Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O.CN(C)[CH:29]=[O:30]>[Pd].[H][H]>[C:29]([NH:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:30])[C:6]([CH3:11])([CH3:7])[CH3:5]
Reactant: [H][H]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)(C)C)cc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (10.8 g) in N,N-dimethylformamide (380 ml) was shaken with 10% palladium on carbon (3.6 g) in hydrogen atmosphere at ambient temperature until hydrogen gas (2030 ml) was absorbed. The catalyst was removed by filtration and washed with a small volume of N,N-dimethylformamide. To the combined filtrate and washings was added pyridine (17 ml) and the mixture was cooled over an ice-bath. To the solution was added dropwise pivalic chloride (6.33 g) for 20 minutes and then the reaction mixture was stirred for 2 hours and 40 minutes at ambient temperature. To the resultant mixture was added ice-water under stirring and then the mixture was concentrated under reduced pressure. To the residue was added chloroform and then the mixture was washed with an aqueous solution saturated with sodium bicarbonate and with water. Insoluble materials were removed by filtration from the chloroform layer. The filtrate was washed with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant oil was subjected to a chromatography using silica gel (developing solvent: dichloromethane) to give the first Fraction A and the second Fraction B. The Fraction A was concentrated under reduced pressure to give crystalline diethyl [(6-pivalamido-4-quinazolinylamino)methylene]propanedioate (4.6 g). Further, Fraction B was concentrated under reduced pressure to give a solid (3.6 g), which was suspended in methanol. Insoluble materials were separated by filtration and recrystallized from ethyl acetate to give crystalline diethyl [(6-formamido-4-quinazolinylamino)methylene]propanedioate (0.58 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Cl.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([F:16])[CH:15]=1)[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([N:12]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cl
Product: Fc1cc(F)cc(N2CCNCC2)c1
Yield: 69.3 %

Procedure:
13.7 g of bis-(2-chloroethyl)amine was suspended in 120 ml of butanol. To the obtained solution was added 10 g of 3,5-difluoroaniline and the mixture was heated under reflux for 48 hours. After cooling, 10.6 g of potassium carbonate was added and the obtained mixture was heated under reflux for additional 24 hours. Then crystals were collected by filtration, dissolved in water, extracted with chloroform, successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in a small amount of chloroform and converted into hydrochloride by adding a 4N hydrochloric acid/dioxane solution. After filtration, 12.6 g of the title compound was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([I:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.C[O-].[Na+].CO.CN([CH:33]=[O:34])C.C(OCC)(=O)C>CCCCCC>[I:11][C:9]1[CH:10]=[C:2]([O:34][CH3:33])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: CN(C)C=O
Reactant: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(I)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.226 g, 0.5 mmol), 30% sodium methoxide-methanol (0.7 mL) and DMF (0.12 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.071 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.83 (s, 3H), 4.12 (s, 2H), 4.75 (s, 2H), 6.87 (bs, 1H), 7.17 (d, 2H), 7.33 (d, 2H), 7.44 (bs, 1H). GC-MS: m/z 463 (M)+, 394 (M−69)+, 378 (M−85)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (23.7 mg) with purity >90%: MS (pos) m/z 399.2, 401.2; HRMS m/z 397.9103 (calc. of monoisotopic mass for C12H9Cl3N2O3S2 gives 397.9120).
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[OH:1][C:2]([CH3:40])([CH3:41])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.32 g), dibutyltin oxide (0.072 g), azidotrimethylsilane (2 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.67 mL) was added and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was extracted with ethyl acetate and 1 N hydrochloric acid, and the ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 45%).
