Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[Br:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16](I)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.CN(C)[CH:23]=[O:24]>C(OCC)C.O1CCCC1>[Br:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([CH:23]=[O:24])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
Ethylmagnesium bromide in ethyl ether (3.0 M, 3.472 mL) was added dropwise to a solution of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1173 mg, 3.000 mmol) in 20 ml of tetrahydrofuran at −30° C. The mixture was stirred at this temperature for 20 min and allowed to warm to 15° C. The mixture was cooled to −25° C. again and N,N-dimethylformamide (929.2 uL, 12.00 mmol) was added. The mixture was left for 18 hours. The mixture was quenched with sat. aq. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over mgSO4 and concentrated in vacuum. Yield 0.92 g. MS: 293.1
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[N:17]1([C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[N:11][CH:12]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)c1ccc(N2CCNCC2)cn1
Temperature: 120 °C
Yield: 48.3 %

Procedure:
To a mixture of 5-chloro-2-pyridinyl phenyl sulfone (10.2 g, 40.2 mmol) in pyridine (100 mL) was added piperazine (13.8 g, 161 mmol). The mixture was heated to 120° C. in a preheated oil bath for 18 h. The mixture then was removed from heat and cooled to room temperature. The mixture was partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water (2×50 mL). The organic layer was dried with anhydrous magnesium sulfate and concentrated. The solids obtained after concentration were recrystallized from water and dried to give 5.89 g of the title compound; m.p. 126-127° C.; IR (drift) 1568, 1479, 1447, 1306, 1290, 1254, 1175, 1154, 1145, 1104, 830, 756, 715, 688, 602 cm−1. 1H NMR (CDCl3) δ 3.0, 3.29, 7.13, 7.53, 8.01, 8.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)cc1F
Yield: 87 %

Procedure:
To a solution of 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid (1.25 g) in methanol (40 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, and iced water was poured into the residue. The precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography, and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) were recrystallized from ethyl acetate-hexane to give a colorless prism (1.15 g, yield 87%) of methyl 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionate. melting point: 40–41° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[F:18].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(F)c(F)c2)n1
Yield: 93.9 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine (0.7 g), 2-(3,4-difluoro-phenyl)-ethylamine (0.66 g) and sodiumbicarbonate (0.88 g) in EtOH (25 mL) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine (1.1 g). MS: 312 (M+H); 1H NMR (300 MHz, CDCl3) □6.9-7 (3H, m); 6.05 (1H, s); 3.95 (3H, s); 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:17][OH:18])=[O:8])=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: O=C(NO)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure of Example 1 part (b), but using 4-biphenyl carboxylic acid and hydroxylamine hydrochloride the desired compound was obtained.
Reaction SMILES: C([C:3]1[C:7]2=[C:8]([C:12](O)=[O:13])[CH:9]=[CH:10][CH:11]=[C:6]2[O:5][C:4]=1[CH3:15])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:15][C:4]1[O:5][C:6]2[C:7](=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=1
Reactant: CCc1c(C)oc2cccc(C(=O)O)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc2c(CO)cccc2o1
Yield: 77.4 %

Procedure:
Ethyl 2-methyl-benzofuran-4-carboxylic acid (5.11 g, 26.6 mmol) was reduced with LAH (2 g, 53 mmol) similar to the above procedures to give the product as a clear oil (3.34 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[NH3:11].[OH-].[Na+]>C(#N)C>[NH2:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 14.99 g of 2-chloro-5-(chloromethyl) pyridine, 63.01 g of 25% ammonia water and 60 ml of acetonitrile in a stainless steel autoclave was stirred for 2 hours in an oil bath of 80° C. After adding 12.3 g of 30% sodium hydroxide aqueous solution, the reaction mixture was concentrated. The residue to which 200 ml of ethanol were added was dried over anhydrous magnesium sulfate and filtered to remove insoluble materials. The filtrate was concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 7.66 g of 5-(aminomethyl)-2- chloropyridine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6]([C:18]([OH:20])=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[C:28]#[N:29]>CN(C)C=O.ClCCl>[C:28]([C:23]1[CH:24]=[N:25][N:26]([CH3:27])[C:22]=1[NH:21][C:18]([C:6]1[C:7]2[S:11][C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20])#[N:29]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)O)c2sc(N3CCOCC3)nc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCOCC3)nc12
Yield: 11.4 %

