Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH2:59])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=1)[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH:59][C:7]([C:5]1[N:4]=[N:3][N:2]([OH:1])[CH:6]=1)=[O:9])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([Br:58])=[CH:56][CH:57]=1)[CH3:45]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(Br)cc1
Reactant: O=C(O)c1cn(O)nn1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
1-Hydroxy-1H-1,2,3-triazole-4-carboxylic acid (163 mg, 1.3 mmol),), HCTU (523 mg, 1.3 mmol), and DMF were combined and stirred for 5 minutes at room temperature. DIPEA (661 μL, 3.8 mmol) and (2R,4R)-4-amino-5-(4-bromophenyl)-2-hydroxypentanoic acid ethyl ester (4 mg, 1.3 mmol) were added and the resulting mixture was stirred for 10 minutes. The reaction mixture was evaporated under reduced pressure and purified (C18 column; 20-70% MeCN in water with 0.05% TFA) to yield the title compound (330 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C#N)[C:9](=[O:20])[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.C(OC(C)C)(C)C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:20])[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]2=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A 3 liter flask was equipped with a mechanical stirrer, reflux condenser, addition funnel, N2 inlet, and thermometer. The flask was charged with 156.77 g (0.52 mol) of ethyl 6-(4'-methylphenyl)-6-cyano-5-keto-3,3-dimethylhexanoate dissolved in 370 ml of glacial acetic acid, followed by 132 ml of water, and finally 132 ml of conventrated sulfuric acid was added. The reaction mixture was refluxed for 48 hours, cooled to room temperature and 600 ml of water and 300 ml of isopropyl ether added. This two-phase system was refluxed for 1 hour, cooled in an ice bath, and filtered. The precipitate was washed thoroughly with water and isopropyl ether, then dried overnight in a vacuum oven to give 68.09 g (57% yield) of the desired product as a pale yellow powder; m.p. 199.5°-201.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]#[C:8][NH2:9].C(O)(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2/[CH:27]=[C:28]1/[C:29](=[O:35])[N:30]=[C:31](SC)[S:32]/1>O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2/[CH:27]=[C:28]1/[C:29](=[O:35])[N:30]=[C:31]([NH:9][C:8]#[N:7])[S:32]/1
Reactant: N#CN
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(NC#N)=NC3=O)c2c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a room temperature suspension of potassium t-butoxide (73 mg, 0.65 mmols) and cyanamide (96 mg, 2.27 mmols) in mL of t-butanol is added (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)-4(5H)-thiazolone (146 mg, 0.46 mmols). The mixture is heated at reflux for 5 minutes, then cooled to room temperature. The mixture is poured into 50 mL of water and the orange solution is washed with diethyl ether. The layers are separated and the aqueous layer is acidified with 10% aqueous hydrochloric acid. The orange solid is collected by filtration, washing with water to give 106 mg (74%) of (Z)-[4,5-dihydro-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-4-oxo-2-thiazolyl]cyanamide; mp>300.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH2:10]([NH2:13])[CH:11]=[CH2:12].CC(N=NC(C#N)(C)C)(C#N)C>C(O)CCC>[CH2:1]([P:3]([CH2:12][CH2:11][CH2:10][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CCN
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCO
Product: CCCCOP(=O)(CC)CCCN
Yield: 65.1 %

Procedure:
150 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 68.4 g (1.2 mol) of allylamine are initially charged in 200 ml of butanol in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet, and heated. At about 100° C., in the course of 1 h, 98.4 g of a 5% solution of AIBN in butanol are added dropwise, whereafter the solvent is distilled off in vacuo. Chromatographic purification yields 135 g (65% of theory) of butyl ethyl(3-aminopropyl)phosphinate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([NH2:20])=[O:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(N)=O)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
44.5 ml (351 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. to a suspension of 50.0 g (281 mmol) 3-(4-Methoxyphenyl)-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide. Stirring was continued at 0–5° C. for 30 min. and thereafter for 2 h at room temperature. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 48.8 g (98%) 3-(4-Methoxyphenyl)-acrylamide were obtained.
Reaction SMILES: [CH3:1][S:2](Br)(=[O:4])=[O:3].OO.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>[N+](C)([O-])=O.C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])=[O:3]
Reactant: C=Cc1ccccc1
Reactant: CS(=O)(=O)Br
Agent: OO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CS(=O)(=O)C=Cc1ccccc1
Reaction time: 50 h

