Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15](O)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20](C)[C:21](OCC3C=CC=CC=3)=O)[C:12]3[CH:32]=[CH:33][CH:34]=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].[BrH:48].C(O)(=[O:51])C.CCOCC>N1C=CC=CC=1.C(O)(=O)C>[BrH:48].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:44][C:43](=[O:51])[C:42]3[CH:46]=[CH:47][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:32]=[CH:33][CH:34]=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)O
Agent: Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CNCCN1C(=O)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-benzyloxycarbonylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 60 ml of pyridine, and 5.94 g of 4-nitrobenzoyl chloride are added thereto under ice-cooling. The mixture is stirred at room temperature overnight. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove solvent. The oil thus obtained is dissolved in 70 ml of acetic acid, and the solution is ice-cooled. 100 ml of 25% hydrogen bromide-acetic acid are added to the solution, and the mixture is stirred at room temperature for 45 minutes. Ether is added to the mixture, and the precipitates (yellow powder) are collected by filtration, washed with ether and then dried under reduced pressure. 13.3 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-nitrobenzoyloxy)-5-[2-(methylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide are thereby obtained.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12]([Cl:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[ClH:19].[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 100 g (0.637 mole) of ethyl isonipecotate, 80.64 g (0.64 mole) of benzyl chloride and 67.84 g (0.64 mole) of sodium carbonate in 1 liter of absolute ethanol was heated at reflux for 8 hours and then was stirred at room temperature for 10 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo to give the free base of the title compound as a liquid. The free base was converted to the hydrochloric acid salt, and the salt was recrystallized from ethanol-ether to give 89.33 g (49.7%) of white, crystalline solid, m.p. 154°-155° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1Cc2cccc(N)c2C1=O
Temperature: 80 °C
Yield: 96.2 %

Procedure:
At room temperature, a solution of N-Methyl-7-nitro-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated with SnCl2.2H2O (2.68 g), stirred at 80° C. under reflux for 5 h, and treated with 30 mL of 5N NaOH at 0° C. After the both layers are separated, the aqueous layer is extracted with EtOAc (2×8 mL), the combined extracts are washed with brine (5 mL), dried (MgSO4), and evaporated to give 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (455.9 g, 2.81 mmol) in 96%. Yellow solid. Rf (CH2Cl2/EtOAC 1:1) 0.53. 1H-NMR (400 MHz, CDCl3) 3.12 (s), 4.28 (s), 5.20 (br. s), 6.56 (d, J=8.0), 6.68 (d, J=8.0), 7.21 (dd, J=8.0, 8.0).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:26])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1Cl
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(-c2ccncc2)nc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 7.9 %

Procedure:
A suspension of 0.6 g (2 28 mmol) 4-chloro-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester, 0.27 g (2 50 mmol) o-cresol and 2.97 g (9.10 mmol) Cs2CO3 in 15 ml acetonitrile was stirred for 17 h at RT. The suspension was poured into 150 ml H2O and extracted three times with 90 ml ethyl acetate. The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/MeOH 100:1) to give 0.74 g (97%) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid, MS (EI): 335.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][C:20]([NH2:23])=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+].CCOCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:20]1[CH:21]=[CH:22][N:18]([C:5]2[CH:6]=[CH:7][C:8]([C:25]3[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]4[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]4)=[CH:27][CH:26]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:19]=1
Reactant: COc1cc(-n2ccc(N)n2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2ccc(N)n2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
A degassed reaction mixture of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine (474 mg, 1.505 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-1 (370 mg, 1.308 mmol) tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.065 mmol) and 1 M NaHCO3 (330 mg, 3.92 mmol) in 1,4-dioxane (7 mL) and water (2.3 mL) was heated at 100° C. for 14 h. After cooling to RT, the mixture was filtered through celite, washed with EtOAc, and the filtrate was concentrated. The residue was suspended in MeOH, acidified to pH 2-3 using 1 M aqueous HCl and loaded on a 10 g SCX column. The column was washed with MeOH, then eluted with 2 N NH3 in MeOH. The collected fractions were concentrated to give a light brown oil, which was treated with ether and concentrated to give 570 mg of 6-(4-(3-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as a light brown solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[CH2:45][OH:46])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[CH2:45][O:46][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCc1cc(C)ccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (144 mg, 0.247 mmol) and (2-allyl-4-methylphenyl)methanol (40 mg, 0.247 mmol) in DMF (5 mL) at 0° C. was added NaH (9.86 mg, 0.247 mmol). The reaction mixture was stirred h at 0° C. for 2 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4-methylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol, 32.8% yield) as an oil. LCMS (M+1)=619.4.
Reaction SMILES: [Cl-:1].[NH4+].[OH:3][CH:4]([CH3:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18]>[Zn]>[ClH:1].[OH:3][CH:4]([CH3:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC(C)O
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(=O)Nc1cc(N)ccc1OCC(C)O
Product: Cl
Temperature: -20 °C