Procedure:
Starting with 4-methoxy-2-(morpholin-4-yl)benzothiazole-7-carboxylic acid (0.13 g) oxalyl chloride (0.10 ml), dichloromethane (10 ml) and dimethylformamide (1 drop), followed by 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (0.11 g), sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.88 ml) and dichloromethane (10 ml). Purification by flash chromatography (eluent ethyl acetate) yielded the title compound as an off-white solid (0.02 g). TLC Rf 0.45 (ethyl acetate); Mpt 299-300° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][CH2:23]O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[O:39]=[C:40]1[NH:45][C:44]2[CH:46]=[C:47]([C:50]#[N:51])[CH:48]=[CH:49][C:43]=2[O:42][CH2:41]1.[H-].[Na+].S([O-])(=O)(=O)C>C(Cl)Cl.CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:12]([CH2:22][CH2:23][N:45]2[C:44]3[CH:46]=[C:47]([C:50]#[N:51])[CH:48]=[CH:49][C:43]=3[O:42][CH2:41][C:40]2=[O:39])[CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxyethyl)piperidine-1-carboxylate (Intermediate 187, 1.27 g) in methylene chloride (15 mL) at 0° C. were added diisopropylethylamine (1.2 mL) and methanesulfonyl chloride (0.50 mL). At the same time in a separate flask, to a solution of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (0.66 g) in DMF (8 mL) at 0° C. was added 60% suspension in oil of NaH (0.25 g). After 30 minutes, the mesylate solution was diluted with methylene chloride, washed with NaHCO3 and brine, dried over sodium sulfate and concentrated. This residue was dissolved in DMF (5 mL) and added to the sodium salt of Intermediate 60. The reaction was stirred over the weekend, diluted with ethyl acetate, washed with NaHCO3 and brine, dried over sodium sulfate and concentrated to give the product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CN(C=O)C.O.C(OCC)(=O)C>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 1.00 g (6.35 mmol) of 2-chloronicotinic acid is slowly added to a suspension of 635 mg (15.9 mmol) of 60% sodium hydride in 25 ml of DMF, and the mixture is then stirred at 0° C. for 30 min. 1.15 g (6.98 mmol) of 5-phenyl-1-pentanol are dissolved in 5 ml of DMF and slowly added dropwise to the above reaction solution. The solution is stirred at room temperature for 3.5 hours. It is then heated at 75° C. and stirred overnight. The substance is taken up in water, ethyl acetate is then added and the aqueous phase is acidified using 1M HCl. The mixture is then extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:12]=1[CH3:13])[C:5](OCC)=[O:6].CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:12]=1[CH3:13])[CH:5]=[O:6]
Reactant: CCOCCCc1cc(C(=O)OCC)cc(Br)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCCCc1cc(C=O)cc(Br)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane (0.07 M) solution of ethyl 3-bromo-5-(3-ethoxypropyl)-4-methylbenzoate (1 eq.) from the previous step was added DIBAL-H (1.5 M solution in toluene, 2.2 eq.). The resulting solution was stirred at RT for 1.5 h and then carefully quenched with 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude alcohol thus obtained was taken up again in dichloromethane (0.07 M) and then added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 40 min, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:24]=[C:25]([C:32](O)=[O:33])[C:26](=[CH:30][CH:31]=1)[C:27](O)=[O:28])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.C(N=C=NC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:32](=[O:33])[C:25]4[C:26](=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=4)[C:27]3=[O:28])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccc([N+](=O)[O-])cc3C1=O)OC2
Reaction time: 0 h

Procedure:
In a 4-ml scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (58 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 4-nitrophthalic acid (63 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropylcarbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 h. The solution was diluted with ethyl acetate (25 ml), washed with 0.5N aqueous hydrochloric acid (25 ml), saturated aqueous sodium bicarbonate (25 ml), and brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. Crude 2-amino-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained as a solid and used immediately in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14](Cl)[CH:15]=[CH2:16].[OH-].[Na+]>O>[CH2:16]([NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])[CH:15]=[CH2:14]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1c(C(C)C)cccc1C(C)C
Yield: 84.3 %

