Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]1[CH2:13][CH2:12][CH2:11]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: BrC1CCC1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnn(C2CCC2)c1
Temperature: 25 °C

Procedure:
To a cooled (0 C) stirred solution of 4-bromo-1H-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was added sodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed to stir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol) was added. The vessel was sealed and the reaction mixture heated at 95 C for 23 h. The mixture was allowed to cool to rt and diluted with 200 mL EtOAc, washed with 500 mL water, then 2×100 mL water, sat NaHCO3, then the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a CH2Cl2 in hexanes gradient. (I2 stain for visualization). The title compound was collected as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.Cl.CN.[CH2:22]([N:24](CC)CC)C>C(O)(C)C>[CH3:22][NH:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1NC
Yield: 81.7 %

Procedure:
A mixture of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate (10 g), methylamine hydrochloride (2.8 g), triethylamine (8.5 g) and isopropanol (100 ml) is refluxed for six hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give ethyl 4-methylamino-2-phenylpyrimidine-5-carboxylate (8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:6]2=[N:7][CH:8]=1.[CH:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[C:17]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:4]=[C:5]4[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:6]4=[N:7][CH:8]=3)[CH2:22][CH2:21]2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1C(=O)Cc2cc(CBr)cnc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc(CN3CCN(c4ccccc4)CC3)cnc21
Yield: 65 %

Procedure:
1,3-dihydro-5-bromomethyl-1-methyl-2H-pyrrolo[2,3-b]pyridin-2-one from Preparation 18 (0.14 g, 0.6 mmol) is dissolved in dioxane (20 ml) at room temperature and under argon. Phenylpiperazine (0.1 ml, 0.66 mmol, 1.1 equiv.) and triethylamine (0.1 ml, 0.72 mmol, 1.2 equiv.) are added in succession at the same temperature. After 1 hour 30 minutes' reaction, the reaction mixture is concentrated under reduced pressure and the product is purified on a silica column (dichloromethane/methanol: 97:3). The title compound is obtained in the form of a yellow oil in a yield of 65%. ##STR74##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:27]=[CH2:28])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[C:29]1([C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:23][N:22]3[C:24]([CH:27]=[CH2:28])=[CH:25][N:26]=[C:21]3[CH:20]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12

Procedure:
168 mg Of the crude {1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester were stirred in 11.5 mL 4M hydrogen chloride in dioxane for 16 hours at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a PoraPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH3 yielding 34 mg (21.6%) of the title compound which was however slightly contaminated.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].C(N(CC)CC)C.COC(O)C.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NCC(O)CO
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Nc1nc(NCC(O)CO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.544, 2 mmol), 3-amino-1,2-propanediol (1.87 mg, 2 mmol), triethylamine (607 mg, 6 mmol) and methoxyethanol (6 ml) were refluxed overnight under nitrogen. 1 N NaOH (2 ml) was added and the solution was concentrated under vacuum and dried by evaporation of ethanol. The residual oil was chromatographed on silica gel. Title compound was eluted with 20% methanol-chloroform; white powder after crystallization from acetonitrile-methanol (0.300 g, 47%), m.p. 119-121° C. 1H-NMR: (DMSO-d6) δ 7.60 (s, 1, H-8), 6.90-6.80 (br m, 1, NH), 6.10 (m, 1, =CH), 5.85 (m, 3, =CH and NH2), 5.40 (br m, 1, CH--N), 4.90 (m, 1, OH), 4.72 (t, J=5.3,1, OH), 4.62 (t, J=5.9, 1, OH), CH), 2.70-2.50 (m, overlapping solvent, 0.5 CH2), 1.70-1.50 (m, 1, 0.5 CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:14]N.CO>>[CH3:14][NH:1][C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CN
Solvent: CO
Product: CNc1cc(C)ccc1[N+](=O)[O-]
Yield: 96 %

