Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5]2.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31].C(Cl)Cl>CCO>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: Ic1ccc2c(c1)CNC2
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A product of Example 2, Step C (1.32 g; 2.71 mmol) in 60% CF3CO2H/CH2Cl2 (10 ml) was stirred for 10 min at room temperature under N2, then diluted to 30 ml with EtOH and stirred for additional 15 min. This was evaporated to dryness under reduced pressure and the residue was dissolved in EtOAc (10 ml) and hexane (20 ml) was added. After standing overnight at room temperature, the precipitate formed was filtered off, washed with hexane and dried to give the title compound (0.77 g; 79%), as off white solid, which was used in the next step without further purification. 1H-NMR (CDCl3) 4.47 (5, 2H); 4.51 (s, 2H); 6.7-6.8 (m, 1H); 7.0-7.21 (m, 1H); 7.4-7.7 (m, 1H); 10.6 (broad s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](C)=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1CC)[CH:2]=[CH2:3].O[C:19]1C=CC(C=O)=C(C)C=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[C:13]([CH3:19])[CH:14]=1)[CH:2]=[CH2:3]
Reactant: Cc1cc(O)ccc1C=O
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1CC
Product: C=CCOc1ccc(C(=N)NO)c(C)c1

Procedure:
The title compound is prepared in analogy to 4-allyloxy-3-ethyl-N-hydroxy-5-methyl-benzamidine starting from commercially available 4-hydroxy-2-methyl-benzaldehyde; LC-MS: tR=0.62 min, [M+1]+=207.10; 13C NMR (CDCl3): δ 20.72, 68.91, 104.72, 112.75, 116.45, 118.32, 118.53, 132.25, 134.19, 144.09, 161.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([OH:19])=O)[C:9]=1[CH3:20])=[O:7].Cl.[NH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[C:9]=1[CH3:20])=[O:7]
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)O)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2ccccc12

Procedure:
This compound is obtained according to the same method as the preceding compound, by coupling 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarboxylic acid with ethyl glycinate hydrochloride.
Reaction SMILES: [C:1]12([C:11]([NH:13][NH2:14])=[S:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O>>[C:1]12([C:11]3[S:12][CH:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[NH:14][N:13]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)C=O
Reactant: NNC(=S)C12CC3CC(CC(C3)C1)C2
Product: CCOC(=O)C1NN=C(C23CC4CC(CC(C4)C2)C3)S1

Procedure:
The product of step (b) was treated with ethyl glyoxylate by the process of Example 3, step (a) to give the sub-title product (1.5 g) as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]([C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](OCC1C=CC=CC=1)=O)=O)=[CH2:8]>C1COCC1>[CH:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:25])=[CH2:8]
Reactant: C=Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 69.8 %

Procedure:
A solution (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl )-5-bromo-1H-indole (Example 5a, 252 mg, 0.59 mmol), tributyl(vinyl)tin (0.20 mL, 0.68 mmol) and tetrakistriphenyphosphine palladium (0) (84 mg, 0.073 mmol) in anhydrous DMF (3 mL) was stirred at 95-100° C. for 1 day. After cooling to room temperature, the product was taken into ethyl acetate, filtered through celite, washed with water (2×) and brine (1×), dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography on silica gel (60-100% ethyl acetate in hexanes) yielded (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl)carbonyl]-1H-indole (115 mg, 52%). A solution of LAH (0.77 mL, 1M in THF, 0.77 mmol) was added slowly to a cooled (0° C.) solution of (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl) carbonyl]-1H-indole (115 mg, 0.31 mmol) in THF (5 mL). Once the addition was completed, the reaction mixture was stirred at reflux for 2 h prior to quenching with sodium sulfate decahydrate. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. Flash chromatography on silica gel (5% 2M methanolic ammonia in dichloromethane) yielded (R)-5-vinyl-3-[(N-methylpyrrolidin-2-yl) methyl]-1H-indole (52 mg, 71%). HRMS-FAB+ for C16H20N2 : calculated MH+ :241.17047; found MH+ :241.17036.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH2:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN
Product: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 10 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and methylamine (40% in water) to give the title compound in 10% yield; NMR Spectrum: 2.63 (s, 3H), 3.25 (t, 2H), 4.07 (t, 2H), 5.24 (s, 2H), 7.16 (d, 1H), 7.36 (t, 1H), 7.48 (d, 1H), 7.57 (d, 1H), 7.87 (t, 1H), 7.98 (s, 1H), 8.22 (s, 1H), 8.24 (br s, 1H), 8.58 (d, 1H); Mass Spectrum: 426 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br.Br.Br[CH2:23][C:24]1[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCCC1>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:23][C:24]3[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(CN2CCN(c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
A solution of 0.14 g (0.00086 mol) of 1-phenyl-piperazine in 10 ml of tetrahydrofuran was treated with 0.6 ml (0.0043 mol) of triethylamine and 0.24 g (0.00086 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 0.14 g (57%) of 5-(4-phenyl-piperazin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 263°-265°. A further 0.04 g of yellowish crystals was recovered from the mother liquor.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[CH:14]1([C:29]2[C:30]([O:43][CH2:44][CH:45]3[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CC1(C)CCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CC1
Product: CC1(C)CCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-chloro-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as a pale yellow oil (2.13 g, 73%): MS (ES+) m/z 399.2 (M+23).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)N.N([O-])=O.[Na+].[I-:15].[K+]>O>[I:15][C:6]1[CH:5]=[C:4]([S:3][CH3:2])[CH:10]=[CH:9][CH:8]=1
Reactant: CSc1cccc(N)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CSc1cccc(I)c1
Temperature: 5 °C