Procedure:
130 mg of zinc chloride, 3.2 g (20 mmoles) of methanesulfonic acid bromide and 0.15 ml of 50% strength hydrogen peroxide are successively added to a solution of 2.1 g (20 mmoles) of styrene in 5 ml of nitromethane. After 50 hours at room temperature, the mixture is taken up in methylene chloride and the solution is washed with water. The crude 1-methylsulfonyl-2-bromo-2-phenylethane which remains after stripping off the methylene chloride is dissolved in 10 ml of benzene and dehydrobrominated by adding 25 mmoles of triethylamine. Distillation at from 121° to 124° C. at 0.01 mm Hg gives β-methylsulfonylstyrene, of melting point 77° - 79° C. (after recrystallization from ether). According to the NMR spectrum (J = 15.5 Hz), the product is in the trans-configuration.
Reaction SMILES: [K+].[Cl:2][C:3]1[N:4]=[C:5]([C:16]([O-:18])=O)[N:6](COCC[Si](C)(C)C)[CH:7]=1.[C:19]1([C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:28]=[CH:27][C:26]=2[NH2:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.FC(F)(F)C(O)=O>>[ClH:2].[C:19]1([C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH:28]=[CH:27][C:26]=2[NH:39][C:16]([C:5]2[NH:4][C:3]([Cl:2])=[CH:7][N:6]=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)nc1C(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1)c1ncc(Cl)[nH]1

Procedure:
The title compound was prepared by coupling 4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt and (as prepared in the previous step) and 2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenylamine (as prepared in Example 33, step (c)) according to the procedure in Example 34, step (c), followed by SEM deprotection according to the procedure in Example 34, step (d). The hydrochloride salt was prepared from the trifluoroacetic acid salt using a BioRad AG2-X8 resin, Cl− ion form. 1H-NMR (400 MHz, DMSO-d6): δ 13.73 (s, 1H), 10.52 (s, 1H), 9.58 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.53 (s, 1H), 7.20 (dd, J=8.1, 2.1 Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 5.77 (m, 1H), 4.00 (m, 2H), 3.74 (m, 2H), 3.57-3.41 (m, 4H), 3.19-2.93 (m, 4H), 2.27-2.13 (m, 4H), 1.79-1.65 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H27ClN4O2, 415.2 (M+H). found 415.1
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([N:27]5[CH2:34][CH2:33][CH2:32][C@H:28]5[C:29]([OH:31])=[O:30])[CH:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:23])([F:22])[F:24])[N:16]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(CC(F)(F)F)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCC[C@H]4C(=O)O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and L-proline were reacted to give (S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-pyrrolidine-2-carboxylic acid. LCMS: RT=3.06 min, [M+H]+=463.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)=O.Cl.[OH:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>CC#N>[CH3:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:5]2[CH:4]=[CH:3][N:29]=[C:27]([NH:26][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[N:28]=2)=[CH:8]1
Reactant: CN(C)/C=C/C(=O)c1cn(C)c2ccccc12
Reactant: N=C(N)Nc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2ccccc21

