Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(O)=O.C([BH3-])#N.[Na+]>O.C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Reaction time: 2.5 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64.0 mmol), morpholine (20 mL) and AcOH (1.0 mL) was stirred for 2.5 h. Sodium cyanoborohydride (8.05 g, 128.0 mmol) was then added in one portion followed by more morpholine (15 mL). An exothermic reaction occurred and the mixture was cooled for 2 min with an ice-bath. Then the mixture was stirred at room temperature for 16 h. Ethanol (120 mL) and water (28 mL) were added to the resulting thick slurry and the white solid filtered, washed with ethanol (2×) and the filtrate concentrated. Ethyl acetate was then added, the precipitate filtered off, washed with ethyl acetate and the filtrate concentrated. The residual oil was purified by Kugelrohr distillation to give 1 (9.03 g, 62%; b.p.140° C./0.05 mmHg) as a clear oil which solidifies on standing.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:5]=21.[C:30](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([O:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(O)cccc32)cc(Br)c1OC
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(OC)cccc32)cc(Br)c1OC
Reaction time: 1 h
Yield: 92 %

Procedure:
2-Amino-7-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (8) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (43 mg, 92%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)CCC(CCC#N)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCC(CCC(=O)O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 6-cyano-4,4-diphenylhexanoate (25.5 g) in ethanol (400 ml) was added 1N-aqueous sodium hydroxide solution (120 ml) and the mixture was heated and stirred at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the group was made acidic to with 1N-hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The group (25 g) was recrystallized from chloroform-hexane to provide the title compound (22 g) as white powder.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:11]([Si:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:16][CH2:17][CH2:18][CH2:19][CH:20]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)[OH:21])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCC(O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 63 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a suspension of Mg turnings (145 mg, 6.0 mg-at.) and catalytic amount of iodine in 20 mL THF was added dropwise 1-Bromo-4-chloro-benzene (382 mg, 2.0 mmol) with heating over a period of 30 min. After stirring for an additional 30 min at 63° C. the mixture was cooled to −30° C. and 4-(tert-Butyl-diphenyl-silanyloxy)-butyraldehyde (500 mg, 1.53 mmol) was added slowly as a solution in 5 mL THF. The temperature was maintained at −30° C. for 1 h and slowly raised to room temperature. The excess Grignard reagent was destroyed by careful addition of saturated aqueous NH4Cl (20 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). After removal of the solvent under reduced pressure the product was isolated by flash column chromatography eluting with 0 to 50% EtOAc/hexanes to afford 330 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:19][C:14]1[CH:13]=[N:12][N:11]2[C:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:7][C:8]([C:15]([F:16])([F:17])[F:18])=[N:9][C:10]=12
Reactant: CC(C)CCc1cc(C(F)(F)F)nc2ccnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)CCc1cc(C(F)(F)F)nc2c(Br)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 4.0 gm (0.0155 mol) of 7-isopentyl-5-trifluoromethylpyrazolo[1,5-a]pyrimidine in 50 ml chloroform was cooled to 15° and 2.73 gm. (0.0155 mol) of N-bromosuccinimide was added. The solution was stirred for 30 minutes at ambient temperature, then poured on ice (50 gm, crushed). The chloroform layer was washed with sat. K2CO3 solution and then dried (Na2SO4) and chromatographed on neutral alumina (Woelm, grade I). Elution of the compound with chloroform, followed by evaporation of the solvent and distillation, afforded 4.0 gm (58%) of the product as an amber oil, b.p. 123°-126° /0.5 mm.