Procedure:
20 ml of distilled water and 20 ml of 12 N hydrochloric acid are placed, with stirring, in a three-necked flask, and 10 ml of 3-methylthioaniline are then added using a dropping funnel. The mixture is warmed to ensure dissolution and is then cooled down to 5° C. 5.86 g of sodium nitrite dissolved in 15 ml of water are subsequently added slowly, using a dropping funnel, while maintaining the temperature between 5 and 8° C. 20 min after having completed the addition, 13.57 g of potassium iodide dissolved in 15 ml of water are added over a period of 10 min and the mixture is then stirred at room temperature for 15 h. The oil which forms is separated from the aqueous phase by decantation, and an aqueous solution of sodium thiosulphate is then added to it. The aqueous phase is decanted and the product is extracted with 100 ml of dichloromethane. The organic phase is washed with 100 ml of water, and the aqueous phase is adjusted to pH 9 with concentrated sodium hydroxide solution, and then separated off. The organic phase is washed with 2 times 100 ml of water, separated off, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (50 kPa) at 40° C. The resulting product is purified by flash chromatography (eluent, cyclohexane) in order to yield 13 g of 3-iodo-1-methylthiobenzene in the form of a yellow liquid (Merck Silica 5719, Rf=0.8/cyclohexane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[I-:17].[K+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCI
Temperature: 25 °C
Reaction time: 120 h
Yield: 67.5 %

Procedure:
A solution of 5.0 g (0.018 mol) of N-(4-bromobutyl)phthalimide in 116 mL of acetone was treated with 20.7 g (0.125 mol) of potassium iodide and stirred at room temperature for 5 days. The reaction was filtered and the filtrate was diluted with 400 mL of ether, then filtered again through celite. The filtrate was concentrated at reduced pressure. The resulting solid was recrystallized from 300 mL of hexane (filtered hot and boiled down to 150 mL) to yield 4.0 g (68.6%) of 3 as white needles.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 6 h
Yield: 76 %

Procedure:
A solution of 0.1 mol (21.4 g) of 4'-hydroxybiphenyl-4-carboxylic acid and 0.11 mol (19.9 g) of tetramethylammonium hydroxide (pentahydrate) in 200 ml of DMF was stirred for 2 hours. To this was then added 0.1 mol (17.1 g) of benzyl bromide and the mixture was stirred for 6 hours. After the reaction, the reaction solution was extracted with ether and the extract was dried and concentrated. The resulting crude product was purified by column chromatography to obtain the objective ester compound of the following formula. (yield: 76%) ##STR44##
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].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].O1CCOCC1>[CH3:10][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=Cc1ccncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnccc1C=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
3-Chloropyridine-4-carbaldehyde (141.6 mg, 1.00 mmol), trimethylboroxine (278.4 μl 2.00 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (81.6 mg, 0.10 mmol) and potassium carbonate (414.6 mg, 3.00 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (1.8 mL) and stirred at 100° C. for 3 hours. After completion of the reaction, the reaction solution was allowed to cool, and the solvent was removed by vacuum distillation. The resulting crude reaction product containing the desired product was used for the next step (594.7 mg).
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][OH:24])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)c1ccc(C(C)(COS(C)(=O)=O)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one in 20 ml tetrahydrofuran is mixed at ambient temperature with 1.3 ml (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 mmol) of methanesulphonyl chloride are added dropwise at 2-5° C. After 2 hours at ambient temperature the precipitate formed is suction filtered and the filtrate is concentrated by evaporation. The crude product is further reacted without being purified.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[N:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:15]1([CH2:14][CH2:13][N:12]=[S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(CCCOc2ccccc2)=NCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(CCCOc2ccccc2)=NCCN2CCOCC2)cc1