Procedure:
A solution of 9.10 g of 3,4-dinitrotoluene in 100 ml of 30% methylamine/methanol was reacted at 150° C. for 6 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (200 g). Elution with ethyl acetate-hexane (1 : 3) gave 7.95 g (96%) of 3-(N-methylamino)-4-nitrotoluene.
Reaction SMILES: ICI.[Sn](Cl)(Cl)(Cl)Cl.C(Cl)Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]([F:22])[F:21])=[CH:15][CH:14]=1.[C:24](=O)(O)[O-].[Na+]>C1COCC1.[Zn]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:20]([F:22])[F:21])=[CH2:24])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)F
Reactant: O=C([O-])O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [Zn]
Solvent: ICI
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(c1ccc(Br)cc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To activated zinc dust (13.3 g, 0.2 mol) in a 1 L flask was added THF (200 mL). Diiodomethane (8.9 mL, 110 mmol) was added dropwise over ˜10 min. The mixture was stirred at room temperature for 30 min. The mixture was cooled with an ice-acetone bath, a solution of tin(iv) chloride 1M in CH2Cl2 (22.1 mL, 22.1 mmol) was added over ˜15 min (needle tip inserted inside the mixture). The mixture was stirred for 15 min and the cooling bath was removed. The mixture was stirred at r.t for 30 min. After cooling back with an ice-acetone bath, a solution of 1-(4-bromophenyl)-2,2-difluoroethanone (5.2 g, 22.12 mmol) in THF (30 mL) was added dropwise over ˜10 min. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. The mixture was then poured portionwise to a mixture of sodium bicarbonate (300 mL, 300 mmol) and hexanes (300 mL) at 0° C. After stirring for 15 min, the mixture was filtered through celite. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes: Ethyl acetate (20:1) gave the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(CO)CC2)nn1
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC2CCN(c3ccc(OC)nn3)CC2)cc1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a stirred and cooled solution of 6.7 parts of 1-(6-methoxy-3-pyridazinyl)-4-piperidinemethanol, 5 parts of ethyl 4-hydroxybenzoate and 7.8 parts of triphenylposphine in 135 of tetrahydrofuran was added a solution of 5.6 parts of diethyl diazenediacarboxylate in 45 parts of tetrahydrofuran. Upon complete addition, stirring was continued overnight at room temperature. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 6.7 parts (60.1%) of ethyl 4-[[1-(6-methoxy-3-pyridazinyl)-4-piperidinyl]methoxy]benzoate; mp. 147.2° C. (comp. 142).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].O1CCCC1.Cl>N1C=CC=CC=1>[Cl:22][C:5]1[CH:4]=[C:3]([F:23])[C:2]([NH:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][C:6]=1[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(=O)OCC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
Into a mixture of ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23], ethyl chloroformate and tetrahydrofuran is added dropwise pyridine, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain ethyl [2-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A8-23].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[N:32]([CH2:33][CH3:34])[N:31]=[CH:30][C:29]=1[CH3:35].C(Cl)Cl.C1CCN2C(=NCCC2)CC1>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].CS(C)=O.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[N:32]([CH2:33][CH3:34])[N:31]=[CH:30][C:29]=3[CH3:35])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: CCn1ncc(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1ncc(C)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 120 °C

Procedure:
To a microwave vial containing 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (40 mg, 0.11 mmol, 1 equiv.) were added 5-bromo-1-ethyl-4-methyl-1H-pyrazole 11 (64 mg, 0.34 mmol, 3 equiv.), Pd(dppf)Cl2. CH2Cl2 (9 mg, 0.011 mmol, 0.1 equiv.), DBU (101 μL, 6 equiv.) and DMSO-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated under reduced pressure and purification was carried out by reverse phase HPLC.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:60])=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) was dissolved in dichloromethane (30 ml), and to the solution was added 3-chloroperbenzoic acid (0.46 g) under ice-cooling and the mixture was stirred at room temperature for 4 hours. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methylbenzoic acid (20 g, 146.90 mmol, 1.00 equiv) in thionyl chloride (60 g). The mixture was stirred for 2 h at 80° C. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (200 mL). This was followed by the addition of triethylamine (29.7 g, 293.51 mmol, 2.00 equiv) dropwise with stirring at 0° C. To this was added aniline (13.6 g, 146.04 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring overnight at room temperature. The resulting mixture was washed with 3×100 mL of hydrogen chloride (5%) and 2×100 mL NaOH (5%). The mixture was washed with 3×100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 19.37 g (62%) of 4-methyl-N-phenylbenzamide as a white solid. MS (ESI) m/z 212 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1.[C:23]1(C)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[CH2:10][N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1
Reactant: COC(=O)CC1CNc2cc(C(=O)OC(C)(C)C)ccc2O1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CC1CN(c2ccccc2)c2cc(C(=O)O)ccc2O1
Yield: 51.2 %

