetonitrile. The reaction was stirred for 3 hours, poured into ice/water, and extracted with hexane. The extracts were combined, dried (K2CO3), and concentrated in vacuo to give 16 g of crude 1-methylthio-4-[1[(trimethylsilyl)oxy]ethenyl]benzene as an oil: NMR (CDCl3) δ0.26 (s, 9H), 2.48 (s, 3H), 4.39 (d, J=2 Hz, 1H), 4.87 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:46])[F:47])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 83 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at room temperature overnight. Dilute the mixture with 5 mL of Methanol and add sodium borohydride (0.8 mmol). Stir the suspension at room temperature for 30 min then dilute with water (20 mL) and ethyl acetate (20 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×20 mL). Separate the organics, dry over sodium sulfate, and filter. Remove the solvent under vacuum to afford (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate crude (0.2 g, MS (ES+): 557 (M+H)). Without further purification, add acetyl chloride (0.8 mmol) and pyridine (0.8 mmol) to a solution of (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in dichloromethane. After stirring for 2 h remove solvent under vacuum and chromatograph over silica gel using ethyl acetate/hexane (5-40%) to elute. This affords the title compound as an oil (0.2 g, 83%) which foams under vacuum: MS (ES−): 597 (M−H).
Reaction SMILES: [C:1]([C:3](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8]1)[C:4]([NH2:6])=[O:5])#[N:2].[CH2:17](OC(OCC)(OCC)C)[CH3:18]>CN(C)C=O>[CH3:17][C:18]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:16])[C:8]=12
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CC(C(N)=O)=C1C=C(O)c2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)c2c1C(=O)c1ccccc1-2

Procedure:
A mixture of 1 part of 2-cyano-2-(3-hydroxy-1H-inden-1-ylidene)acetamide, 1 part of 1,1,1-triethoxyethane, and approximately 6 parts of N,N-dimethylformamide is heated at 90°-95° under reflux for 2 hours, whereupon the precipitate which forms is filtered out, washed with ethyl acetate, and dried in vacuo. Crystallization from ethyl acetate affords needles of 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carbonitrile melting above 300°. The product has the formula ##STR7##
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) and triethylamine (1 ml) in dichloromethane (20 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.312 ml). The RM was stirred for 17 h at rt then was added acetyl chloride (0.3 ml), the RM was stirred for 3 h at rt. Acetyl chloride (0.1 ml) was added and the RM was stirred for 1 h at rt. The RM was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=249, 251 MS-ES)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](CO)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.3 %

Procedure:
The compound (12.2 g, 45.3 mmol) synthesized in Example 6 (6b) was dissolved in pyridine (100 mL) and p-toluenesulfonyl chloride (13 g, 68.0 mmol) and 4-dimethylaminopyridine (553 mg, 4.53 mmol) were added thereto, followed by stirring of the mixture at room temperature for 12 hours. The reaction mixture was poured to 10% aqueous hydrochloric acid solution (80 mL) under ice cooling, and ethyl acetate (200 mL) and the organic layer was washed with 10% aqueous hydrochloric acid solution (80 mL), saturated aqueous sodium hydrogencarbonate solution (80 mL) and saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired title compound (16.9 g, yield: 88%) as pale yellow amorphous matter.