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9]C(C)C)(C)[CH3:7].[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=1[F:25].ICC#N.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=1[F:25])[CH2:7][C:6]#[N:9]
Reactant: COC(=O)Cc1c(F)ccc(Cl)c1F
Reactant: CC(C)NC(C)C
Agent: N#CCI
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1c(F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Butyllithium (4.1 mL of 2.5M solution in hexanes, 10.3 mmol) was added to a solution of diisopropylamine (1.4 mL, 10.3 mmol) in THF (15 mL) under nitrogen at 0° C. After 15 minutes the reaction mixture was cooled to −78° C. and a solution of 3-chloro-2,6-difluorophenylacetic acid methyl ester (2.15 g, 9.8 mmol) in THF (15 mL) was added. After 30 minutes, iodoacetonitrile (3.5 mL, 49 mmol) was added rapidly to the reaction mixture. The reaction mixture was allowed to warm to 0° C. and ammonium chloride solution added (10 mL, saturated aqueous). The reaction mixture was concentrated and the residue partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organics were dried over magnesium sulfate then concentrated to afford a black oil. The crude product was purified by column chromatography (silica, 25% EtOAc-petrol to EtOAc) to afford the title compound as a pale yellow oil (1.51 g, 59%); 1H NMR (400 MHz, DMSO) δ 3.06 (1H, dd), 3.19 (1H, dd), 3.67 (3H, s), 4.64 (1H, dd), 7.29 (1H, t), 7.70 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH:12]C(=O)OC(C)(C)C)[CH:10]=2)[N:5]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1
Reactant: COc1ccc(Cn2nc(OC)c3cc(NC(=O)OC(C)(C)C)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (0.0159 g, 0.0414 mmol) was dissolved in trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to provide 3-methoxy-1 (4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine, which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([N:33]2[CH2:37][CH2:36][C@H:35]([CH2:38][OH:39])[CH2:34]2)(=[O:32])=[O:31])[CH2:3]1.[Li+].[OH-].CO.C1COCC1>CC(O)=O.O>[CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([N:33]2[CH2:37][CH2:36][C@H:35]([CH2:38][OH:39])[CH2:34]2)(=[O:32])=[O:31])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)N5CC[C@H](CO)C5)CC4C)ncnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CC(CS(=O)(=O)N2CC[C@H](CO)C2)CCC1N(C)c1ncnc2[nH]ccc12
Reaction time: 8 h

Procedure:
A mixture of ((3S)-1-((3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)pyrrolidin-3-yl)methanol (0.050 g, 0.09 mmol), LiOH (0.009 g, 0.4 mmol), MeOH (1.5 mL), THF (1.5 mL), and H2O (1.0 mL) was stirred overnight. The mixture was then treated with 1 drop AcOH and the mixture concentrated. The resulting mixture was purified using reverse phase chromatography to afford the title compound. MS for C20H31N5O3S (ESI) (MH)+ m/z=422.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14](N)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.CC[OH:21].C(=O)([O-])[O-].[K+].[K+]>O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14](=[O:21])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=O
Temperature: 82.5 °C
Yield: 76 %

Procedure:
Stir 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (82.5 g, 0.291 mol) as a suspension in deionized water (2475 mL) at ambient temperature. Add EtOH (830 mL) and stir for 15 minutes. Add potassium carbonate (301 g, 2.18 mol) with stirring and heat to gentle reflux (80-85° C.) for 3-4 days. Allow cooling to ambient temperature. Filter the product and rinse with 3:1/water:EtOH, then water. Dry the solid at 50-60° C. to give 55.2 g (76%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 9.18 (bs, 1H), 9.00 (bs, 1H), 6.90 (m, 1H), 6.73 (m, 1H), 6.60 (m, 2H), 2.24 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9FN2OS 249.0498; found 249.0488.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:19])[C:7]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC(C)C)C2C3C=CC(O)=CC=3N=CC=2N=1)C.Br[CH2:41][CH2:42][CH2:43][CH2:44][C:45]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46].BrCC(N1CCOCC1)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[CH2:1]([C:5]1[N:6]([CH3:19])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:46])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CCCCBr)N1CCOCC1
Reactant: CCCCc1nc2cnc3ccc(O)cc3c2n1C
Agent: CCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: CCCCc1nc2cnc3ccc(OCCCCC(=O)N4CCOCC4)cc3c2n1C
Temperature: 80 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