Reaction SMILES: C(OC(=O)NC1C=CC=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.[C:42](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:56]([Si:60]([CH3:71])([CH3:70])[O:61]CCN1C=CC(N)=N1)([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl.CO>[C:56]([Si:60]([CH3:71])([CH3:70])[O:61][CH2:10][CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:42])[CH:30]=2)[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:16]1)([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 193 mg, 0.62 mmol) was dissolved in methylene chloride (4 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 320 μL, 0.65 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (150 μL, 1.24 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 150 mg, 0.62 mmol) in methylene chloride (2 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction was diluted with a small amount of methanol in methylene chloride and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes). The combined fractions were then washed with a 1 N aqueous hydrochloric acid solution and then a saturated brine solution, dried over sodium sulfate and concentrated in vacuo to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (309 mg, 94%) as a colorless gum: [α]30589=−9.70° (c=0.33, methanol); ES-HRMS m/e calcd for C27H43N3O4SSi (M+H)+ 534.2817, observed 534.2814; 1H NMR (300 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.78 (s, 9H, 3×CH3), 1.02-1.20 (m, 2H, CH2), 1.36-1.84 (m, 8H, 4×CH2), 2.04-2.17 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.80-3.90 (m, 3H, ArCH and SiOCH2), 4.04 (t, J=5.4 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.41-7.47 (m, 2 H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.73 (s, 1H, NH)
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.S(Cl)([Cl:29])=O.O1CCCC1>CN(C)C=O.O>[Cl:29][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1
Reactant: CN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.10 g), thionyl chloride (0.03 ml), N,N-dimethylformamide (one drop) and tetrahydrofuran (6 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, aqueous sodium bicarbonate and saturated brine, dried (MgSO4), and concentrated to give the title compound (0.08 g, yield 76%) as yellow crystals. melting point 204-205° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[C:13]1([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([OH:2])=[CH:4]3)=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2ccc(-c3ccccc3)cc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
The title compound was prepared by reacting 2-methoxy-7-phenylnaphthalene (0.53 g, 2.26 mmol) with pyridinium HCl (10 g) at 190° C. according to method B to yield 0.36 g (72%) of a white solid: mp 142-143° C.; 1H NMR (DMSO-d6): δ 7.10 (1H, dd, J=2.75 Hz, J=8.70 Hz), 7.23 (1H, d, J=2.29 Hz), 7.37-7.40 (1H, m), 7.48-7.51 (2H, m), 7.58 (1H, dd, J=1.83 Hz, 8.70 Hz), 7.78-7.90 (3H, m), 7.86 (1H, d, J=8.24 Hz), 7.99 (1H, d, J=0.92 Hz) 9.81 (1H, s); MS (ESI) m/z 219 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[CH2:39][N:38]([CH3:43])[C:37]5=[O:44])=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CO.O1CCOCC1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[C:18]3[NH:29][N:30]=[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]5[C:40]([CH2:39][N:38]([CH3:43])[C:37]5=[O:44])=[CH:41][CH:42]=4)[C:17]3=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH:21]=2)=[CH:23][CH:24]=1
Reactant: CN1Cc2ccc(/C=C/c3nn(C4CCCCO4)c4nc(-c5ccc(O)cc5)cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c34)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: CN1Cc2ccc(/C=C/c3n[nH]c4nc(-c5ccc(O)cc5)cc(C(=O)N5CCNCC5)c34)cc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.3 %

Procedure:
To a solution of 4-[6-(4-Hydroxy-phenyl)-3-[(E)-2-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 0.28 mmol) in methanol (4 ml) was added 4N HCl in dioxane (0.7 ml). The reaction mixture was stirred at room temperature for 3 days, diethyl ether was then added, the resulting precipitated was filtered and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.15 g, 96%) as an orange solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was added N,N-diisopropyl-N-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80° C. and stirred for 17 hours. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-50% EtOAc/Hexanes) to afford the desired product, 5a.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:17][CH3:18])[CH2:8][CH2:9][NH:10][C:11](=O)[C:12](F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)C=C.[OH-].[K+]>CC(C)=O>[C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:17][CH3:18])[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=[CH2:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: COC(CCNC(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCNCCC(OC)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 93 %

Procedure:
16.7 g. of N-(3,3-diphenyl-3-methoxypropyl)-trifluoroacetamide, prepared according to Example 4, and 24.2 g. of allyl bromide in 150 ml. of anhydrous acetone are heated to 50°C. and 11.2 g. of powdered potassium hydroxide are added. The mixture is then boiled for 5 minutes and the solvent is distilled off in vacuo. The residue is boiled for one hour with 100 ml. of water and 100 ml. of methanol and is worked up as in Example 4. 13.1 g. of 1,1-diphenyl-1-methoxy-3-allylaminopropane of melting point 45° to 50°C. are obtained, corresponding to a yield of 93% of theory.
