Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[NH2:20]
Reactant: [H][H]
Reactant: CC1(C)Cc2cccc(Oc3ccc([N+](=O)[O-])cc3Cl)c2O1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(Oc3ccc(N)cc3Cl)c2O1
Yield: 90.6 %

Procedure:
To a solution containing 42.5 g of 3-chloro-4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)-1-nitrobenzene in 600 ml of toluene was added 1.5 g of 5% Pt on carbon. This mixture was then placed in a 1 L rocking hydrogenator. An atmosphere of hydrogen at 100 psi was introduced into the bomb. The pressure was maintained between 100 psi and 80 psi until the hydrogen uptake ceased. The contents were removed from the bomb and filtered through celite. Removal of the solvents from the filtrates afforded 34.91 g of white solid, mp 102°-104° C. NMR (CDCl3) δ1.45 (s, 6H), 3.0 (s, 2H), 3.55 (broad s, 2H), 6.2-6.9 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:11]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccncc1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 4-bromopyridine hydrochloride (Fluka), the title compound was obtained as a yellow solid after purification by precipitation in dioxane.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 1-chloro-4-isocyanato-2-trifluoromethyl-benzene gave the titled compound in quantitative yield as white foam. MS: 531.20 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH2:16]Br.CN(C=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].CCOCC>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH2:16][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 18 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
A 12 L flask was charged with (4-bromo-3-bromomethyl-phenoxy)-tert-butyl-dimethyl-silane (568 g 1.49 mol), DMF (3.1 L), and potassium phthalimide (316 g 1.71 mol). An exotherm to 34° C. occurred. After 40 min, the reaction mixture was cooled to 18° C. Ether (6.2 L) and DI water (4.9 L) were added, and the layers were separated. The organic layer was washed with saturated NaCl solution (2 L), dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from heptane (1.5 L) to give the title compound (454 g, 68%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CS(C)=O.C(OCC)(=O)C.[NH4+].[Cl-]>[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 1H-indole-3-carboxaldehyde (300 mg, 2.07 mmol) in 6.2 mL of dry dimethylsulfoxide was added sodium hydride (108 mg, 55%, 2.5 mmol) under nitrogen at 0° C. After the reaction mixture was stirred for 30 min at room temperature, p-toluenesulfonyl chloride (434 mg, 2.28 mmol) was added with additional stirring for 1 h. The reaction mixture was diluted with 10 mL of ethyl acetate and 10 mL of saturated NH4Cl aqueous solution, successively, and the solution was extracted with 100 mL of ethyl acetate. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4 After filtration, the solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound as a pale yellow solid (310 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12](Br)[C:13]#[CH:14]>>[CH2:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:13]#[CH:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C#CCBr
Product: C#CCNc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 3-trifluoromethylaniline (30 g) ad propargyl bromide (12 g) was stirred at 80° C. for 3 hours, followed by filtration of the reaction mixture. The filtrate was subjected to column chromatography to give N-propargyl-3-trifluoromethylaniline (7 g). A solution of N-propargyl-3-trifluoromethylaniline thus obtained (5.1 g) and ethoxycarbonyl isothiocyalate (3.7 g) in tetrahydrofuran (100 ml) was stirred at room temperature for 8 hours, and the solvent was removed under reduced pressure. The concentrated residue was extracted with chloroform (200 ml), washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 5.7 g of 2 -ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (i)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:39])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([Br:39])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Yield: 94.1 %

Procedure:
To a stirred mixture of 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5 g, 14.70 mmol) in CCl4 (100 mL) was added AIBN (0.24 g, 1.46 mmol) and NBS (2.88 g, 16.18 mmol). The mixture was heated to reflux overnight. Then the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to afford 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5.8 g, 94%) as a light yellow solid; LC-MS: 422.3 (M+3). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J=2.4 Hz, 1H), 7.53 (dd, J1=8.6 Hz, J2=2.44 Hz, 1H), 7.10 (d, J=8.64 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 4.57 (m, 2H), 3.93 (s, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClC1C=CC=CC=1Cl>[CH:9]1[C:4]2[NH:1][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[CH:7][C:8]=1[CH:10]=[O:11]
Reactant: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: O=Cc1ccc2c(c1)[nH]c1ccccc12
Yield: 66.2 %