A modification of the general method described in Part D of Example 30 was followed using 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol (1.2 g, 4.7 mmol) in lieu of 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol and 4-(5-bromopentanoyl)morpholine (3.7 mmol) in lieu of 4-(2-bromoacetyl)morpholine. After the reaction was heated overnight, an analysis by TLC indicated the presence of starting material. Additional 4-(5-bromopentanoyl)morpholine (2.2 g) and cesium carbonate (0.5 g) were added, and the reaction was heated at 80° C. overnight. After the solution was concentrated, the residue was further dried under high vacuum overnight and then dissolved in ethyl acetate. The resulting solution was washed with water and concentrated under reduced pressure. The solid was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) to provide an oil, which was stirred with diethyl ether and allowed to stand over three days in a refrigerator. A precipitate formed, which was isolated by filtration to provide 0.770 g of 2-butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-1H-imidazo[4,5-c]quinoline as pale yellow crystals.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1.Br[CH2:19][CH3:20].C(O)(C)C>CN(C=O)C.C1(C)C=CC=CC=1>[Br:4][C:5]1[C:6](=[O:17])[N:7]([CH2:19][CH3:20])[CH:8]=[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1
Reactant: O=c1[nH]cc(-c2cnccn2)cc1Br
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCn1cc(-c2cnccn2)cc(Br)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1.5 g of sodium methoxide is added to a stirred mixture of 3-bromo-5-(2-pyrazinyl)-2(1H)-pyridone (6.3 g) in DMF (200 ml) warmed to a temperature of 80° C. 4 ml of bromoethane are added to the warmed reaction mixture which is stirred for 30 minutes at 80° C. The reaction mixture is cooled to RT, stirred overnight, filtered and the filtrate acidified to pH 5.7 by addition of methanolic HCl. The acidified filtrate is evaporated resulting in a thick red oil. The oil is treated with hot isopropanol and the inorganic salts filtered off. The isopropanol solution is warmed, charcoal added, and filtered while hot. The filtrate is evaporated resulting in a tan solid which is dissolved in warm toluene and chromatographed on a column of silica gel (40 g per g tan solid) dispersed in toluene. The column is eluted increasing concentrations of ethyl acetate in toluene followed by methanol and ethyl acetate. The purified product is recrystallized from decane and toluene. The initial crop of crystals is identified as the O-ethylated product isomer while the addition of toluene caused the crystallization of a second crop of crystals which is identified as the desired N-ethyl pyridone, M.P. 129°-132° C.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[OH:8][CH:1]([CH:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(C(=O)c2ccccc2)CO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1NC(C(O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3 g (15.8 mMole) of 4-benzoyl oxazolidin-2-one are dissolved in 100 ml of ethanol, followed by the addition in portions at room temperature of 900 mg (23.8 mMole) of sodium borohydride. The mixture is then stirred for 2.5 hours at room temperature. The reaction solution is then hydrolysed with a saturated ammonium chloride solution. The aqueous phase is repeatedly extracted with CHCl3, the organic phases are combined, dried over Na2SO4 and concentrated in a rotary evaporator. The oil is taken up in methanol. The crystals are filtered under suction.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[C@@H:30]([C:31]#[C:32]/[CH:33]=[CH:34]\[C:35]#[CH:36])[C@:29]23[O:37][C@:24]2([C@@H:25]([OH:43])[C:26]([O:41][CH3:42])([O:39][CH3:40])[CH2:27][C@@H:28]3[CH3:38])[C:23]2[CH:22]=[C:21]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:20]=[CH:19][C:18]1=2)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C.P([O-])([O-])([O-])=O>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[C@@H:30]([C:31]#[C:32]/[CH:33]=[CH:34]\[C:35]#[CH:36])[C@:29]23[O:37][C@:24]2([C:25](=[O:43])[C:26]([O:39][CH3:40])([O:41][CH3:42])[CH2:27][C@@H:28]3[CH3:38])[C:23]2[CH:22]=[C:21]([O:44][Si:45]([C:48]([CH3:49])([CH3:51])[CH3:50])([CH3:46])[CH3:47])[CH:20]=[CH:19][C:18]1=2)=[O:16])[CH:12]=[CH2:13]
Reactant: C#C/C=C\C#C[C@@H]1N(C(=O)OCC=C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2[C@@]23O[C@@]12[C@@H](C)CC(OC)(OC)[C@@H]3O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#C/C=C\C#C[C@@H]1N(C(=O)OCC=C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2[C@@]23O[C@@]12[C@@H](C)CC(OC)(OC)C3=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (4.22 mL, 59.5 mmol, 15.0 equiv) was added to a solution of oxalyl chloride (3.46 mL, 39.7 mmol, 10.0 equiv) in dichloromethane (75 mL) at -78° C. After stirring at -78° C. for 20 min, a solution of allyl(6S,6aS,7S,10R,10aS)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-10-hydroxy-9,9-dimethoxy-7-methyl-6a,10a-epoxyphenanthridine-5(6H)-carboxylate (23, 2.30 g, 3.97 mmol, 1 equiv) in dichloromethane (75 mL) was added over 10 min via cannula to the cold reaction solution. The reaction mixture was warmed to -40° C. and was held at that temperature for 10 h. The reaction mixture was then cooled to -78° C., triethylamine (16.6 mL, 119 mmol, 30.0 equiv) was added, and the resulting solution was stirred in an ice bath for 30 min. The product solution was poured into aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 150 mL). The aqueous layer was separated and extracted further with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (2% ethyl acetate-dichloromethane initially, grading to 5% ethyl acetate-dichloromethane) to afford allyl(6S,6aS,7S,10aR)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-oxo-6a,10a-epoxyphenanthridine-5(6H)-carboxylate (24) as a light brown foam (2.10 g, 92%). ##STR35##
