Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:33]([CH2:34][CH2:35][C@:17]12[CH3:18])[C@:30]1([CH2:31][OH:32])[C:25](=[CH:26][C:27](=[O:36])[CH2:28][CH2:29]1)[CH2:24][C@H:23]3[CH3:37].[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:37][C@@H:23]1[CH2:24][C:25]2[C@:30]([CH2:31][OH:32])([CH2:29][CH2:28][C@@H:27]([OH:36])[CH:26]=2)[C@@H:33]2[C@@H:22]1[C@H:19]1[C@@:17]([CH2:35][CH2:34]2)([CH3:18])[C@@H:16]([OH:15])[CH2:21][CH2:20]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: C[C@@H]1CC2=C[C@H](O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 0.5 M solution of potassium tri-sec-butylborohydride in tetrahydrofuran under nitrogen is cooled to -78° C. in a dry ice-acetone bath. 17β,19-Dihydroxy-7α-methyl-4-androsten-3-one in tetrahydrofuran is added slowly and the reaction mixture is stirred for a period of 2 hours at this temperature, warmed to 0° C., and stirred for an additional two hours. The reaction mixture is decomposed by the addition of 3 N sodium hydroxide followed by a 30% hydrogen peroxide solution. Solid potassium carbonate is added and the tetrahydrofuran solution decanted. The solid residue is washed with fresh tetrahydrofuran and the combined tetrahydrofuran solutions are dried over anhydrous sodium sulfate, filtered and the filtrate removed by evaporation. The residue is crystallized from acetone to yield 7α-methyl-4-androstene-3α,17β,19-triol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18].[BH4-].[Na+].[Cl:21]CCl>>[Cl:21][CH2:13][CH2:14][CH2:15][CH2:16][C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18]
Reactant: ClCCl
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: ClCCCC[c-]1cccc1
Reaction time: 8 h

Procedure:
A cold solution of freshly distilled trifluoroacetic acid (5 ml) was added to a solution of the ferrocene derivative, 1-Oxo-4-chlorobutylferrocene I, (5 g, 17.2 mmole) in dry dichloromethane (15 ml) at 0° C. Sodium borohydride (0.78 g) was added to the reaction mixture at 0° C. and the reaction mixture was stirred overnight at this temperature. After completion of the reaction as indicated from TLC, the reaction was quenched by adding water (50 ml) and the mixture was extracted with dichloromethane (2×25 ml).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>O.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:24][N:23]=[N:22][N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCCCCC#N)cc(C(C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCCCCc2nnn[nH]2)cc(C(C)(C)C)c1
Temperature: 120 °C
Yield: 18.2 %

Procedure:
A mixture containing 2.87 g (0.10 mole) of 5-(3,5-di-t-butylphenoxy)pentanenitrile, 1.95 g (0.03 mole) sodium azide, 1.60 g (0.03 mole) ammonium chloride, 0.42 g (0.01 mole) lithium chloride and 25 ml of dimethylformamide was heated at 120° C. in a stoppered flask for about sixteen hours. Analysis of the reaction mixture by high pressure liquid chromatography revealed that the reaction still contained nitrile. The reaction was recharged with 1.95 g of sodium azide and 1.60 g of ammonium chloride and heated for an additional sixteen hours. The reaction mixture was poured into 250 ml of water. The resulting precipitate was collected, rinsed with water, air dried and recrystallized twice from aqueous methanol to give 1.8 g of white solid 5-[4-(3,5-di-t-butylphenoxy)butyl]tetrazole, m.p. 140°-141° C. Analysis: Calculated for C19H30N4O: %C, 69.1; %H, 9.2; %N, 17.0; Found: %C, 69.0; %H, 9.1; %N, 17.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:19])[CH:13]=[C:14]([N:16](C)C)[CH3:15].Cl.NO.CC1C=C([N+]([O-])=O)C(C)=CC=1C1ON=C(C)C=1>C(O)C.CO.[Pd]>[CH3:11][C:5]1[CH:4]=[C:3]([C:12]2[O:19][N:16]=[C:14]([CH3:15])[CH:13]=2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: CC(=CC(=O)c1cc(C)c([N+](=O)[O-])cc1C)N(C)C
Agent: [Pd]
Agent: Cc1cc(-c2cc(C)c([N+](=O)[O-])cc2C)on1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(-c2cc(C)c(N)cc2C)on1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one (Step 2, 100 mg, 0.38 mmol) and hydroxylamine monohydrochloride (132 mg, 1.9 mmol) in ethanol (3 mL) was heated in a microwave at 100° C. for 15 min. The obtained 5-(2,5-dimethyl-4-nitrophenyl)-3-methylisoxazole was dissolved in methanol (10 mL). To this solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred under H2 (1 atm.) overnight. The mixture was filtered and concentrated to afford 2,5-dimethyl-4-(3-methylisoxazol-5-yl)aniline. ESMS m/z 203 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COCCNCc1ccc(SC(C)(C)C(=O)OC(C)(C)C)cc1

