Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C(=O)C.C(O)C.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: Cc1cc(Br)cc2nnc(Nc3ccccc3)nc12
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: COc1cccc(OC)c1-c1cc(C)c2nc(Nc3ccccc3)nnc2c1
Yield: 42 %

Procedure:
To a solution of (7-Bromo-5-methyl-benzo[1,2,4]triazin-3-yl)-phenyl-amine (10 mg, 0.032 mmol) dissolved in 2 ml N,N-Dimethylacetamide in a 20 ml vial, 2,6-dimethoxy-phenylboronic acid (23 mg, 0.126 mmol) dissolved in 1 ml ethanol and potassium carbonate (6.4 mg, 0.06 mmol) dissolved in 1 ml water were added. Triphenylphosphine (1 mg, 0.0038 mmol) and tris(dibenzylideneacetone) dipalladium (0) (1 mg, 1.09 umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 5 mg [7-(2,6-Dimethoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 42.4%; ESI-MS: [M+H]+, 373; 1H NMR (CDCl3): δ 2.72 (s, 3 H), 3.78 (s, 6 H), 6.70 (d, J=8.4 Hz, 2 H), 7.13 (m, 1 H), 7.35 (t, J=8.38 Hz, 1 H), 7.44 (m, 2 H), 7.89 (m, 1 H), 7.92 (dd, J1=8.78 Hz, J2=2.02 Hz, 2 H), 8.18 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:16][OH:17]
Reactant: O=C1CCOc2c(Br)cc(F)c(F)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: ON=C1CCOc2c(Br)cc(F)c(F)c21
Yield: 94.9 %

Procedure:
To a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one (7.2 mmol) in 40 mL of ethanol was added hydroxylamine hydrochloride (0.55 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol). This mixture heated at reflux for 20 hrs. The mixture was cooled, diluted with EtOAc, washed with water and brine, and then dried over Na2SO4. Concentration of the solvent provided the title compound as a white solid (1.9 g). 1H NMR (300 MHz, 10% CD3OD in CDCl3): δ 7.3 (t, 1H), 4.2 (t, 2H), 2.9 (t, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:13])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:14])=[N:4][CH:5]=1)=[O:13])[CH2:29]2
Reactant: COc1nc(N(C)C)ncc1C(=O)O
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1nc(N(C)C)ncc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 2-(dimethylamino)-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][N:13]2[CH:17]=[N:16][NH:15][C:14]2=[O:18])[CH:6]=1>N1C=CC=CC=1>[C:1]([N:15]1[C:14](=[O:18])[N:13]([N:12]=[CH:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:17]=[N:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Solvent: c1ccncc1
Product: CC(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
2.4 g of acetyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-ylmethyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue and extraction is carried out with chloroform. The organic phase is concentrated by evaporation and the residue is stirred with ether. The crystals are filtered off with suction and then dried under a high vacuum. 4 g of the title compound having a melting point of 164-166° are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[ClH:39]>O1CCCC1>[ClH:39].[ClH:39].[NH2:31][CH2:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=4)=[C:2]([CH3:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1
Reactant: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccn(CCN)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
tert-Butyl {2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (2.9 g) obtained in Example 188 (i) was dissolved in tetrahydrofuran (80 mL)/2N hydrochloric acid (40 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (80 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (2.58 g) as a solid powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[NH2-].[Na+].Cl[CH:26](Cl)[C:27]([O-:29])=[O:28].[K+].Cl.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:22][CH:26]([C:27]([OH:29])=[O:28])[O:9][C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=C([O-])C(Cl)Cl
Reactant: Oc1ccc(Cl)cc1C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1Oc2ccc(Cl)cc2C(c2ccccc2)(c2ccccc2)O1
Yield: 31.4 %

Procedure:
A mixture of 12.4 g of 5-chloro-2-hydroxy-α,α-diphenyl-benzene methanol, 150 ml of toluene and 3.2 g of sodium amide was refluxed for 6 hours and was then cooled to room temperature after which 6.8 g of potassium dichloroacetate were added thereto. The mixture was refluxed for another 6 hours and was cooled to room temperature after which 300 ml of water were added thereto. The mixture was slowly acidified with N hydrochloric acid solution and was then made alkaline wiith a saturated sodium bicarbonate solution. The mixture was washed twice with 100 ml of methylene chloride and was then acidified with 2 N hydrochloric acid. The mixture was extracted 3 times with 100 ml of ether and the combined ether extracts were washed twice with 80 ml of water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness under reduced pressure. The 7 g of residue were crystallized from 300 ml of benzene to obtain 4.6 g of 6-chloro-4,4-diphenyl-[4H]-1,3-benzodioxin-2-carboxylic acid melting at 226° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[CH2:1]([N:8]([CH3:24])[C:9]1[C:10]([O:23][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)Cc3ccccc3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[benzyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.62 mmol) in dichloromethane (30 mL) was added pyridine (196 mg, 2.48 mmol), followed by Tf2O (349 mg, 1.24 mmol) at room temperature. The mixture was stirred overnight at room temperature, then quenched with water (100 mL), extracted with dichloromethane (3×20 mL1), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 3-(benzyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red solid (300 mg, crude).
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[C:6]([F:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl.[OH-].[NH4+:18]>>[NH2:18][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:13])[C:6]=1[F:14]
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Agent: Cl
Agent: [OH-]
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Yield: 64 %

