Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[N:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][N:6]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][N:6]=1
Reactant: Clc1ncc(C=Nc2ncccc2-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ncc(CNc2ncccc2-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-[(2-chloro-5-thiazolyl)methylene]-3-phenyl-2-pyridinamine (i.e. the product of Step B) was added portionwise to a stiffed excess of sodium borohydride (0.379 g, 100 mmol) in methanol (8 mL). After addition was complete, the reaction mixture was allowed to stir for 5 min at ambient temperature. The excess reducing agent was quenched by adding glacial acetic acid until gas evolution ceased. Water (20 mL) was added, and the reaction mixture was concentrated to remove methanol. The resulting aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried (MgSO4) and concentrated to give the title compound as a yellow solid (0.659 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[OH:32][CH:30]([C:26]1[CH:25]=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:22])=[CH:21][CH:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:31]
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: CC(O)c1cccc(N)c1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3cccc(C(C)O)c3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 1-(3-aminophenyl)ethanol (36 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-(1-hydroxyethyl)phenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as an off white solid. Yield: 52 mg (46%). 1H-NMR: 10.45 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.75-7.74 (m, 1H), 7.68-7.64 (m, 3H), 7.30 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.75-4.68 (m, 1H), 3.75 (s, 3H), 3.15 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]([CH3:57])[C:20](=[O:56])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=2[NH:39][C:40]([CH2:42][N:43]2[C:47](=[O:48])[C:46]3=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]3[C:44]2=[O:53])=O)=[O:29])=[C:23]([O:54][CH3:55])[CH:22]=1)=[O:5])[CH3:2].C(O)(=O)C>C(O)C.[Fe]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]([CH3:57])[C:20](=[O:56])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]3[N:39]=[C:40]([CH2:42][N:43]4[C:47](=[O:48])[C:46]5=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]5[C:44]4=[O:53])[NH:36][C:32]=3[CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:54][CH3:55])[CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2NC(=O)CN2C(=O)c3ccccc3C2=O)c(OC)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2cccc3[nH]c(CN4C(=O)c5ccccc5C4=O)nc23)c(OC)c1
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A mixture of N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(3-nitro-2-phthalimidomethylcarbonylaminophenyl)carbonylaminobenzamide (3.96 g), iron powder (1.42 g) and acetic acid (3.05 g) in ethanol (50 ml) was refluxed for 4 hours and the solvent was removed under reduce pressure. The residue was stirred in a mixture of chloroform (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) for 30 minutes and the solution was filtered through a bed of celite. The organic phase was separated and washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was solidified with diethyl ether to give N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-phthalimidomethyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (3.64 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH:34]3[CH2:37][CH2:36][CH2:35]3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:38].[CH:34]1([C:18]2[N:17]=[N:16][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][C:19]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:25][CH:26]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-[6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.35 mmol, 0.18 g) in DCM (1.0 mL) was added 4 N HCl in dioxane (1.0 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether and filtered to give 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.14 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[C:23]([NH2:25])[N:24]=3)[CH:21]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[C:23]([NH:25][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[N:24]=3)[CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)nn2c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}carbamate (1.50 g, 4.22 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring cyclopropanecarbonyl chloride (1.15 mL, 12.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate and hexane to give the title compound (1.59 g, 89%) as a white compound.
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])=[N-].[O:28]1CCOCC1.O>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:28][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:12])=[O:5]
Reactant: C1COCCO1
Reactant: [N-]=[N+]=CC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
1,4-Dioxane-water (5 ml-5 ml) was added to the crude (R)-4[[(S)-2-(diazoacetyl)-1-pyrrolidinyl]carbonyl]-3-(phenylmethyloxycarbonyl)thiazolidine (970 mg) and copper sulfate pentahydrate (several mg), and the mixture was heated at 100° C. for 0.5 hour. 1,4-Dioxane was distilled away under reduced pressure and a saturated sodium hydrogencarbonate was added. The mixture was extracted with ethyl acetate. The extract was washed with 10% citric acid and saturated brine in order, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform - methanol) to give the title compound (92 mg) (see Table 4).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.71 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.12 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.38 g, 100%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[NH2:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O>CO>[CH2:19]([O:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:3]=[C:1]([CH3:2])[NH:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: CCN(CC)CC
Solvent: CO
Product: Cc1nc(=O)c2ccc(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 0.695 g (5.62 mmol) of ethyl acetoamidate hydrochloride in MeOH (16 ml) were added under stirring at RT 0.82 ml (5.86 mmol) of triethyl amine and 5 minutes later 1.14 g (4.69 mmol) of 2-amino-4-benzyloxy-benzoic acid. The reaction mixture was heated at reflux for 5 h, cooled to RT, the precipitate that had formed was filtered off by suction and dried in a high vacuum to give 0.9 g (69.4%) of the desired 7-benzyloxy-2-methyl-1H-quinazolin-4-one as an white solid. ISP mass spectrum, m/e: 267.3 (M+1 calculated for C16H14N2O2: 267).