Procedure:
4.00 g (14.27 mmol) of tert-butyl 2-[(4-formylphenyl)sulphanyl]-2-methylpropanoate (Example II-2) and 1.07 g (14.27 mmol) of 2-methoxyethylamine are dissolved in 80 ml of 1,2-dichloroethane and, after 30 min and after 10 hours, admixed with 4.54 g (21.40 mmol) of sodium triacetoxyborohydride. The reaction is checked by TLC, and ethyl acetate and saturated sodium bicarbonate solution are then added and the product is extracted with ethyl acetate. The organic phase is washed with 1 N HCl and dried over magnesium sulphate, and the product is, after distillative removal of the solvent, purified by silica gel chromatography (ethyl acetate/cyclohexane 1:1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:13])[N:11]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].C(O)=O>CO.O1CCOCC1.CCN(CC)CC>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]([C:10]1[N:11]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])[S:8][CH:9]=1)=[O:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1ccccc1C(=O)c1csc(NCCCN)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccccc1C(=O)c1csc(NCCCNS(=O)(=O)c2cccs2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
A solution of 15.6 mg (0.5 mmol) [2-(3-Amino-propylamino)-thiazol-4-yl]-o-tolyl-methanone hydrochloride in 1 ml methanol was treated with 11.9 mg (0.65 mmol) thiophene-2-sulfonyl chloride in 0.13 ml dioxane and 34.7 ul NEt3. The mixture was stirred at 60° C. for 16 h and after addition of 0.5 ml formic acid subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 6.2 mg (29%) of the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH2:20][CH2:21][CH2:22][C@H:23]2[C@H:27](Cl)[CH2:26][C@@H:25]([OH:29])[C@@H:24]2[C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=2)=[CH:18][CH:19]=1)=[O:14].CCN(CC)CC>C(Cl)Cl.O>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH2:20][CH2:21][CH2:22][C@@H:23]2[C@@H:24]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=4)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=3)[C:25](=[O:29])[CH:26]=[CH:27]2)=[CH:18][CH:19]=1)=[O:14]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)[C@H](Cl)C[C@H]2O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C=C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of DMSO (120 μL, 1.69 mmol) in 1 mL CH2Cl2 was added to a −78° C. solution of oxalyl chloride in CH2Cl2 (400 μL, 0.80 mmol, 2 M), rinsing with 1 mL CH2Cl2. The reaction was stirred at −78° C. for 30 min. and then a solution of 5 (297 mg, 0.49 mmol) in 1.2 mL CH2Cl2 was added dropwise by cannula, rinsing with 1.2 mL. Et3N (400 μL, 2.9 mmol) was added and the reaction was allowed to warm to room temperature. After 5 h, 60 mL H2O was added and the resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (0%→100% ethyl acetate/hexanes) to give compound 6 (276 mg, 99%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)#[N:8].O.[OH-].[Na+]>C(OCC)C>[CH3:20][N:19]([CH3:21])[C:9]1([CH2:7][NH2:8])[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11][CH2:10]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)C1(CN)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A 0.4 g portion of lithium aluminum hydride (LAH) is cooled in 10 ml of diethyl ether under nitrogen atmosphere. Then 2.0 g of 8-cyano-[1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine (U.S. Pat. No. 4,065,573, Example 41, part B) was added over 20 minutes while stirring at room temperature. Then, in turn, there was added 0.4 ml of water, 0.4 ml of 15 percent sodium hydroxide and 1.2 ml of water. The inorganic gel in the mixture was filtered off. The filtrate was dried by evaporation under vacuum. A thin layer chromatography (tlc) sample analysis showed the residue to be largely one spot material. The Nuclear Magnetic Resonance spectrum (NMR) for this material was very good for the above-named chemical intermediate.