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].CCN(C(C)C)C(C)C>C(#N)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1.0 g (3.23 mmol) of (3-(R)-t-Butyldimethylsilyloxymethyl-4-(S)-(3-fluorophenyl)pyrrolidine in 8 mL of acetonitrile was treated with 0.47 mL (4.95 mmol) of methyl bromoacetate and 0.86 g (4.95 mmol) of DIEA and the reaction was heated in 80° C. bath. After 2 hr, the solution was cooled, and partitioned between water-EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 10-20% EtOAc in hexanes to isolate 0.45 g of the title compound. 1H NMR (CDCl3) 0.027 (2s, 6H), 0.87 (s, 9H), 2.4 (m, 1H), 2.7-3.1 (m, 5H), 3.33 and 3.47 (ABq, 2H), 3.63 (m, 2H), 3.76 (s, 3H), 6.8-7.3 (m 4H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([C:12]1C=C(O)C(=C[CH:18]=1)O)(C)(C)[CH3:9].S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O.C=C/C=C/C>>[CH2:9]1[CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18][CH:12]=[CH:8]1)=[O:7]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: O=C1C=CC(=O)O1
Agent: C=C/C=C/C
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12

Procedure:
3Me--THPA was produced by the liquid phase aeration method. Thus, the air in a 300 ml four-necked flask similar to the one used in Example 5 was replaced with nitrogen and, then, the flask was charged with 98 g of maleic anhydride, 300 ppm of p-tert-butylcatechol by way of auxiliary polymerization inhibitor and 800 ppm of dilauryl thiodipropionate by way of auxiliary polymerization inhibitor and the charge was melted at 60° C. Then, the internal atmosphere of the reaction system was replaced with nitrogen gas, and thereafter nitrogen gas containing 1 volume % of oxygen was passed into the reaction mixture at a rate of 5 ml/min throughout the reaction. Under this atmosphere, 374 g of crude trans-1,3-pentadiene of the same composition as that used in Example 1 was continuously added at 60° C. for 4 hours. Major portion of unreactive fractions was distilled off from the reaction mixture in the course of reaction. Thereafter, the reaction mixture was treated in the same manner as in Example 5 to give 164 g of 3Me--THPA. The investigation revealed no gels in the product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:4]#[C:5][CH3:6].I[CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[CH2:22]([N:14]([C:12]1[CH:13]=[C:8]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:9]=[CH:10][N:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:23][CH3:24]
Reactant: CCCI
Reactant: CC#CCOc1cc(Nc2ccccc2)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CCC)c2ccccc2)ncn1
Temperature: 25 °C
Yield: 51 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-(2-butynyloxy)-6-anilinopyrimidine was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.3 ml of a tetrahydrofuran solution containing 0.17 g of iodopropane was slowly added dropwise at room temperature, followed by stirring for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(N-propyl-N-phenylamino)-6-(2-butynyloxy)pyrimidine (the present compound (98)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20](OC)=[O:21])[CH2:13][C@@H:14]([C:16]([F:19])([F:18])[F:17])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].[BH4-].[Na+]>CCO>[F:17][C:16]([F:18])([F:19])[C@@H:14]([CH3:15])[CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20][OH:21]
Reactant: COC(=O)[C@H](C[C@H](C)C(F)(F)F)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: C[C@@H](C[C@@H](CO)NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 0.21 h

Procedure:
To a solution of methyl (4S)—N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucinate (5.4 g, 16.2 mmol) in EtOH (150 mL) at room temperature was added LiCl (2.8 g, 66 mol) and the mixture was stirred for 10 to 15 min, followed by the addition of NaBH4 (2.5 g, 66 mmol). The mixture was stirred at room temperature for 6 h. After dilution with H2O (60 mL), the mixture was quenched with 6M aqueous HCl (18 mL). More H2O was added and the mixture was extracted with EtOAc (2×). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated to give the crude benzyl (1S,3S)-4,4,4-trifluoro-1-(hydroxymethyl)-3-methylbutylcarbamate.