Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.CO.C(Cl)Cl.O>C(O)C.[Pd]>[CH3:13][NH:12][S:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[CH:3][CH:2]=1)(=[O:15])=[O:14]
Reactant: CNS(=O)(=O)c1cc2[nH]ccc2cc1Br
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CNS(=O)(=O)c1ccc2cc[nH]c2c1
Yield: 9.2 %

Procedure:
A solution of 8.68 g (0.299 mol) of 5-bromo-6-methylsulfamoylindole in ethanol was degassed under nitrogen for 15 minutes. Then triethylamine (0.036 mol) was added and then 1.09 g of palladium catalyst. The mixture was hydrogenated (40 psi) for 3 hours. Thin layer chromatography (2.5% methanol/methylene chloride) showed the reaction was complete. The mixture was filtered to remove the catalyst and then concentrated under reduced pressure. The oil remaining was taken up in chloroform and concentrated under reduced pressure four times to remove traces of ethanol solvent. The oil was chromatographed on a silica gel column eluted with 2.5% methanol/methylene chloride. The golden solution was concentrated under vacuum to give an oil. The oil was mixed with water and a tan solid precipitated. After cooling overnight, the tan solid was isolated by vacuum filtration and then washed with water. The solid was allowed to dry and then crushed to a powder which was allowed to further dry. 5.76 g (91.2% by weight yield) of 6-methylsulfamoylindole was obtained. M/e 210 1H-NMR: (DMSO) δ7.859 (m,1H), 7.728 (d, 1H), 7.63 (t, 1H), 7.39 (dd,1H), 7.25 (q, 1H), 6.57 (t,1H), 2.37 (d,3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[NH:20]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[NH2:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:20]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:21]=1
Reactant: NNCc1cccnc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2cccnc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 5 h with 6.2 g of 3-hydrazinomethylpyridine hydrochloride (57616-01-0) and 13 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxy-phenyl)-1-(pyridin-3-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 174-176° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[CH3:32][S:33][C:34]1[N:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][N:35]=1.[Cl-].[NH4+]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:40][C:38]1[CH:37]=[CH:36][N:35]=[C:34]([S:33][CH3:32])[N:39]=1
Reactant: CSc1nccc(C=O)n1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (68.6 g, 0.2 mol) was dissolved in THF (1000 mL), and lithium diisopropylamide (100 mL, 0.2 mol) was added to the solution at −20° C. After stirring at room temperature for 0.5 hour, the solution of 2-(methylthio)pyrimidine-4-carbaldehyde (15.4 g, 0.1 mol) in THF (400 mL) was added to the solution dropwise. The reaction mixture was stirred at room temperature overnight. Then saturated aqueous ammonium chloride solution (200 mL) was added to the mixture, extracted with ethyl acetate (1500 mL), and dried over with anhydrous sodium sulfate. The organic layer was concentrated and purified by chromatography (petroleum ether:ethyl acetate, 3:1) to give 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine as a yellow solid. (Yield 11.2 g, 61.2%). LC-MS: [M+H]+ 183.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[NH:14][CH2:13][CH2:12][N:9]3[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH2:23](Cl)Cl.CB1OB(C)OB(C)O1.C1COCC1.[F-].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]23[NH:14][CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]2[N:6]([C:2]([CH3:23])=[CH:3][CH:4]=2)[CH2:7]3)=[CH:16][CH:17]=1
Reactant: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C23Cn4c(C)ccc4C(=O)N2CCN3)cc1
Temperature: 140 °C
Yield: 525.5 %

Procedure:
To a suspension of 8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (60 mg, 0.17 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (13 mg, 0.016 mmol) and trimethylboroxine solution in THF (3.5, M, 0.84 mmol, 0.24 mL) in 1,4-dioxane (1.5 mL) was added a solution of potassium fluoride (30 mg, 0.52 mmol) in water (0.5 mL). The reaction vessel was flushed with argon and then heated at 140° C. for 20 minutes in the microwave. The suspension was then diluted with CH2Cl2 and filtered. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, 12 g cartridge, CH2Cl2 3 CV, gradient 0-10% MeOH in CH2Cl2 15 CV) to give 10a-(4-methoxyphenyl)-8-methyl-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as off-white solid (25 mg, yield 40%). ESI-MI m/z [M+H]+298.0.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:33]2[CH:34]=[CH:35][C:36](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:37][C:32]=2[CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:40](=[O:41])/[CH:39]=[CH:38]/[C:36]4[CH:35]=[CH:34][C:33]5[O:29][CH2:30][CH2:31][C:32]=5[CH:37]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCO2
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,3-dihydrobenzofuran-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C32H38N4O3: 527 (M+H). Found: 527
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:6]2[CH2:5][NH:4][CH2:3]1)=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.O>ClCCl>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH2:9][C:10]4[C:15]([CH:6]3[CH2:5]2)=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=4)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc2c(cc1OC)C1CNCC(=O)N1CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2c(cc1OC)C1CN(C(=O)c3ccc(Cl)cc3)CC(=O)N1CC2
Yield: 99.9 %