Reaction SMILES: Br[O-:2].[Na+].[C:4]([C:7]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]2[C:13]([CH3:20])([CH3:19])[CH2:12][CH2:11][C:10]([CH3:22])([CH3:21])[C:9]=2[C:8]=1[O:23][CH3:24])(=[O:6])C>O1CCOCC1.O>[CH3:24][O:23][C:8]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]=2[C:15]([O:17][CH3:18])=[CH:16][C:7]=1[C:4]([OH:6])=[O:2]
Reactant: COc1cc(C(C)=O)c(OC)c2c1C(C)(C)CCC2(C)C
Reactant: [O-]Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)c(OC)c2c1C(C)(C)CCC2(C)C
Reaction time: 8 h

Procedure:
In a second stage, this hypobromite solution is slowly added to a stirred solution, cooled to about 5° C., of 43 g of 2-acetyl-1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene, obtained in stage (b) above, in 500 cm3 of dioxane. The rate of introduction is such that the temperature does not exceed 15° C. The reaction mixture is then left to stand overnight, diluted with 300 cm3 of water, then, at a temperature lower than 20° C., the excess sodium hypobromite is destroyed by the slow addition of a 25% aqueous solution of sodium bisulfite. The expected acid is then precipitated by acidifying the mixture by the addition of 380 cm3 of 6N HCl. The precipitate is filtered, washed with water and dried under reduced pressure. 40.8 g of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene carboxylic acid are obtained in the form of a white solid having a melting point of 187° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:22][C:16]1[C:17](=[O:18])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6](=[O:7])(=[O:8])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCNS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 6.1 %

Procedure:
A solution of N-(2-methoxyethyl)-1-phenylmethanesulfonamide (3.5 g, 14.5 mmol) and diethyl oxalate (2.33 g, 16.0 mmol) in dry DMF was cooled in an ice-bath. Potassium tert-butoxide (2.17 g, 18.4 mmol) was added and after 5 min the ice-bath was removed and the reaction was stirred at rt for 22 h. HCl (2M, 45 mL) was added to the mixture and the acidic solution was extracted 3 times with DCM. The combined organic layer was washed 4 times with water, dried through a phase separator and evaporated. The residue was purified by preparative HPLC [0.1M N OAc/MeCN, gradient A:B (9:1 to 1:9)] to give the title compound (0.250 g, 6%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.90-7.94 (m, 2H), 7.28-7.33 (m, 2H), 7.10-7.15 (m, 1H), 3.79 (t, 2H), 3.68 (t, 2H), 3.34 (s, 3H); Mass Spectrum: M−H+ 282.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[C:12]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:22])=[CH:13][CH:14]=1)=[O:9]
Reactant: Oc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(O)c2ccccc12
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a suspension of AlCl3 (1.11 g, 8.3 mmol) in 50 mL DCM, methylchloroglyoxylate (1.02 g, 8.3 mmol) was added. The resulting solution was stirred for 5 min., after which naphthalen-1-ol (1 g, 6.9 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (10-30% EtOAc/Hex), to afford the target compound in 38% yield. Calculated mass=230. Observed mass=231.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]=[S:24]1(=[O:31])[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25]1>>[O:23]=[S:24]1(=[O:31])[CH2:28][CH2:27][CH:26]([N:29]([CH3:30])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: CNC1CCS(=O)(=O)C1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)C1CCS(=O)(=O)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N-(1,1-dioxidotetrahydrothien-3-yl)-N-methylamine to give 256. MS: (ESI+)=445.1
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15](OB(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:17]1[CH:18]=[C:13]([OH:12])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)Oc1cccc(O)c1
Reactant: Brc1ccc2ccccc2c1
Product: Oc1cccc(-c2ccc3ccccc3c2)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
The compound is prepared by the reaction of 2-bromonaphthalene (303 mg, 1.46 mmol, 1 eq) with 3-hydroxyphenylboric acid (242 mg, 1.76 mmol, 1.2 eq) according to method A within 18 h. Purification by column chromatography with dichloromethane as the eluent yields the desired product in a yield of 47%, 152 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]2=O.O.[NH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:7][NH:24][N:23]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: COc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Reactant: NN
Solvent: O
Product: COc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1
Yield: 46 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-(3-methoxy-phenyl)-chromen-4-on (1.0 g, 3.3 mmol), Hydrazine hydrate (8 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-[4-(3-methoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.48 g, 46%); Rf 0.5 ethyl acetate/hexane (80/20)].