Procedure:
1.5 g of ammonium chloride and 37.5 g of powdered zinc are added to 70 ml of an aqueous-ethanolic solution (60 ml of C2H5OH/10 ml of H2O) and this mixture is preheated to the reflux temperature, with stirring. 0.048 mol (12.2 g) of 2-acetylamino-4-nitrophenyl β-hydroxypropyl ether is then added, the addition being adjusted so as to maintain the reflux without heating. When the addition has ended, the mixture is kept under reflux for 10 minutes and filtered at the boil onto a mixture of 5 ml of ethanol and 5.1 ml of 36% strength hydrochloric acid, cooled to -20° C. The expected product precipitates in the form of the monohydrochloride. It is filtered off, washed with a small amount of ice-cold ethanol and dried in vacuo at 50° C. It melts with decomposition at between 220° and 225° C.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:23]3[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]3)[CH:7]=[CH:8]2)=[C:16]([Cl:20])[N:15]=1
Reactant: OCc1cn[nH]c1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture comprising carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AA2) (1.00 g, 2.92 mmol), (1H-pyrazol-4-yl)-methanol (preparation shown below) (0.34 g, 3.50 mmol) and triphenyl phosphine (0.115 g, 0.44 mmol) in deoxygenated THF (10 mL) under an inert atmosphere of argon is treated with tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.15 mmol) and stirred at 50° C. for 1 hour. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with MeOH/DCM (1:25) to yield the title compound.
Reaction SMILES: C[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[CH:5]=1)=[O:3].Cl[O-:14].[Na+].Cl>C(Cl)Cl>[Cl:10][C:9]1[CH:8]=[C:7]([F:11])[C:6]([F:12])=[CH:5][C:4]=1[C:2]([OH:3])=[O:14]
Reactant: CC(=O)c1cc(F)c(F)cc1Cl
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cc(F)c(F)cc1Cl
Yield: 85.1 %

Procedure:
To 19.1 g (0.1 mol) of 2-chloro-4,5-difluoroacetophenone, 280.4 g (0.4 mol) of a 12% sodium hypochlorite aqueous solution was added, and the mixture was reacted under reflux for 4 hours. After cooling, concentrated hydrochloric acid was dropwise added thereto until the pH became 1. The formed white crystals were dissolved in methylene chloride and separated from the aqueous phase. The separated aqueous phase was extracted twice with methylene chloride, and the extracts were added to the oil phase. Then, the solvent was distilled off to obtain 16.4 g (yield: 85.1%) of 2-chloro-4,5-difluorobenzoic acid as white crystal.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCCl>[CH2:1]([S:8][CH:9]([CH2:34][N:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: CN(c1cccc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1cccc2cc(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.30 g), thiomorpholine 1,1-dioxide (0.15 g) and 1,2-dichloroethane (12 mL) was added sodium triacetoxyborohydride (0.25 g), and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-40:60) to give the title compound (0.37 g, yield: 100%) as a colorless oil. MS: 628 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[Na+].[NH2:21]OS(O)(=O)=O>C(O)C>[NH2:21][N:17]1[CH:18]=[C:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[N:16]1)=[C:2]([NH2:1])[C:3]1[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=1)[N:9]=3
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c2c(nc3ccccc13)CCc1cn(N)nc1-2
Temperature: 55 °C
Yield: 13.6 %