Procedure:
To a solution of 2.62 g of (±)-4-oxo-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (I; R1 =H, R2 =R2 =OCH3) in 10 ml of dichloromethane was added 2 ml of triethylamine, and then 1.9 g of p-chlorobenzoyl chloride was slowly added 0°~5° C. The resultant mixture was stirred at 10° C. for 1.5 hours. To the reaction mixture was added water, and the organic layer was seperated. The organic extract was concentrated, and then the residue was triturated with ethyl acetate-ether to obtain 4.0 g (~100%) of the product, m.p. 139°~140° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O-]CC.[Na+].[F:30][C:31]([F:54])([F:53])[O:32][C:33]1[CH:52]=[CH:51][C:36]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:47]2[CH:46]=[CH:45][C:44]([N:41]3[CH2:42][CH2:43][CH:38]([O:37][C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:53])([F:30])[F:54])=[CH:52][CH:51]=4)[CH2:39][CH2:40]3)=[CH:49][CH:48]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: CC[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
Toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-butyl ester (0.78 g) was suspended in ethanol (12 ml), an ethanol solution (0.68 ml) of 20% sodium ethoxide was added thereto, followed by stirring at room temperature for 1 hour. 4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (0.707 g) and tripotassium phosphate (0.509 g) were added thereto and stirred at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered through Celite to remove insoluble matter and, then the residue was washed with ethyl acetate. The filtrate and liquid were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→9:1) to afford the title compound as a pale yellow powder (0.314 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].Cl>ClCCl>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1OCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCON1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 2-(3-hydroxy-propoxy)-isoindole-1,3-dione (17.5 g, 79.1 mmol) and imidazole (5.92 g, 86.1 mmol) in dichloromethane (200 mL) was added tert-butyldimethylsilyl chloride (13.2 g, 86.1 mmol). After 30 min, the reaction was transferred to a separatory funnel and shaken with dilute aqueous hydrochloric acid (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to afford 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-isoindole-1,3-dione (26.3 g, 99% yield) as a viscous liquid: 1H NMR (400 MHz, CDCl3) δ 7.76 (m, 2H), 7.67 (m, 2H), 4.25 (t, 2H, J=5.9 Hz), 3.77 (t, 2H, J=6.0 Hz), 1.91 (quintet, 2H, J=6.1 Hz), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: C(OC)=O.[N-:5]=[N+:6]=[N-:7].[Na+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@H:17]1[O:23][C@H:18]1[C:19]([O:21][CH3:22])=[O:20].C(OCC)(=O)C>CO.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@H:17]([N:5]=[N+:6]=[N-:7])[C@@H:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1F
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: COC(=O)[C@H](O)[C@@H](N=[N+]=[N-])c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 43 h
Yield: 96.3 %

Procedure:
Under argon atmosphere, 1 ml of methyl formate and 360 mg of sodium azide were added to a solution of 237 mg of methyl (2R,3R)-3-(2,4-difluorophenyl)-2-epoxypropionate dissolved in 9 ml of methanol-water (8:1), and the mixture was stirred at 50° C. for 43 hours. After the reaction mixture was cooled, ethyl acetate and ice water were added to the reaction mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=5:1) to obtain 274 mg of methyl (2R,3S)-3-(2,4-difluorophenyl)-3-azido-2-hydroxypropionate.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:35]=[CH:34][N:16]3[C:17](=[O:33])[C:18](/C=C/C(O)=O)=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([OH:27])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(NC(C2C=CN3C(=O)CC(=O)N=C3C=2)=O)SC=1)(C)(C)C.O[C@@H]1CCCNC1>>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:35]=[CH:34][N:16]3[C:17](=[O:33])[CH:18]=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([OH:27])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCC[C@@H](O)C4)nc3c2)n1
Agent: CC(C)(C)c1csc(NC(=O)C2=CC3=NC(=O)CC(=O)N3C=C2)n1
Agent: O[C@@H]1CCCNC1
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCC[C@@H](O)C4)nc3c2)n1
Yield: 65 %

Procedure:
Reactions were performed in the same manner as in Example 8, (E) by using N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-8-carboxamide (300 mg, 0.871 mmol) and (R)-(+)-3-hydroxypiperidine (530 mg, 5.226 mmol) to obtain 241.8 mg (65%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6](C2C=C3C(=CC=2)NC(C)(C)C=C3C)[CH:7]=1.[I:24]C1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([I:24])[CH:7]=1
Reactant: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc([N+](=O)[O-])c3)cc21
Reactant: Nc1cc(I)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(5-Fluoro-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 280, structure 4 of Scheme II, where R1 =5-fluoro-3-nitrophenyl) 1-Fluoro-3-nitroidobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was place din an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2)#[N:7].CN([CH:33]=[O:34])C>>[CH:33]([C:24]1[CH:23]=[CH:22][C:21]2[N:15]([CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]#[N:7])[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH2:19][C:20]=2[CH:25]=1)=[O:34]
Reactant: N#Cc1ccccc1CN1c2ccccc2CCc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccccc1CN1c2ccccc2CCc2cc(C=O)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
DMF (5 ml) was added dropwise to 5 ml of phosphorus oxychloride with cooling. To the solution was added dropwise 40 ml of a solution of 7.0 g of Compound 37-a in DMF, followed by stirring at 70° C. for 6 hours. The reaction mixture was poured onto ice, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 5.83 g (75%) of the product as a yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]I.[CH:12]#[CH:13]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:12]#[CH:13]
Reactant: C#C
Reactant: COC(CCCCCI)OC
Product: C#CCCCCCC(OC)OC
Yield: 96 %