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cc(C)nn3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a solution of AlCl3 (1.382 g, 10.36 mmol) in CH2Cl2 (4 mL) and MeNO2 (1 mL) was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindole (0.155 g, 0.677 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.29 mL, 3.15 mmol) was added and the mixture was allowed to stir for 18 h. Another portion of ClCOCO2Me (0.29 mL, 3.15 mmol) was then added and stirring continued for a further 24 h. The mixture was subsequently cooled to 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and then extracted with EtOAc. The aqueous layer was separated and acidified with 6 M HCl and then the resultant precipitate was filtered and dried to give the title acid (0.158 g, 69%): LCMS: m/e 302 (M+H)+. The organic layer was washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.037 g, 15%): LCMS: m/e 316 (M+H)+. This material was hydrolyzed by dissolving in MeOH (2 mL) and treating with 1M NaOH (0.3 mL). The mixture was allowed to stir for 4 h, at which point the solvent was removed and the residue diluted with H2O (4 mL). The mixture was then acidified to pH 1 using 6N HCl and the precipitated acid was filtered and dried to give a further 0.021 g of the title compound. Total yield=0.179 g (78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc(Br)ccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(Br)ccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,5-dibromoaniline to yield 2-[(2,5-dibromophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN(C)c1cc(C)ncn1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1cc(C)ncn1
Yield: 56 %

Procedure:
4-Chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added to a solution of 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) and the mixture heated at reflux for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (75 mg, 39%).
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][C:14]1[C:15]2[C:22]([CH3:23])=[C:21]([CH3:24])[NH:20][C:16]=2[N:17]=[CH:18][N:19]=1)([O-])=O>[Fe].C(OCC)(=O)C.O1CCCC1>[NH2:7][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][C:14]1[C:15]2[C:22]([CH3:23])=[C:21]([CH3:24])[NH:20][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cc1[nH]c2ncnc(Oc3cccc([N+](=O)[O-])c3)c2c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1[nH]c2ncnc(Oc3cccc(N)c3)c2c1C
Temperature: 85 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
After adding iron powder (0.12 g), ammonium chloride (0.24 g), ethanol (5 ml) and water (1 ml) to the 4-(3-nitrophenoxy)-5,6-dimethyl-7H-pyrrolo [2,3-d]-pyrimidine (110 mg) synthesized by the intermediate synthesis method described above, the mixture was stirred at 80-90° C. for 3 hours. After returning the reaction system to room temperature and adding tetrahydrofuran (3 ml) and ethyl acetate (3 ml), the mixture was filtered with celite, the filtrate was subjected to liquid separation and extraction with ethyl acetate, and the organic layer was washed with water and saturated brine in that order. It was then dried over sodium sulfate, concentrated to dryness under reduced pressure and washed with diethyl ether to obtain the title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:22]C.C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22]
Reactant: COc1c(N)c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
1.0M Solution of borontribromide in DCM (6.4 mL, 6.4 mmol) was added to a solution of 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-methoxy-1,3-dihydro-benzoimidazol-2-one (I-11a: 1.4 g, 3.2 mmol) in DCM (50 mL) at 0° C. and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was quenched with water and stirred for 1 hour. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 1.15 g of the product (85.1% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:29](=[O:30])[NH:28][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[N:20](C5CCCCO5)[CH:19]=[N:18][N:17]=4)=[CH:12][C:11]=3[CH3:27])[N:9]=[C:4]2[N:3]1[CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CC1C=C(C2N(C3CCCCO3)C=NN=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1N=C2N(CCC3CCOCC3)C(C)(C)C(=O)NC2=NC=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(O)(C)C.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]>[CH3:1][C:2]1([CH3:39])[C:29](=[O:30])[NH:28][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:20][CH:19]=[N:18][N:17]=4)=[CH:12][C:11]=3[CH3:27])[N:9]=[C:4]2[N:3]1[CH2:31][CH2:32][CH:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)C(=O)Nc2ncc(Br)nc2N1CCC1CCOCC1