Procedure:
To a mixture of (E)-3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (1.0 mmol, 0.21 g) in MeCN (3.5 mL) was added 1.0 mmol 1-(3-hydroxyphenyl)guanidine hydrogen chloride salt in the presence of NaOH (1.0 mmol). The mixture was irradiated at 150° C. for 20 minutes in microwave. The mixture was purified by chromatography using EtOAc/PE (1:1, v/v) to elute the titled product as a off-white solid. 1H-NMR (DMSO-d6) δ: 3.89 (s, 3H, CH3), 6.38 (m 1H, Ph-H), 7.07 (m, 1H, Ph-H), 7.19 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.25 (m, 1H, Ar—H), 7.38 (s, 1H, Ph-H), 7.53 (d, 1H, J=8.0 Hz, Ph-H), 8.32 (m, 2H, Ar—H and Pyrimidin-H), 8.64 (d, 1H, J=8.0 Hz, OH), 9.23 (s, 1H, Ar—H), 9.27 (s, 1H, Ar—H). MS (ESI+) m/z 317.1311 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9](OC)=[N:8]1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[NH:8][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC1=NC(Cc2ccco2)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C1CCCCC(Cc2ccco2)N1

Procedure:
The title product of Example 48 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH2:11][CH2:12][Br:13])=[C:7]([CH2:16][CH2:17][CH3:18])[C:6]=1[OH:19])=[O:4].[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br-:13].[F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH2:11][CH2:12][P+:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:7]([CH2:16][CH2:17][CH3:18])[C:6]=1[OH:19])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(=O)C(F)(F)F)c1O
Product: CCCc1c(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C(=O)C(F)(F)F)c1O
Product: [Br-]

Procedure:
The title compound is prepared analogously to Example 1c) from 3-(4-trifluoroacetyl-3-hydroxy-2-propylphenoxy)-propyl bromide and triphenylphosphine; m.p. 170°-190° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]=1[NH2:19].C([O:23][CH2:24][CH3:25])(=O)C>>[CH3:1][C:2]([CH3:7])([CH3:3])[CH2:25][C:24]([NH:19][C:3]1[C:4]([CH3:18])=[C:5]([CH3:17])[C:6]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[C:2]=1[CH3:1])=[O:23]
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)CO2
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccccc1)CO2
Yield: 50 %

Procedure:
Using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 306, the title compound was synthesized in the same manner as in Example 1. Yield: 50%. Melting point: 146-147° C. (ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])([CH3:14])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC=C1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CNCCC1c1ccc(F)cc1
Reaction time: 48 h
Yield: 97.3 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3,3-dimethyl-1,2,3,6-tetrahydropyridine (450 mg, 2.192 mmol), palladium hydroxide on carbon (308 mg, 2.192 mmol), and acetic acid (1.5 mL, 26.2 mmol) in methanol (10 mL) was degassed under nitrogen/vacuum, then hydrogenated at 50 psi for two days. The catalyst was removed by filtration and rinsed with methanol, and the filtrate was concentrated in vacuo to yield the title compound (442 mg, 2.132 mmol, 97% yield) as a pale yellow oil. MS (ESI+)=208.29, (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:23]#[C:24]Br.O>C1COCC1.C(OCC)(=O)C>[F:15][C:13]([F:16])([F:14])[C:9]1[N:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC1=N[C@@H](CCc2cccc(C(F)(F)F)n2)CO1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred mixture of (S)-2-amino-4-(6-trifluoromethyl-pyridin-2-yl)-butan-1-ol (0.224 g, 0.96 mmol) and K2CO3 (0.198 g, 1.43 mmol) in THF (7 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.152 g, 1.05 mmol) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded the title compound as off-white solid, (0.096 g, 39%); MS (ISP): 260.0 ((M+H)+.).
Reaction SMILES: [CH:1]1([C@H:7]([OH:21])[CH2:8][NH:9][CH2:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:11]12([CH2:10][N:9]3[CH2:8][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:21][C:30]3=[O:32])[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1O[C@@H](C2CCCCC2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of (S)-1-cyclohexyl-2-((1-adamantylmethyl)amino)ethanol (22 mg, 0.077 mmol) and Et3N (15.6 mg, 0.154 mmol) in dry CH2Cl2(2 mL) at 0° C. was added triphosgene (9.2 mg, 0.031 mmol) in dry CH2Cl2(2 mL). The mixture was stirred for 30 min and then concentrated in vacuum to give the crude product, which was purified by preparative TLC to afford (S)-3-((1-adamantyl)methyl)-5-cyclohexyloxazolidin-2-one (5 mg, 21%). 1H NMR (MeOD, 400 MHZ): δ=1.18-1.97 (m, 25H), 2.75-2.95 (m, 2H), 3.42 (t, 1H), 3.72 (t, 1H), 4.83 (m, 1H); MS: m/z=318.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][N:15]=1)[CH2:6][C:7](=O)[CH2:8][C:9](=O)C)#[N:2].Cl.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=3)[N:25]=[C:8]([CH3:9])[CH:7]=2)[CH:13]=[CH:14][N:15]=1)#[N:2]
Reactant: Cc1cccc(NN)c1
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(C#N)c2)c1
Yield: 81.7 %