Procedure:
Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) δ 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) δ −128.69 to −128.76 (m), −153.60 (d).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[OH:26])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
6-Chloro-5-(4-chloro-phenyl)-nicotinic acid (1.4 g, 5 mmol) was dissolved in N,N-dimethylformamide (30 mL). To this solution was added sequentially (1R,2R)-2-amino-cyclohexanol hydrochloride (0.87 g, 6 mmol), TBTU (1.84 g, 6 mmol), and N-ethyldiisopropylamine (4.47 mL, 26 mmol). The reaction mixture was stirred at room temperature for 72 hours then concentrated in vacuo. The residue was then dissolved in ethyl acetate (100 mL) and washed with 0.5 N HCl (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous phases were extracted with ethyl acetate (2×100 mL), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The solid residue was purified by stirring with (ethylacetate/heptane 1:2, 50 mL) to give 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as a colorless solid, 1.4 g (73% yield). m/z (ISP+): 364.9, 366.9 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[NH:26][C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1>CN(C=O)C.CC#N>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:26]1[C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:17]([CH3:16])=[N:18][N:19]=3)[C:22]=2[CH:28]=[C:27]1[CH3:29]
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1Cl
Temperature: 50 °C

Procedure:
K2CO3 (44 mg, 0.32 mmol) and 1-(bromomethyl)-2-chloro-benzene (0.022 g, 0.11 mmol, Aldrich) were added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20. mg, 0.11 mmol, from Example 2, Step 5) in DMF (3.0 mL). The reaction was heated to 50° C. for 35 minutes. The reaction mixture was diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (2.6 mg, 8%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(OC(F)(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-(trifluoromethoxy)benzoic acid. MS (m/e): 461.1 (MH−, 100%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.C>C(O)C>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: OCC1CCNCC1
Yield: 89.1 %

Procedure:
105 g of 1-benzyl-4-piperidinemethanol hydrochloride, 2 l of ethanol and 12.5 g of palladinized charcoal are introduced into a Parr bottle, and a hydrogenolysis is performed at 50° C. under a pressure of 0.4 MPa. The mixture is filtered and the filtrate evaporated off under reduced pressure. 58.7 g of solid are obtained. Melting point: 128°-130° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[H-].[Na+]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:7]#[N:8])[CH2:4][CH:3]=[CH:2][CH2:6]1
Reactant: N#CCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccs2)CC=CC1

Procedure:
Thiophene-2-acetonitrile and 1,4-dichloride-2-butene were added to a DMF solution of sodium hydride washed with hexane and the whole was reacted at room temperature to obtain 1-(2-thienyl)cyclopent-3-ene-1-carbonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([O:18]CC)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]>C(N)C=C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:9][CH2:8][CH:7]=[CH2:11])=[O:18])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Solvent: C=CCN
Product: C=CCNC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: 80 °C

Procedure:
In a microwave tube, ethyl 2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylate, Compound (1), (1.0 g, 3.21 mmol, 1 eq.) is dissolved in allylamine (Fluka)(6 ml). The reaction mixture is heated at 80° C. for 20 min under microwave irradiation. The reaction is complete, but some desacetylation is observed. The solvents are evaporated and the crude product is recrystallized in MeOH. Compound (2) is isolated as pale yellow solid (492.9 mg; 47%). 1H NMR (DMSO-d6, 300 MHz) δ 2.15 (s, 3H), 2.50 (s, 3H), 3.91 (m, 2H), 5.10 (d, J=12 Hz, 1H), 5.17 (d, J=18 Hz, 1H), 5.88 (m, 1H), 7.99 (s, 1H), 8.94 (t, J=5 Hz, 1H), 12.14 (br s, 1H). M− (ESI): 321.17; M+ (ESI): 323.18. HPLC (method A), Rt: 2.84 min (purity: 99.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:26][C@@:24]3([CH3:25])[C@@H:20]([CH2:21][CH2:22][C:23]3=[O:27])[C@H:19]3[C@H:10]2[C@@H:11]2[C:16]([CH2:17][CH2:18]3)=[CH:15][C:14](=[O:28])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[CH2:29](OC(OCC)OCC)[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)C>[CH2:29]([O:28][C:14]1[CH2:13][CH2:12][C@H:11]2[C:16](=[CH:17][CH2:18][C@@H:19]3[C@@H:10]2[C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C:23]2=[O:27])[CH:15]=1)[CH3:30]
Reactant: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC1=CC2=CC[C@@H]3[C@H]([C@@H](c4ccc(OC)cc4)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Reaction time: 3.5 h