Reaction SMILES: [Li].[CH2:2]([Li])[CH2:3][CH2:4][CH3:5].FC(F)(F)S(O[CH2:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2C1=CC=[CH:19][CH:20]=2)(=O)=O>C(OCC)C.CCCCCC.C1(C)C=CC=CC=1>[CH3:5][CH:4]1[C:26]2[C:25](=[CH:24][CH:23]=[C:22]3[CH:21]=[CH:20][CH:19]=[CH:15][C:27]3=2)[CH:2]=[CH:3]1.[CH2:13]=[CH2:14]
Reactant: O=S(=O)(OCCC1c2ccccc2-c2ccccc21)C(F)(F)F
Reactant: [Li]CCCC
Agent: [Li]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=C
Product: CC1C=Cc2ccc3ccccc3c21
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A mixture of isomeric 2-methylbenzindenes was prepared by the method described by Stehling et al., Orgtinometallics, 13, 964 (1994). A solution of 3.6 g of this material was dissolved in 90 mL diethyl ether and converted to the lithium salt by dropwise addition of 8 mL 2.5M butyllithium in hexane. This was added to 20 mmole flu-CH2—CH2—OSO2CF3 (Example 1) in 100 mL toluene. After stirring overnight , the reaction mixture was filtered and evaporated. The residual gum was extracted with 300 mL boiling heptane. The extract was cooled to −5° C. and the yellow solids which separated were collected on a filter. Further purification of the solids was carried out by chromatography on an 20.3×3.8 cm silica gel column, eluting with 1:1 (v/v) toluene - heptane. Evaporation of the eluate gave 3.6 g crude methylbenzindene-C2H4-flu as an amber resin.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:26])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:26][CH3:27])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(OCC)c2c(c1O)S(=O)(=O)N(Cc1ccccc1)C2=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (2.45 g), potassium carbonate (2.76 g) and methyl iodide (1.84 g) in acetone was heated at 50° C. with stirring for two hours, then poured with stirring into ice-water (500 mL). The resulting gooey precipitate crystallized overnight affording 2-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin, 2.35 g, 92% yield, mp 92°-94° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23](=[O:25])[CH3:24])=[CH:4][C:5]2[CH2:6][CH:7]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:8]3[CH:13]([C:14]=2[CH:15]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[BH4-].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[OH:25][CH:23]([C:3]1[C:2]([OH:1])=[CH:15][C:14]2[CH:13]3[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:7]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:6][C:5]=2[CH:4]=1)[CH3:24]
Reactant: CC(=O)c1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)c1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Yield: 103.4 %

Procedure:
Combine 1-[3-Hydroxy-9-(4-hydroxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-2-yl]-ethanone (0.013 g, 0.04 mmol) and NaBH4 (0.016 g, 0.42 mmol) in ethanol (1.5 ml) and heat at 60° C. for 30 minutes. Remove solvent in vacuo and take into ethyl acetate, water, and sodium bicarbonate solution solution. Separate organic layer and wash with water. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield the titled compound (0.014 g, 100%). 1H NMR (CD30D): 7.16 (d, J=7.9 Hz, 2H), 7.1 (s, 1H), 6.78 (d, J=8.4 Hz, 2H), 5.12 (m, 1H), 3.2 (m, 3H), 2.8 (dd, J=10.5 and 7.5 Hz, 1H), 2.5 (m, 1H), 2.34 (m, 1H), 2.05 (m, 1H), 1.8-1.6 (m, 2H), 1.48 (m, 3H), 1.4-0.8 (m, 4H). MS m/z 337 (M−1).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([O-])([O-])[O:15]C.[CH3:19]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1>[CH:1]1([NH:7][C:8](=[O:13])[CH2:9][C:10]([O:15][CH3:14])([O:12][CH3:19])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Product: COC(C)(CC(=O)NC1CCCCC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 36.6 g of N-cyclohexyl-acetylacetamide, 32 g of methyl orthoformate, 100 ml of methanol and 1 g of p-toluene sulfonic acid was stirred for 4 hours at 25° C. and after the addition of 2 g of quinoline, the mixture was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was cooled and vacuum filtered. The recovered precipitate was dried to obtain 40 g of N-cyclohexyl-3,3-dimethoxy-butyramide melting at 66° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38](=C)[CH2:39]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:38]([CH3:39])=[CH2:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CO
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)COC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 61.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methyl-2-propen-1-ol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 58%).