Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:27])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([Cl:26])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[Cl:26][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:24]#[N:25])=[C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([CH:6]([OH:8])[CH3:7])[CH:10]=3)[N:16]2[CH3:27])=[CH:21][CH:20]=1.[NH2:5][CH:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:27])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([Cl:26])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[CH3:7]
Reactant: [NH4+]
Reactant: CC(=O)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Product: CC(O)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Ammonium acetate (0.567 g, 7.207 mmol) is added to a solution of 2-(5-acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (0.470 g, 1.441 mmol) in MeOH (10 mL), and the reaction is stirred at 50° C. for 48 h. Sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for 24 h at 50° C. Additional sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for another 24 h at 50° C. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile and minor amounts of 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile. The mixture is redissolved in THF (5 mL) and phthalimide (0.181 g, 1.206 mmol) and triphenylphosphine (0.172 g, 0.804 mmol) are added, followed with di-isopropylazodicarboxylate (0.157 mL, 0.804 mmol). The reaction is stirred at room temperature for 4 h. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford a mixture of 6-chloro-2-{5-[1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile and triphenyl phosphine. The mixture is redissolved in ethanol (5 mL). Hydrazine hydrate (65%) (0.411 mL, 8.506 mmol) is added and the reaction is stirred at room temperature overnight. It is then acidified with 2M aqueous HCl and concentrated in vacuo. The residue is redissolved in dichloromethane and filtered through celite to remove the precipitate formed. The organic layer is washed with water. The aqueous layer is separated and basified to with 4M aqueous NaOH, and then extracted with dichloromethane thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile as a solid. MS (ESI) m/z 311.1 (M+H)+
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOC.O>[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[CH:3][C:1]#[N:2])[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#CC=C1CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl (cyanomethyl)phosphonate (0.189 mL) in 1,2-dimethoxyethane (1 mL) at room temperature under nitrogen was added 60% sodium hydride oil dispersion (46 mg). Upon completion of addition, the mixture was stirred for 1 h. After this time, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (69 mg) in 1,2-dimethoxyethane was added (1 mL). The reaction mixture was stirred at room temperature for 1 h, and then heated to reflux for 4 h. At the conclusion of this period, the reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (38 mg) as a mixture of olefin isomers.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=[O:18])C.P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:1]1([C:10]2[C:9](=[O:18])[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: [Li]c1ccccc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCCC=C1c1ccccc1

Procedure:
When phenylmagnesium bromide (a) or phenyllithium (b) is used in place of 3-pyridylmagnesium bromide, the phenylcarbinol enol ether 13 arises (Scheme 3). This is refluxed with acetic anhydride (c) or dehydrated with phosphorous oxychloride and pyridine (d) and hydrolyzed with aqueous hydrochloric acid (e) to give 2-phenyl-2-cyclohexenone (14). Reduction of 14 with sodium borohydride and cerium chloride in methanol (f) provides the allylic alcohol 15 which is dehydrated (d) to 2-phenyl-1,3-cyclohexadiene 16. Reaction of 16 with tertiary butyl nitrosoformate (2) as in Scheme 1, provides the Diels-Alder cycloadduct 17, which can be converted in four steps to (±) exo-2-phenyl-7-azabicyclo[2.2.1]heptane (18), the phenyl analog of epibatidine. ##STR6##
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:8]=1)=[O:6].Cl>[Pt](=O)=O.C(O)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[NH:8]1)=[O:6]
Reactant: COc1ccc(-c2cccc(C(=O)NCCO)n2)cc1OC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CCCC(C(=O)NCCO)N2)cc1OC
Reaction time: 8 h