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Temperature: 100 °C
Yield: 97 %

Procedure:
3,3-Dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (1 equiv), 6-bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.1 equiv), 1 M sodium carbonate in water (3 equiv), 1,4-dioxane and isopropanol were combined and the system was purged with nitrogen. The resulting mixture was stirred vigorously and heated at 100° C. for 1.5 h. The resulting mixture was cooled to room temperature, diluted with methanol and the volatiles removed under reduced pressure. The residue was partitioned between dichloromethane and water, shaken and the layers separated. The water layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-100% ethyl acetate in hexane followed by 0-10% methanol in dichloromethane) to give the desired product in 97% yield. MS (ESI) m/z 532.7 [M+1]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@H:13]([CH2:14][CH2:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][C:11]2=[O:21])([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.C(Cl)Cl.C(OC(OCC)OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CO>[CH3:1][C@@H:2]1[CH:19]=[C:18]2[C@H:13]([CH2:14][CH2:15][C:16](=[O:20])[CH2:17]2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][C:11]2=[O:21])([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2C(=O)C[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2C(=O)C[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
A mixture of 7α-methylestr-4-ene-3,11,17-trione (B, Example 23, 4.1 g), methylene chloride (50 ml), ethylene glycol (31 ml), triethylorthoformate (14 ml) and p-TSA (41 mg) are refluxed for 3 hours. The mixture is then cooled and washed with bicarbonate and water, then dried to a solid. NMR shows a mixture of Δ5 (10) and Δ5 isomers. The product is used without further purification.
Reaction SMILES: [Cl-].C(PC(C)(C)C)(C)(C)C.[C:11]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]2[CH:25]=[C:24]4[C:37]([CH3:45])([CH3:44])[C:38]5[C:43]([C:23]4=[CH:22][C:21]3=2)=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:13][CH:12]=1.Br[C:53]1[CH:65]=[CH:64][C:63]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:56]([CH3:67])([CH3:66])[C:55]=2[CH:54]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:11]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:16]=[CH:15][C:14]([N:17]([C:53]2[CH:65]=[CH:64][C:63]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]([CH3:67])([CH3:66])[C:55]=3[CH:54]=2)[C:18]2[CH:19]=[C:20]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]2[CH:25]=[C:24]4[C:37]([CH3:44])([CH3:45])[C:38]5[C:43]([C:23]4=[CH:22][C:21]3=2)=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:13][CH:12]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(Nc5ccc(-c6ccccc6)cc5)ccc4n(-c4ccccc4)c3cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)PC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc4c(c3)c3cc5c(cc3n4-c3ccccc3)C(C)(C)c3ccccc3-5)cc21
Temperature: 60 °C

Procedure:
190 μl (1 mmol) of di-tert-butylphosphine chloride and then 112 mg (0.5 mmol) of palladium(II)acetate are added to a suspension of 26.3 g (50 mmol) of biphenyl-4-yl-(12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-7-yl)amine, 13.3 g (49 mmol) of 2-bromo-9,9-dimethylfluorene and 7.7 g (80 mmol) of sodium tert-butoxide in 500 ml of toluene, and the mixture is subsequently heated under reflux for 5 h. After cooling to 60° C., 500 ml of water are added, the organic phase is separated off, filtered through silica gel, evaporated virtually to dryness under reduced pressure at 80° C., and 300 ml of ethanol are then added. After cooling, the solid is filtered off with suction and then recrystallised five times from dioxane. Yield: 31.5 g (43 mmol), 88%, purity 99.9% (HPLC).