Procedure:
To a stirred suspension of tert-butyl 2-(2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (5.3 g, 17.3 mmol) in toluene (50 mL) 1,4-cyclohexandione (2.8 g, 25 mmol) and p-toluenesulfonic acid (1 g) were added. The resulting solution was stirred at reflux for 4 hours, using a condenser equipped with a Dean-Stark apparatus. The reaction mixture was concentrated in vacuo. The remaining oil was purified by flash chromatography on silica gel column eluting with ethyl acetate to give 2-(2-methoxy-2-oxoethyl)-4-phenyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (2.9 g, 52%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][CH:7]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[N:8]1)[CH3:2].[CH2:30](C1C=C(C=CC=1)CC1C(=O)N(C)C2C=CC(Cl)=CC=2C(C2C=CC(O)=CC=2)=N1)C.C(C1C=CC(CC2C(=O)N(C)C3C=CC(Cl)=CC=3C(C3C=CC(O)=CC=3)=N2)=CC=1)C.C(C1C=CC(CC2C(=O)NC3C=CC(Cl)=CC=3C(C3C=CC(O)=CC=3)=N2)=CC=1)C>>[Cl:19][C:17]1[CH:16]=[CH:15][C:11]2[N:12]([CH3:30])[C:13](=[O:14])[CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][CH:1]=[CH:2][C:27]=3[CH2:28][CH3:29])[N:8]=[C:9]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:10]=2[CH:18]=1
Reactant: CCc1cccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3NC2=O)c1
Reactant: CCc1cccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)c1
Agent: CCc1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)cc1
Agent: CCc1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3NC2=O)cc1
Product: CCc1ccccc1CC1N=C(c2ccc(O)cc2)c2cc(Cl)ccc2N(C)C1=O

Procedure:
1H NMR (300 MHz, DMSO-d6), δ 1.11 (t, 3H), 2.69 (q, 2H), 3.34 (m, 2H), 3.74 (m, 1H), 6.78 (m, 2H), 7.08-7.32 (m, 7H), 7.58 (d, 1H), 7.67 (dd, 1H), 9.98 (s, 1H). MS, m/z 419.3 [M+1]. (Z)-3-(3-Ethylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, DMSO-d6) δ 1.16 (t, 3H), 2.57 (q, 2H), 3.2-3.35 (m, contains signals for benzylic protons and H2O), 3.60 (t, 1H), 6.79 (d, 2H), 7.02 (dt, 1H), 7.07-7.31 (m, 7H), 7.61 (dd, 1H), 9.94 (s, 1H), 10.62 (s, 1H). MS, m/z 405.2 [M+1]. (Z)-3-(3-Ethylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, 3H), 2.57 (q, 2H), 3.3-3.4 (m, contains signals for benzylic protons and NMe, 5H), 3.81 (t, 1H), 6.86 (d, 2H), 7.02 (dt, 1H), 7.08-7.20 (m, 3H), 7.27 (fine d, 1H), 7.38 (d, 2H), 7.63 (d, 1H), 7.73 (dd, 1H), 9.5-11 (br s). MS, m/z 419.2 [M+1]. (Z)-3-(4-Ethylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, DMSO-d6) δ 1.14 (t, 3H), 2.58 (q, 2H), 3.36-3.41 (m, 5H), 3.95 (m, 1H), 6.90 (m, 2H), 7.10-7.42 (m, 7H), 7.66 (d, 1H), 7.83 (dd, 1H), 10.0 (br s, 1H). MS, m/z 419.3 [M+1]. (Z)-3-(4-Ethylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20].CCN(CC)CC.[Cl:38][CH2:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[Cl:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:19]([NH:18][C@@H:10]1[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]1[NH:8][S:40]([CH2:39][Cl:38])(=[O:42])=[O:41])=[O:20])=[CH:29]2
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=S(=O)(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NS(=O)(=O)CCl)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide trifluoroacetic acid salt (Method 5, 2.2 g, 5.0 mmol) and Et3N (2.1 mL, 15.0 mmol) dissolved in dry THF (30 mL) at 5° C., chloromethyl sulphonyl chloride (820 mg, 5.5 mmol) in dry THF (5 mL) was added and the reaction allowed to warm to ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and the residue dissolved in EtOAc (75 mL), washed with water (2×25 mL), brine (25 mL) and dried (MgSO4). Removal of the volatiles under reduced pressure gave the title compound (2.16 g, 98%) as a buff powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C@:10]1([CH3:31])[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:13]2([CH3:14])[C:12](=[O:30])[CH2:11]1)[C:24]1[CH:23]=[CH:22][C:21]([O:28][CH3:29])=[CH:20][C:19]=1[CH2:18][CH2:17]3)([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:7]([C@:10]1([CH3:31])[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:13]2([CH3:14])[C@@H:12]([OH:30])[CH2:11]1)[C:24]1[CH:23]=[CH:22][C:21]([O:28][CH3:29])=[CH:20][C:19]=1[CH2:18][CH2:17]3)([CH3:9])[CH3:8]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C[C@](C)(C(C)C)[C@@H]12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@](C)(C(C)C)[C@@H]12
Yield: 92.2 %