Procedure:
A solution of S-(4-nitrophenyl)-S-(3-phenoxypropyl)-N-[2-(4-morpholinyl)ethyl]sulfoximine in ethanol is treated with 5% palladium on carbon catalyst and subjected to hydrogenation on a Parr apparatus. When hydrogen uptake ceases, the catalyst is removed by filtration and the filtrate is concentrated to obtain the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]#[N:12])[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([OH:22])C.[OH-].[K+].OO>O>[C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]([NH2:12])=[O:22])[C:7]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(Nc2ccccc2)c(C#N)c1N
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)n1nc(Nc2ccccc2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
1-tert-Butyl-3-phenylamino-5-amino-1H-pyrazole-4-carbonitrile (1.0 g, 0.004 mol), 50% aqueous ethanol (30 ml), potassium hydroxide (1.8 g, 0.03 mol) and 30% hydrogen peroxide (2.5 ml, 0.02 mol) were combined and stirred at room temperature for 24 hours, then refluxed on a steam bath for 1 hour. The reaction mixture was added to water, and the obtained solid was filtered and washed with water to afford 0.68 g (64%) of 1-tert-butyl-3-phenylamino-5-amino-1H-pyrazole-4-carboxamide as a gray solid, m.p. 225°-227° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:16](=[O:30])[C:15]([CH2:38][CH2:39][OH:40])([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1.CC(C)=[O:43].OS(O)(=O)=O.O=[Cr](=O)=O>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([CH2:26][CH:27]3[CH2:28][CH2:29]3)[C:16](=[O:30])[C@:15]([CH2:38][C:39]([OH:43])=[O:40])([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N(CC2CC2)[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)CC1(CCO)CCN1CCCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C[C@@]1(CCN2CCCC2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled solution of 2.05 g (20.5 mmol) of chromium(VI) oxide in water (4 mL) was treated with 1.75 mL (32.7 mmol) of sulfuric acid via syringe. The mixture was diluted with additional water (4 mL) and stored at 0° C. at prior to use. In a separate flask, 105 mg (0.21 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one (Example 69, Step D, mixture of diastereomers) was dissolved in acetone (20 mL) and then treated with Jones reagent (see above) slowly via pipette at room temperature. After 30 min, the resulting dark red solution was heated at 55° C. for an additional 17.5 h. The reaction was concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (4×). The organic layers were over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 55% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound (single enantiomer) as a white solid. [Note that the desired C-3 (3S) epimer is the less polar epimer and elutes off second].
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.O>C1(C)C=CC=CC=1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2([C:20]3[CH:21]=[CH:22][C:17]([OH:23])=[CH:18][CH:19]=3)[CH2:6][CH2:5][CH:4]([C@H:1]3[CH2:3][CH2:2][C@H:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-(Trans-4-n-propylcyclohexyl)cyclohexanone (449 g), phenol (756 g) and CaCl (446 g) were mixed, followed by gradually dropwise adding conc. hydrochloric acid (335 ml) with vigorous stirring at room temperature, further agitating the mixture for 30 minutes after completion of the dropwise addition, allowing the resulting material to stand at room temperature, further for 50 hours, adding hot water (2 l) and toluene (3 l), heating the mixture, cooling, filtering off crystals, washing the crystals with water and then with toluene, drying the crystals and recrystallizing from tetrahydrofuran solvent to obtain white crystals of 1,1-bis(4-hydroxyphenyl)-4-(trans-4-n-propylcyclohexyl)cyclohexane as a diol compound of the present invention (436 g). M.P.: 222.0°-222.8° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[NH:26][C:22]=3[CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: O
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. Melting Point: >260° C. (water)
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:12]2)=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(C2CSc3ccccc3NC2=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C2CSc3ccccc3NC2=O)cc1Br
Temperature: 25 °C
Reaction time: 22 h

Procedure:
24 ml of a N solution of bromine in acetic acid were added to a solution of 2.28 g of 2,3-dihydro-3-(4-methoxy phenyl)-1,5-benzothiazepin-4(5H)-one of Step D of Example 1 in 16 ml of acetic acid. After 22 hours of stirring at ambient temperature, 100 ml of essence G were added and the gummy precipitate obtained was separated off by decanting the solution. Then, it was crystallized from 20 ml of ethanol and stirred for 30 minutes, followed by separation to obtain 2.22 g of the desired product melting at 200° C., then 220° C. The product was used as is for the following step. An analytical sample was prepared by dissolving 540 mg of the above product in 20 ml of methylene chloride and the solution was treated with activated charcoal and filtered. 50 ml of ethanol were added followed by concentration to 25 ml. After separating, 450 mg of product melting at 206° C., then 220° C. were obtained. The product was re-dissolved in 60 ml of ethanol at reflux, concentrated to 40 ml and separated after one night at ambient temperature to obtain 350 mg of the desired product melting at 210° C., then 220° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][C:3]=1[O:16][CH3:17].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH:24]=1>>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH:24]=1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: COc1cc(CCCn2cncn2)ccc1O
Product: COc1cc(CCCn2cncn2)ccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 62 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxy-3-methoxyphenyl)propyl]-1,2,4-triazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give 1-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole. The yield was 62%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 113-114° C.