Procedure:
A 250-mL round-bottom flask was charged with 2-nitrobiphenyl-4-carbaldehyde (6.5 g, 28.63 mmol, 1.00 equiv), PPh3 (18.8 g, 71.76 mmol, 2.50 equiv) and 1,2-dichlorobenzene (70 mL). The resulting solution was refluxed for 18 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:30) affording 9H-carbazole-2-carbaldehyde as yellow solid (3.7 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent, (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester was obtained in sufficient purity for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:5]3[N:6]=[CH:7][C:2]([C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)=[CH:3][CH:4]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccc(CN2CCN(C3CCC3)CC2)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(CN3CCN(C4CCC4)CC3)nc2)cc1

Procedure:
1-(5-Bromopyridin-2-ylmethyl)-4-cyclobutylpiperazine (1.163, 3.75 mmol) and 4-cyanophenyl-boronic acid (0.82 g, 5.6 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the free amine. Yield: 467 mg (44%)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14]>C1C=CC=CC=1>[CH3:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:14])[CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCNC
Solvent: c1ccccc1
Product: CN1CCN(C)C1c1ccccc1

Procedure:
Using the method of Birch and Dastur, Austral. J. Chem., 26, 1364 (1973), a solution of 5.5 g of benzaldehyde in 25 ml of benzene was added dropwise to a stirred solution of sym-dimethylethylenediamine in 15 ml of benzene, and heated at 60° for 2 hrs. Evaporation and distillation at 55° (0.35 mm) afforded 6.4 g, identified by nmr.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23]Br)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCBr)c2)c2cccnc21
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCN3CCCC3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-bromo-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (400 mg, 0.65 mmol) in THF (5 ml) was added pyrrolidine (139 mg, 1.96 mmol), and the mixture was stirred at room temperature for four hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to give the title compound (340 mg, 0.56 mmol).
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]=[C:1]=[O:4])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: CC(N)c1ccc(Br)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](N=C=O)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(+1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tint=2-5° C. for 30 min, at which point HPLC analysis indicates >99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4% yield). 1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H). The material was used in Step 3 without further purification.
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:27])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:26])=[C:16]([O:24]C)[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[CH:28]#[CH:29].Cl>CO.O>[C:28]([C@:7]1([OH:27])[CH:6]=[CH:5][C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]12[CH3:9])[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:26])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)#[CH:29]
Reactant: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: C#C
Agent: Cl
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=C(C)C(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
3.5 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one is reacted with acetylene analogously to Example 5. The resultant 17α-ethynyl-3-methoxy-4-methylandrosta-3,5,15-trien-17β-ol is allowed to react, as described in Example 5with concentrated hydrochloric acid in a mixture of methanol/water. After the crude product has been chromatographed on silica gel with a hexane-ethyl acetate gradient, 1.3 g of 17α-ethynyl-17β-hydroxy-4methylandrosta-4,15-diene-3-one is obtained as a foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][NH:17][CH2:16]2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-:25])([O-])=[O:23].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][N:17]([CH2:13][CH2:8][NH:7][C:22]([O:25][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:16]2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CNCC2O)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CC(O)C(Cc2cccc(NC(=O)OC(C)(C)C)n2)C1

Procedure:
A mixture of [6-(4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester II-1 (0.01 mol), (2-bromo-ethyl)-carbamic acid tert-butyl (0.012 mol), anhydrous K2CO3 (0.02 mol) in 50 mL anhydrous DMF was stirred at room temperature overnight. Solids were filtered off. The filtrate was evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The obtained residue was purified by column chromatography (silica gel, CH2Cl2:MeOH, 9:1). (57%)
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Br[C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][CH:46]=[C:45]2[CH2:51][CH2:52][NH:53][C:54](=[O:69])[C:55]1[CH:60]=[CH:59][C:58]([CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[CH:63]=2)=[CH:57][CH:56]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:68][C:64]1[CH:63]=[C:62]([CH:67]=[CH:66][CH:65]=1)[CH2:61][C:58]1[CH:57]=[CH:56][C:55]([C:54]([NH:53][CH2:52][CH2:51][C:45]2[C:44]3[C:48](=[CH:49][CH:50]=[C:42]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:43]=3)[NH:47][CH:46]=2)=[O:69])=[CH:60][CH:59]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1ccc(Cc2cccc(F)c2)cc1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=C(NCCc1c[nH]c2ccc(N3CCOCC3)cc12)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of palladium acetate (0.004 g; 0.017 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.028 g; 0.071 mmol) in dioxane (0.5 mL) was degassed and sonicated for 30 minutes. This solution was then added to a degassed mixture of sodium 2-methylpropan-2-olate (0.024 g; 0.248 mmol), morpholine (0.031 mL; 0.354 mmol) and N-(2-(5-bromo-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.080 g; 0.177 mmol) in dioxane (2 mL). The resulting mixture was stirred at 100° C. for 18 hours and evaporated to dryness. The residue was partitioned between water and ethyl acetate and the organic layer was dried and concentrated under reduced pressure. The crude material was purified twice by flash chromatography on silica gel (eluent 65 to 100% ethyl acetate in heptane and 20 to 100% ethyl acetate in dichloromethane) and by preparative HPLC (method 2) to afford 0.0052 g (6%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:17]=1.S(=O)(=O)(O)O.[CH3:23]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:23])=[O:15])=[CH:7][C:6]=2[CH:17]=1
Reactant: O=C(O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1