Procedure:
A quantity of 3.0 g (10 mmoles, 1 eq) of 6-(3,4-dimethoxy-phenyl)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide and 0.23 g (1.0 mmoles, 0.1 eq) of platinum dioxide are added into 35 mL of ethanol and 2.0 ml concentrated HCl. The suspension is hydrogenated under 50 psi of H2 at room temperature overnight. After TLC shows no starting material existing, the reaction is filtered through Celite and solvent is removed. The residue is taken in ethyl acetate, washed with saturated Na2CO3 and brine, dried over Na2SO4 and concentrated to give 6-(3,4-dimethoxy-phenyl)-piperidine-2-carboxylic acid (2-hydroxy-ethyl)-amide as a yellowish oil. The oil is triturated with ethyl acetate and hexanes to afford a white solid (1.6 g, 52%). Analysis: NMR (300 MHz, CDCl3): 7.18 (1H, t), 6.90 (2H, m), 6.82 (1H, m), 3.87 (6H, d), 3.66 (3H, m), 3.39 (3H, m), 2.00 (2H, m), 1.80 (1H, m) and 1.22 (2H, m). MS (LC-MS): Calculated for C16H24N2O4 308.37, found 309.34 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15].[OH-].[Na+]>CC(C)=O.O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:12][C:13]([C:14]#[N:15])([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)(N)C#N
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 25 ml of acetone was cooled to -10°, and 2.5 grams of 2-amino-2-methylpropionitrile was added. With the reaction mixture at -10°, a solution of 1.3 grams of sodium hydroxide in 3.5 ml of water was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 30 minutes. The acetone was removed under reduced pressure; the residue was extracted with diethyl ether, and the extract was separated and dried over magnesium sulfate. The extract was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile; mp, 154-158°.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC=C(C)C=3N=2)[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[Cl:46])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([S:57](=S)([O:59]C2SC3C=CC=C(C)C=3N=2)=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:59])=[O:58])[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:34]([Cl:46])=[C:35]([O:44][CH3:45])[C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[C:38]=2[Cl:39])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(OS(=O)(=S)c3ccccc3)nc12
Reactant: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2c(C)cccc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A 1.03 g quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 448 mg of 4-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 8 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 4-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H-].[Na+].Cl[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[N:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>O1CCCC1>[Cl:35][C:29]1[N:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([N:16]3[CH:15]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]4=[O:11])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:24])=[N:26]2)=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C1CCCCN1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCN1CCCOC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 14.6 %

Procedure:
The procedure is as in Example 22, but starting with N-(3-hydroxypropyl)-2-piperidone (7 g) in anhydrous tetrahydrofuran (150 cc), an oily suspension (50% by weight; 2.15 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). The product obtained is purified by chromatography on silica (0.063-0.2 mm; 240 g) contained in a column 5 cm in diameter, collecting 50-cc fractions. Fractions 23 to 27, eluted with a mixture of methylene chloride and methanol (95:5 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is crystallized by stirring in acetonitrile and then recrystallized in carbon tetrachloride. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-[3-(2-oxopiperidino)propoxy]-1-isoindolinone (2 g), m.p. 140° C., is thereby obtained.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)C1)C2.C1(CCO)CCCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH2:35][CH:44]2[CH2:38][CH2:37][CH2:43][CH2:41][CH2:40][CH2:39]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCCC1CCCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cycloheptylethanol, the title compound was obtained as a colorless solid (0.11 g, 26%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.16 (t, J=6.2 Hz, 2H), 2.87 (s, 6H), 1.76-1.35 (m, 13H), 1.29-1.17 (m, 2H); MS (ES−) m/z 419.1, 421.1 (M−1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (trans-4-hydroxycyclohexyl)carbamate (from AstaTech, 0.133 g, 0.618 mmol) and triethylamine (0.12 mL, 0.86 mmol) in methylene chloride (1 mL) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (0.18 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:12].C([O-])(O)=O.[Na+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>C1COCC1.C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH2:12])=[N:4][C:5]=3[CH:10]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cn1c(N)nc2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(N)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 1-Methyl-1H-benzoimidazole-2,5-diamine (0.63 g, 3.89 mmol) in THF (4 ml) and ethanol (12 ml) was added NaHCO3 (0.98 g, 11.67 mmol) and 2,4-dichloropyrimidine (1.45 g, 9.7 mmol) and the reaction was heated to 80° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-Chloro-pyrimidin-4-yl)-1-methyl-1H-benzoimidazole-2,5-diamine as an red solid. MS (ESI) m/z=275 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=CC=CC=1.[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH:25][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:24])[CH3:23])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and dropping funnel were placed 26 g (0.75 mole) of 2-amino-2-methylpropyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, 200 ml of benzene and 8.2 g of triethylamine. To this stirred mixture was added 22.5 g (0.075 mole) of stearoyl chloride, and the mixture stirred for 4 hours. The triethylamine hydrochloride was removed by filtration and the solvent was stripped off. The residue was dissolved in hot hexane. After crystallization, filtration and drying, the title compound melted at 46°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:33])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: Cl