Procedure:
To a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (1.10 g, 0.0058 mol) and 3-methylphenylhydrazine hydrochloride (0.97 g, 0.0061 mol) in 20 mL of ethanol was added triethylamine (0.85 mL, 0.0061 mol) dropwise. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.30 g (87% yield) of product as a yellow solid: mp: 128-130° C.; Anal. Calc'd. for C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C, 74.53; H, 5.22; N, 20.29.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])#N.Cl.[OH2:31].[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][C:1]([CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])=[O:31])[CH3:33]
Reactant: O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
2β-(2-Cyanoethoxy)-3α-hydroxy-5α-pregnane-11,20-dione (430 mg.) was dissolved in absolute ethanol (50 ml) and dry hydrogen chloride passed through the solution until saturation occurred. The mixture was left for one-fourth hour then poured into water (250 ml.). After one-half hour the precipitate formed was extracted into ether (2 × 100 ml), the ethereal solution washed with water and dried over anhydrous sodium sulphate. The dried solution was evaporated to a white form (320 mg) which was purified by preparative T.L.C. using ethyl acetate/petrol (4/1) run twice. The main band (Rf[0.4) gave title compound (140 mg) as an oil. [α]D + 61°(c, 0.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
Tetrakis(triphenylphosphine)palladium (577 mg; 0.5 mM) was added to 3,5-dibromopyridine (5.214 g; 22 mM) in 40 mL of toluene at R.T. under nitrogen. After 10 minutes stirring, 25 mL of 2M aqueous sodium carbonate solution, phenylboronic acid (2.44 g; 20 mM), and 10 mL of ethanol were added, and the mixture was heated 11 hours at 80° C. The reaction mixture was cooled, diluted with 75 mL of ethyl acetate and washed with 2×15 mL of saturated sodium carbonate solution, and then dried over anhydrous magnesium sulfate. Solvent removal gave crude product, which was chromatographed on silica gel using ethyl acetate:hexane (1:5) mixture to give a white solid boiling at 100°-101° C./~0.1 mm in 28% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 56 mg of 4-bromobutyric acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was digested with diisopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of 3-hydroxypyridine(5 g) in DMF(50 ml) was added slowly sodium hydride(2.1 g) under ice cooling. After the addition was completed, the reaction mixture was warmed up to room temperature and stirred at the same temperature for 30 minutes. The mixture was cooled with ice and methyl bromoacetate (8.1 g) was added slowly. After the addition was completed, the reaction mixture was stirred at room temperature for 15 hours and poured into ice water. The product was extracted with ethyl acetate, washed with brine, dried(MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=20:3) to obtain methyl 2-(3-pyridyloxy)acetate(1.7 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][O:16][C:13](=[O:15])[CH3:14])=[N:7][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)Nc1ccc(Cl)cn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)Nc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
2-Chloro-N-(5-chloropyridin-2-yl)acetamide (30.68 g) obtained in Reference Example 26(1) is dissolved in N,N-dimethylformamide (500 ml), thereto is added sodium acetate (24.55 g), and the mixture is stirred at 60° C. for 5 hours. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine. The solution is dried over magnesium sulfate, treated with activated charcoal, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and crystals are collected by filtration, washed with n-hexane, and dried to give N-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g). APCI-MS M/Z:229/231[M+H]+