Procedure:
Lithium aluminum hydride (35 mg; 0.92 mmol) was added to a solution of the 15α-isopropyl-15β-methyl ketone (11) (63 mg; 0.19 mmol) in dry tetrahydrofuran (4 ml) at 0° C. After 10 min. at this temperature, saturated aqueous sodium hydrogen carbonate was added. The mixture was filtered, and the clear solution was given the standard work-up (ethyl acetate) to give 15α-isopropyl-3-methoxy-15β-methylestra-1,3,5(10)-trien-17β-ol (15) (60 mg; 95%), [α]D +54° (c 1.3); νmax 3604 cm-1 (OH); νH (200MHz), 0.88 and 0.92 (each 3H, d, J 6.8 Hz, 15α-CHMe2), 0.96 (3H, s, 13β-Me), 1.13 (3H, s, 15β-Me), 1.73 (1H, dd, J 13.4 and 10.2 Hz, 16-H), 2.13 (1H, dd, J 13.4 and 7.9 Hz, 16-H), 3.54 (1H, dd, J 10.2 and 7.9 Hz, 17α-H), 3.78 (3H, s, 3-OMe), 6.64 (1H, dd, J 2.7 Hz, 4-H), 6.71 (1H, dd, J 8.5 and 2.7 Hz, 2-H), and 7.22 (1H, d, J 8.5 Hz, 1-H); δc 14.1 (C-18), 18.2 and 18.6 (15α-CHMe2), 23.6 (C-11), 26.2 (C-7), 28.5 (15β-Me), 29.9 (C-8), 36.6 (C-12), 37.3 (15α-CHMe2), 39.3 (C-6), 40.7 (C-15), 42.7 (C-13), 44.7 (C-9), 45.0 (C-16), 51.8 (C-14), 55.2 (3-OMe), 80.8 (C-17), 111.4 (C-2), 113.6 (C-4), 126.3 (C-1), 133.0 (C-10), 137.6 (C-5), and 157.7 (C-3) (Found: C, 80.4; H, 9.9%; M+, 342. C23H34O2 requires C, 80.65; H, 10.0%; M, 342).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12])=[O:4].C([O-])([O-])=O.[Ca+2].CN(C=O)C>C1COCC1>[CH3:14][O:13][C:11]([CH:6]1[CH2:7][C:8](=[O:10])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1=CC(=O)CC1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
(1R,2S)-4-oxo-cyclopentane-1,2-dicarboxylic acid dimethyl ester (4.8 g, 23.8 mmol) and CuBr2 (11.9 g, 53.2 mmol) were dissolved in dry THF (70 mL) and the mixture was refluxed for two hours at 90° C. The formed CuBr was filtrated off and the organic phase was concentrated. CaCO3 (2.7 g, 27.2 mmol) and DMF (70 mL) were added and the mixture was held at 100° C. for one hour. The dark brown mixture was poured over ice (35 g) and the formed precipitate was filtrated off. The aqueous layer was extracted with ethyl acetate (1×300 mL+3×150 mL). The organic phases were dried, filtrated and concentrated. Purification by flash chromatography (toluene/EtOAc 9:1) gave 2 (2.1 g, 45%) as yellow crystals