Procedure:
{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 715.4 [(M+H)+]
Reaction SMILES: [Cr]([Cl:5])([O-])(=O)=O.[NH+]1C=CC=CC=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[C:14]=1[NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:5][C:18]1[CH:17]=[CH:16][C:15]([CH:19]=[O:20])=[C:14]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1
Reactant: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
Pyridinium chlorochromate (1.19 g, 5.5 mmol) was added to a solution of N-(2-chloro-6-(hydroxymethyl)phenyl) pivalamide (884 mg, 3.67 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later the mixture was allowed stirring at room temperature for 3 hrs. The reaction mixture was passed through a thin pad layer of silica gel with CH2Cl2 (2×100 mL), concentrated on rotary vacuo, and purified on a flash chromatography column eluting with 20˜50% EtOAc/hexanes (1000 mL) to afford the expected product as a white solid (414 mg, 47% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9H), 7.30 (t, J=7.81 Hz, 1H), 7.64 (dd, J=7.93, 1.39 Hz, 1H), 7.77 (dd, J=7.55, 1.51 Hz, 1H), 8.25 (s, 1H), 9.84 (s, 1H); Mass spec. 240.08 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](C(O)=O)[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[C:52]([O:55][CH2:56][CH3:57])(=[O:54])C>C(O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:42][C:52]([O:55][CH2:56][CH3:57])=[O:54])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (166 mg), diphenylphosphoryl azide (128 mg) and triethylamine (47 mg) in ethanol (3 ml) was refluxed for 4 hours. The mixture was poured into ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-4-(3-ethoxycarbonylaminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (35 mg) as powder.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[CH:13]=[C:12](OCC2C=CC=CC=2)[N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[CH3:25]N.Cl.[CH2:28]([OH:30])C>>[OH:30][CH2:28][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:25])[CH:10]=1
Reactant: O=C1C=C(OCc2ccccc2)N=CC1OCc1ccccc1
Reactant: CCO
Reactant: CN
Agent: Cl
Product: Cn1ccc(=O)c(CO)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 15 %

Procedure:
3-Benzyloxy-6-benzyloxypyrid-4-one (5.0 g) and methylamine hydrochloride (1.56 g) are dissolved in aqueous ethanol (300 ml of 2:1 H2O-C2H5OH by volume containing 2 g of sodium hydroxide). The reaction mixture is stirred at room temperature for 6 days and then acidified with concentrated HCl to pH 2.0. The yellow mixture is evaporated to dryness and the resulting solid residue is heated under reflux with concentrated HCl (50 ml) for 30 minutes. The product is rotary evaporated to dryness yielding a brown residue which on trituration with acetone forms crystals. Recrystallisation of these from ethanol gives 3-hydroxymethyl-1-methylpyrid-4-one in 15% yield, m.p. 185°-186° C.; δ(d6DMSO), 3.9 (s, 3H), 4.6 (s, 2H), 7.4 (s, 1H), 8.3 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:34][N+:35]([O-])=[O:36])(C)C>C(O)(C)(C)C>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:35]([O-:36])=[O:34])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Potassium tert-butoxide (1.70 g, 15 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed together in tert-butanol (25 mL), and heated at reflux temperature under argon atmosphere for 75 minutes. Iso-propylnitrate (0.51 mL, 5mM) is then added to the refluxing reaction mixture, resulting in an exothermic reaction. After one minute, the reaction vessel is removed from heat and allowed to cool to room temperature. The cooled mixture is then made acidic by addition of acetic acid (5mL), and stirred overnight. The mixture is then diluted with dichloromethane so as to form a separate phase sufficient to solubilize the synthesized product. Subsequently, the solids are removed by filtration and washed with dichloromethane. The materials in both the filtrate and wash(es) are combined together and concentrated. The residue is then redissolved in dichloromethane, then purified by flash chromatagraphy on silica gel to give (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one. The crystallization of this material from aqueous acetone gives white needles (m.p. 166-168° C.). IR 3435, 1696, 1623(m), 1633 cm-1MS(CI) 376(100%, M+l), 358(30%, M+l-H2O) 1H-NMR (CDC13) δ 0.73(3H, s, C18 -Me), 1.06(d, C20 -Me), 1.29(s, C19 -Me), 3.38(1H, dd, 1/2·C21 -CH2), 3.64(1H, dd, 1/2·C21 -CH2). Analysis. Calculated for C22 H33NO4 ·(0.2)H20: C, 69.70; H, 8.80; N, 3.62; Found: C, 69.78; H, 9.13; N, 3.40. This compound has the following structure: ##STR10##