Procedure:
A solution containing 2,6-diisopropyl aniline (35.4 g, 0.2 mol) and allyl chloride (7.6 g, 0.10 mol) was refluxed for 12 hr and then poured into water (400 ml). Adding an aqueous NaOH solution to the reaction mixture made the mixture basic. After extraction with diethyl ether (3×50 ml) and distillation (73.25 Pa, 92° C.), 18.33 g (84.3%) of N-allyl-2,6-diisopropyl aniline was isolated. Nd30=1.5205. 1H-NMR (ppm,CDCl3): δ=7.10(d, 2H, Ph-Hm), 6.81(t, 1H, Ph-Hp), 6.05(m, 1H, CH═C), 5.34(d, 1H, C═C—Htrans), 5.16(d, 1H, C═C—Hcis), 3.71(broad, 1H, NH), 3.50(d, 2H, CH2—C═C), 3.26(m, 2H, CH(Me)2), 1.28(d, 12H, C═C(CH3)2).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CS(C)=O>O>[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC1(C)CCCNC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC(C)(C)C3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), 3,3-dimethylpiperidine (107 mg, 0.95 mmol, 2.00 equiv), DMSO (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 20 mL of H2O. The resulting solids were collected by filtration. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 120 mg (64%) of methyl 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=3[CH3:38])=[CH:11][CH:12]=2)[N:7]([CH:39]([CH3:41])[CH3:40])[C:6]=1[CH3:42])=[O:4].[OH-].[Na+].Cl>CO>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:42])[N:7]4[CH:39]([CH3:40])[CH3:41])=[CH:12][CH:11]=3)=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: COC(=O)c1c(C)n(C(C)C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2c(C(=O)O)c(C)n(C(C)C)c2c1
Yield: 25.6 %

Procedure:
A mixture of 6-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-2-methyl-1H-indole-3-carboxylic acid methyl ester (239 mg, 0.390 mmol), sodium hydroxide (5 M, 0.5 mL) and methanol (1 mL) is heated in a microwave reactor utilizing the lowest power setting at 125° C. for 20 minutes. The mixture is acidified with 1 N HCl and extracted with ether. The ether layers are washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue is purified on a via radial chromatography (2 mm plate, 3% MeOH—CH2Cl2) to yield the title compound (59 mg, 25%) as a white solid. ES/MS m/e 592.8 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][CH3:19])=[C:12]2[O:20]C(=O)C1C(Cl)=CC=CC=1Cl)=[O:5]>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[C:13]([CH2:17][O:18][CH3:19])[C:12]2=[O:20])=[O:5]
Reactant: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1OC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1c[nH]c2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
A suspension of 8-(2,6-dichlorobenzoylamino)-4-(2,6-dichlorobenzoyloxy)-3-methoxymethylquinoline (4.88 g) in ethanol (100 ml) and 1N sodium hydroxide solution (30 ml) was stirred for 2 hours at 90° C. After evaporation, the residue was diluted with water, and the solution was neutralized with 1N hydrochloric acid. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-3-methoxymethyl-4-oxoquinoline (3.41 g) as white powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)[CH:2]([CH3:18])[CH3:1]
Reactant: CC(=O)Nc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice water, 10° C.) solution of 30 parts of intermediate 14, namely N-[4-(2-methyl-1-oxopropyl)-2-nitrophenyl]acetamide in 240 parts of methanol were added portionwise 4.5 parts of sodium tetrahydroborate. Upon completion, stirring was continued for 1 hour. The reaction mixture was evaporated and the residue was extracted with dichloromethane (3×104 parts). The combined extracts were washed with water, dried, filtered and evaporated, yielding 32 parts (100%) of N-[4-(1-hydroxy-2-methylpropyl)-2-nitrophenyl]acetamide (interm. 15).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:29][C:30](=[CH2:33])[CH2:31]O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:31][C:30](=[CH2:29])[CH2:33][O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C=C(C)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
Under inert condition a 500 mL round bottom flask with a magnetic stirrer was charged with 6.87 g (30 mmol) of 1-tert.-butyloxycarbonyl-piperidine-4-carboxylic acid, 110 mg (0.09 mmol) DMAP and 11.5 g (60 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride and 150 mL DCM. To the light yellow solution 3.25 g (45 mmol) 2-methyl-2-propen-1-ol was added. The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum, isolute-HM-N was added and evaporated to dryness. The residue was purified over silica eluting with heptane and ethyl acetate to yield after evaporation of the product containing fractions 7.3 g (86%) of the title compound as colourless oil. MS ISP (m/e): 306.2 [(M+H)+].
Reaction SMILES: [OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:29][C:30](=[O:32])[CH3:31])[C@@H:3]1[OH:33]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:5][C@@H:4]([O:29][C:30](=[O:32])[CH3:31])[C@@H:3]1[O:33][C:4](=[O:29])[CH3:5])(=[O:1])[CH3:3]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]1OC(C)=O
Yield: 147.4 %

Procedure:
1α,2α-Dihydroxy-3β-acetoxy-cholesta-5-ene (264 mg) was dissolved in a mixture of acetic anhydride (20 ml) and pyridine (2 ml) and the solution was heated on a boiling water bath for 2 hours to remove acetic anhydride. To the solution was added ice-water and the precipitated crystals were recovered by filtration. Recrystallization of the crystals from methanol yielded 1α,2α,3β-triacetoxycholesta-5-ene (230 mg) having a melting point between 109 and 110° C.