Procedure:
10 g of 11β-(4-methoxyphenyl)-4-oestrene-3,17-dione are placed in a mixture of 260 ml of absolute methylene chloride, 29 ml of ethanol and 26.4 ml of orthoformic acid triethyl ester and, at 0° C., 100 mg of p-toluenesulphonic acid (monohydrate) are added. The whole is then stirred for 3.5 hours at ice-bath temperature and then an excess of saturated sodium hydrogen carbonate solution is added to the reaction mixture. The aqueous phase is extracted repeatedly with methylene chloride and the combined organic phases are dried over sodium sulphate and concentrated in vacuo. The crude product is used directly in the subsequent reaction step. 10.8 g of crude 3-ethoxy-11β-(4-methoxyphenyl)-3,5-oestradien-17-one are isolated.
Reaction SMILES: F[C:2]1C=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS([N:42]1CCN(C2N=CC(C3C=NC=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[N:42]1[CH:2]=[CH:3][CH:4]=[C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:30])[CH3:31])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)[CH:6]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)NO
Yield: 88 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-[4-(5-pyridin-3-ylpyrimidin-2-yl)piperazine-1-sulfonylmethyl]-butyric acid (0.137 g), to provide the title compound as a white solid (0.126 g, 88%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccsc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
A mixture of 2-(2-bromothiophen-3-yl)ethanol (4.5 g, 21.8 mmol), tert-butylchloro-dimethylsilane (3.16 g, 24.0 mmol) and imidazole (1.63 g, 24.0 mmol) in N,N-dimethylformamide (40 mL) was stirred at rt for 24 h. 100 mL of water was added and the mixture was extracted with diethyl ether (3×00 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:20) to give the title compound as an oil (5.9 g, 84%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[CH:17][NH:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)[C:13]([CH3:32])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14](=[CH:17][NH:18][NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)[C:13]([CH3:32])=[N:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NNC=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=CNNC(=O)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 56.6 %

Procedure:
59.4 mg (0.14 mmol) of the 4-methoxycarbonylbenzoic N′-(1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene-methyl)-hydrazide synthesized in 2) was dissolved in 5.0 ml of methanol and stirred with 0.68 ml (0.68 mmol) of 1M aqueous sodium hydroxide at room temperature for 6 hours and then at 60° C. for 3 hours. After the stirring, 0.68 ml (0.68 mmol) of hydrochloric acid was added, and the precipitated solid was collected by filtration and dried to obtain 33.3 mg of the above-identified desired product as a yellow solid (yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([N+:33]([O-])=O)[CH:27]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:30])=[CH:31][CH:32]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5ccc(N)c([N+](=O)[O-])c5)cc4C3)c2cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2nccc(N3CCOc4ccc(-c5ccc(N)c(N)c5)cc4C3)c2cc1OC
Yield: 75.3 %

Procedure:
A solution of 4-{-4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-2-nitroaniline (56 mg, 0.12 mmol) in methanol (20 mL) was hydrogenated at 30 psi over 10% Pd—C (25 mg) for 4 h. The catalyst was filtered off, and the filtrate was concentrated to give 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 77% yield) as a brown oil. MS (EI) for C26H26N4O3: 443 (MH STEP 5: To a solution of 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 0.09 mmol) in acetic acid (2 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (19 mg, 0.09 mmol) and the reaction mixture was stirred at 80° C. for 30 min. After cooling to room temperature the mixture was concentrated, and purified by preparative reverse phase HPLC to provide methyl (6-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-yl)carbamate (17 mg, 25% yield) as a brown solid. 1H NMR (400 MHz, CD3OD): 8.30 (d, 1H), 7.78 (m, 2H), 7.68 (m, 2H), 7.60 (m, 1H), 7.27 (d, 2H), 7.11 (d, 1H), 7.04 (d, 1H), 5.17 (s, 2H), 4.64 (m, 2H), 4.25 (m, 2H), 4.01 (s, 3H), 3.96 (s 3H), 3.63 (s, 3H); MS (EI) for C29H27N5O5: 526 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9](=[CH:15]OCC)[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[CH2:22][S:23][CH3:24].Cl.[NH2:26]O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:15]=[N:26][O:11][C:10]=2[CH:12]2[CH2:14][CH2:13]2)=[O:19])=[C:4]([S:20][CH3:21])[C:3]=1[CH2:22][S:23][CH3:24]
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(CSC)c1SC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CSCc1c(Cl)ccc(C(=O)c2cnoc2C2CC2)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A mixture of 1-[4-chloro-3-(methylsulphenylmethyl)-2-(methylsulphenyl)phenyl]-2-ethoxymethylene-3-cyclopropylpropan-1,3-dione (2.3 g), hydroxylamine hydrochloride (0.52 g) and sodium acetate (0.46 g) in ethanol was stirred at room temperature overnight. The resulting mixture was filtered and the solid collected, washed with water and air dried to yield 4-[4-chloro-2-(methylsulphenyl)-3-(methylsulphenylmethyl)benzoyl]-5-cyclopropylisoxazole (Compound 3, 0.46 g) as a yellow solid, m.p. 79.9°-80.5° C.