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[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:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C1C=CC=CC=1.[OH-]>C(O)C.[Pd]>[NH2:8][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:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl)indole (1.08 g, 2.64 mmol) and palladium [II] hydroxide on carbon (0.6 g) in absolute ethanol (25 mL) was shaken under a hydrogen atmoshpere (3 atm) at 40° C. for 4 hours. The resulting mixture was filtered through diatmaceous earth, and the filtrate was evaporated under pressure to afford the title compound (0.60 g, 2.62 mmol, 99%) as a white foam: 1H NMR (DMSO-d6) δ10.65 (br s, NH), 7.14 (d, J=2.2 Hz, 1H), 7.12 (d, -J=8.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.60 (dd, J=2.0 and 8.6 Hz, 1H), 3.63-2.83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H); [α]25D =+9° (MeOH, c=1.0); HRMS: calculated for C14H19N3 : 229.1575; found 229.1593.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](Br)[CH:6]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1B(O)O)=[O:16]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:21]=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:17]=2[CH:15]=[O:16])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Reactant: COC(=O)Cc1ccc(OC)c(Br)c1
Product: COC(=O)Cc1ccc(OC)c(-c2cc(OC)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-methoxy-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl[CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18]>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-chloro-N,N-dimethylacetamide according to Method AC (heating to 90° C. for 4 h) and was isolated as an orange gum (quantitative). LCMS (ES+) 280 (M+H)+, RT 2.38 minutes (Method 1).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].C([S:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])(=O)C.C(N(CC)CC)C>CO>[C:25]([NH:24][CH2:23][CH2:22][S:21][CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]/[C:8](/[CH3:16])=[CH:7]/[CH2:6][CH2:5]/[C:4](/[CH3:17])=[CH:3]\[CH2:2][OH:1])(=[O:27])[CH3:26]
Reactant: CC(=O)NCCSC(C)=O
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.5 g (0.0148 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 110 ml of methanol is treated with 7.15 g of N-(2-acetylthioethyl)acetamide and 6.2 ml of triethylamine. The solution is stirred under argon at room temperature for 24 hours. The solvents are removed on a rotary evaporator. The residue is taken up three times with toluene and freed from solvent on a rotary evaporator. The crude product can be used directly for the acetylation described in Example 12 or can be chromatographed on silica gel with ether-methanol 15:1. After chromatographic purification there is obtained (2Z,6E)-12-[(2-acetamidoethyl)thio]-3,7,11-trimethyl-10-oxo-2,6-dodecadien-1-ol which exhibits the following bands in the IR spectrum: 1737 cm-1, 1715 cm-1, 1437 cm-1, 1366 cm-1, 1277 cm-1,1235 cm-1, 1157 cm-1, 1136 cm-1, 1022 cm-1.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C@@:27]23[C@:22]([CH3:30])([CH2:23][CH2:24][CH2:25][CH2:26]2)[C@@H:21]2[C@H:5]([C@H:6]4[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]4)[CH2:4][CH:3]3[O:2]1.C(OCC)(=[O:34])C>N1C=CC=CC=1>[CH2:1]1[CH2:29][O:28][C:3]2([C@@H:27]3[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:34])[CH2:26]3)[C@@H:21]3[C@H:5]([C@H:6]4[C@:18]([CH3:31])([CH2:19][CH2:20]3)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]4)[CH2:4]2)[O:2]1
Reactant: CCOC(C)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4OCCO[C@@]45CCCC[C@]5(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4(OCCO4)[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
A solution of 6-ethylenedioxy-5α-cholestan-3β-(3, 12.5 g) in pyridine was added to ice-cold pyridine-CrO3 complex prepared by adding CrO3 (182 g) to ice-cold pyridine (182 ml). An additional amount of pyridine (90 ml) was utilized for complete transfer. The mixture was allowed to come to room temperature and stirred for 10 hr. It was then brought to a volume of 500 ml with ethyl acetate and filtered through a column packed with Celite (a diatomaceous silica product marketed by Johns-Manville Co.) (50 g, 4 cm diameter) slurried in ethyl acetate. Material eluted with a total of 750 ml of ethyl acetate was collected, and filtered through a 6 cm column packed with alumina (100 g) slurried in ethyl acetate. After elution with 1200 ml of ethyl acetate and evaporation of the solvent, a greenish solid was recovered. This was applied to a 2×23.5 cm (50 g alumina, AG-7 minus 200 mesh) column and eluted with ethyl acetate. The first 150 ml of eluant gave 12.3 g (98%) of pure 6,6-ethylenedioxy-5α-cholestan-3-one (4). An analytical sample recrystallized from MeOH was obtained as white crystals: m.p. 115°-116°; nmr (CDCl3) δ 2.35 (m, C-2 and C-4 protons), 3.9 (m, ketal); ir (KBr) 1710 cm+1 (C=O); mass spectrum: m/e 444 (M+, 19%, C29H48O3 : C, 78.33; H, 10.88; obs: C, 78.37; H, 10.93.