Procedure:
To a solution of 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (856 mg) in methanol (10 ml) was added sulfuric acid (0.1 ml), and the resulting mixture was heated at reflux for 23 hours. After concentration under reduced pressure, the reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (848 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:4]=1[O:5][CH2:6][C@H:7]1[CH2:11][O:10]C(C)(C)[O:8]1>CO>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[C:4]=1[O:5][CH2:6][C@H:7]([OH:8])[CH2:11][OH:10]
Reactant: COc1cccc(OC)c1OC[C@H]1COC(C)(C)O1
Solvent: CO
Product: COc1cccc(OC)c1OC[C@H](O)CO
Reaction time: 120 h
Yield: 91.3 %

Procedure:
A mixture of (S)-4-((2,6-dimethoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (2.91 g, 10.85 mmol) and Amberlyst 15® (1.60 g) in methanol (30 ml) were stirred for 5 d. The mixture was filtered and evaporated to dryness to give 2.26 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:16])[C:6]([O:13][CH2:14][CH3:15])=[CH:7][C:8](OC)([CH3:10])[CH:9]=1)[CH3:2].Cl(O)(=O)(=O)=O>>[CH2:1]([O:3][C:4]1[C:5](=[O:16])[C:6]([O:13][CH2:14][CH3:15])=[CH:7][C:8](=[CH2:10])[CH:9]=1)[CH3:2]
Reactant: CCOC1=CC(C)(OC)C=C(OCC)C1=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: C=C1C=C(OCC)C(=O)C(OCC)=C1
Yield: 90.2 %

Procedure:
The same procedure as in Example 6 was repeated by using 226 mg of 2,6-diethoxy-4-methoxy-4-methyl-2,5-cyclohexadienone and 10 mg of perchloric acid, recovering 180 mg of an oily crude product. The crude product was purified by silica gel column chromatography using a 20:1 benzene-ethyl acetate mixture, giving 175 mg of 2,6-diethoxy-4-methylidene-2,5-cyclohexadienone in 90% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:17][C:18](=[O:21])[CH:19]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:20]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=O)C(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of LDA (1.80 M in THF, 20 mmol) in THF (100 mL) at −78° C., was added a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mmol) in THF (10 mL) dropwise. After 20 min, a solution of 4-chlorobenzyl chloride (15 mmol) in THF (10 mL) was added. Then the mixture was warmed to 25° C. and stirred for 16 h. Satd. aq. NaHCO3 (100 mL) was added, and the organic layer was separated and concentrated to give 3-(4-chloro-benzyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester. This residue (⅛ portion, approx. 1.25 mmol) was diluted with EtOH (10 mL) and treated with benzyl hydrazine hydrogen chloride (1.5 mmol) and K2CO3 (5 mmol). The mixture was stirred at 25° C. for 16 h. Concentration and purification by flash chromatography (EtOAc/CH2Cl2) provided 2-benzyl-3-(4-chloro-phenyl)-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester. A solution of the ester and TFA (2 mL) in CH2Cl2 (10 mL) was stirred at 25° C. for 4 h. Concentration and purification by flash chromatography (2 M NH3 in MeOH/CH2Cl2) provided the desired compound (10 mg). MS (ESI): exact mass calculated for C18H16ClN3, 309.10; found, m/z 310.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.37-7.21 (m, 7H), 7.08-7.05 (m, 2H), 5.29 (s, 2H), 4.09 (s, 2H), 4.04 (s, 2H).