Procedure:
Acetylene was bubbled through ca. 300 ml of liquid ammonia while 8.1 g (0.35 atom) of sodium was added in small pieces. After the disappearance of the blue color, dimethylsulfoxide (150 ml) was added cautiously. 1,1-Dimethoxy-6-iodohexane (8.16 g; 0.3 Mole) was then added over a period of 10 min. while acetylene was bubbled through the stirred mixture. The ammonia was allowed to evaporate and was replaced with ether. When the mixture had reached 0°, dilute NH4Cl solution was added. The organic layer was separated, washed with water, dried (Na2SO4), and evaporated. Distillation of the residue gave 48.9 g (96%) of 1,1-dimethoxy-oct-7-yne, b.p. 91°/8 Torr.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][C@H:18]([CH3:21])[CH2:19][OH:20]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: C[C@@H](N)CO
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (3.0 g; 10.9 mol) in acetonitrile (35 mL) was added triethylamine (1.32 g, 1.82 mL, 13.1 mmol), followed by (R)-2-aminopropanol (0.88 g, 11.8 mmol). The mixture was stirred at room temperature for 24 h and was then diluted with ethyl acetate, followed by extraction with brine, 10% aqueous citric acid, and aqueous sodium bicarbonate. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give the title compound (3.0 g, 88% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[CH2:15][C:16]1([CH3:18])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:22]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C)OCCn2c1c(C)c1ccccc12

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol (26.5 g., 0.15 mole), described in Example 1, in toluene (600 ml.), ethyl acetoacetate (36 g., 0.20 mole) and p-toluenesulfonic acid (2.0 g.) is heated at reflux for 6 hr. using a water separator. The toluene solution is washed with water, 5% bicarbonate solution, and again with water. The solution is then dried over sodium sulfate and the solvent evaporated under reduced pressure to give an oil. The oil was subjected to chromatograhy on silica gel. Elution with 10% ethyl acetate is benzene and concentration of the eluate affords the ester, 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, as an oil, γmaxfilm 1725 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:17]2[C:30]([O:32]CC2C=CC=CC=2)=[O:31])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:43]([O:42][C:40]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:17]2[C:30]([OH:32])=[O:31])[CH:12]=[CH:11][N:10]=1)=[O:41])([CH3:45])([CH3:46])[CH3:44]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N(C(=O)Nc3ccccc3)[C@@H]2C(=O)OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N(C(=O)Nc3ccccc3)[C@@H]2C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acylated lactam ester 20 (56 mg, 0.089 mmol) was dissolved in 2 mL of 1:1 methanol-ethyl acetate in a 20 mL glass vial. 10% palladium on carbon catalyst (10 mg) was added, and the solution was stirred under an atmosphere of hydrogen at room temperature overnight under argon, filtered, and then concentrated in vacuo. The residue was pure by HPLC/MS and was taken to the next step without purification. MS: 541.1 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].[OH2:18].[F:19][C:20]1[C:25]([B:26](C2C(F)=C(F)C(F)=C(F)C=2F)[C:27]2[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=2[F:37])=[C:24]([F:49])[C:23]([F:50])=[C:22]([F:51])[C:21]=1[F:52]>C1(C)C=CC=CC=1>[F:19][C:20]1[C:25]([B:26]([C:27]2[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=2[F:37])[OH:18])=[C:24]([F:49])[C:23]([F:50])=[C:22]([F:51])[C:21]=1[F:52]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Moreover, that patent also discloses a method in which aluminum sulfate 18 hydrate is used instead of water. Specifically, aluminum sulfate 18 hydrate containing water of 1.77 molar equivalent vs. tris(pentafluorophenyl)borane is added to a toluene solution of tris(pentafluorophenyl)borane. After the solution is refluxed, insoluble aluminum sulfate is separated from the reaction mixture. A solvent of the filtrate is removed in vacuo. Toluene is added to the thus obtained residues. After stirring, the insoluble material is filtered through a G4 sintered-glass so as to be separated. The solvent of the filtrate is again removed in vacuo. Heptane is added to the residues. The solution is stirred and filtered so that a cake is obtained. Finally, the thus obtained cake is washed with heptane, and dried in vacuo so as to isolate bis(pentafluorophenyl)borinic acid. However, this method has such a problem that it is necessary to remove the byproduct aluminum sulfate and its process is so complicated.