Procedure:
To a suspension of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (40.0 g) in an aqueous sodium hydroxide solution (37.1 g in 561 ml of water) at 50° C. was added ethanol (1550 ml). The resulting solution was heated to 55° C. and solid hydroxylamine-o-sulfonic acid (51.6 g) was added in portions over 15 minutes. The reaction was stirred for a half hour without heat, the resulting solid was filtered, washed with water, boiled in methanol (1500 ml), filtered hot to remove inorganics, concentrated, and triturated with diethyl ether to yield 5.79 g of a product containing approximately 20% of the starting material which was inseparable by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[C:7]([CH3:12])[N:6]=[C:5]([O:13][CH3:14])[CH:4]=1.C([Li])CCC.CO[C:22]1C=[CH:28][C:25]([C:26]#N)=[CH:24][CH:23]=1.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[C:9](=[O:10])[NH:11][C:28]([C:25]3[CH:24]=[C:23]([CH3:22])[C:34]([O:33][CH3:32])=[C:30]([CH3:31])[CH:26]=3)=[CH:12][C:7]=2[N:6]=1
Reactant: COc1cc(OC)c(C(N)=O)c(C)n1
Reactant: COc1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC)c(C)c3)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of 4,6-dimethoxy-2-methyl nicotinamide (2.0 g, 10.2 mmol) in THF (80 mL), n-butyl lithium (19.12 mL, 30.6 mmol, 1.6 M solution in hexane) was added slowly under nitrogen at −78° C. After completion of addition the mixture was stirred for 1 h at 0° C. Then cooled to −78° C. and a solution of 4-methoxy benzonitrile (1.65 g, 10.2 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated NH4Cl solution was added with cooling. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography using 50% ethyl acetate in hexane and then 2% methanol in ethyl acetate to give 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (410 mg, 12%), as a yellow solid. Selected data: MS (ES) m/z: 341.1; mp 262-263° C. (at decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].C[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1>C(C#N)(C)=O>[CH3:9][N:5]1[CH:4]=[N:3][C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:7][CH:6]1[Cl:8]
Reactant: Clc1ncnc(Cl)n1
Reactant: CNc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: CC(=O)C#N
Agent: [K+]
Product: CN1C=NC(Nc2cccc(Cl)c2)=NC1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of the compound 2,4-dichloro-1,3,5-triazine (2.5 g, 16.7 mmol) and solid K2CO3 (6.9 g, 49.9 mmol) was suspended in AcCN (50 mL) under nitrogen at 0° C. followed by addition of N-methyl-3-chloroaniline (2.5 g, 17.7 mmol). The mixture was stirred at 0° C. for 2 h. The reaction was quenched by pouring onto ice/water. The white solid formed was collected by suction filtration and dried under vacuum to give N-methyl-2-chloro-4-(3-chloroanilino)-1,3,5-triazine. MS m/z=256. Calc'd for C10H8Cl2N4: 254.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[C:69]([S:73][CH2:74][C@H:75]([C:77]([OH:79])=[O:78])[NH2:76])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:76][C@@H:75]([C:77]([OH:79])=[O:78])[CH2:74][S:73][C:69]([CH3:72])([CH3:70])[CH3:71])=[O:36])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)SC[C@@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)SC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (20 mg, 0.037 mmol) and N-methylmorpholine (20 μl, 0.18 mmol) were dissolved in DMF (3 ml). TBTU (14.6 mg, 0.046 mmol) was added and the mixture was stirred at 30° C. for 45 minutes. S-(tert-Butyl)-D-cysteine hydrochloride (9.7 mg, 0.045 mmol) was added and the reaction mixture was stirred for 1.5 h. The formation of the ketone of the title compound was confirmed. M/z: 700.0. Methanol (2 ml) and sodium borohydride (14.3 mg, 0.38 mmol) were added and the mixture was stirred for 30 minutes. Ammonium acetate buffer (0.1M, 2 ml) was added and the mixture was concentrated. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 45% MeCN in 0.1M N4OAc buffer was used as eluent. The MeCN was removed from the collected fraction under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (16.5 mg, 65%). H-NMR (400 MHz, DMSO-d6): 1.21 (s, 9H), 2.71-2.78 (m, 1H), 2.82-2.86 (m, 3H), 2.74-2.80 (m, 2H), 2.18-2.26 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 2.67-2.76 (m, 1H), 5.03 (d, 0.5H), 5.05 (d, 0.5), 6.98 (d, 2H), 7.05-7.17 (m, 4H), 7.20-7.25 (m, 2H), 7.30-7.39 (m, 4H), 7.94-8.06 (b, 1H), 8.26 (t, 1H). M/z: 700.0 (M−H) and 702.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: c1ccc2ocnc2c1
Product: Cc1nc2cc(OCC3CO3)ccc2s1

Procedure:
Compound 33 was prepared in the manner of compound 6 substituting 2-methyl- benzothiazol-5-ol for compound 8 in partC-5 of Example 1.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([CH2:33][C:32]([O:34][CH3:35])=[O:31])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Product: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Example 316, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene were reacted to give methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate. M/z 368.2, calc. 367.16
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:20])[CH:13]=[C:14]([OH:19])[C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].C(OC1C2[C@@H]3[C@@H]([C@H:34]4[C@@:38](CC3)(C)[C@@H:37](OC(=O)C)[CH2:36][CH2:35]4)CCC=2C=C(OC(=O)C)C=1)(=O)C.[CH:52]1(Br)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C(O)C>[CH:52]1([O:19][C:14]2[C:15]3[C@@H:16]4[C@@H:7]([C@H:6]5[C@@:2]([CH2:18][CH2:17]4)([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5]5)[CH2:8][CH2:9][C:10]=3[CH:11]=[C:12]([O:20][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH:13]=2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: BrC1CCCC1
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CC[C@@H]2O
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: C[C@]12CC[C@@H]3c4c(cc(OC5CCCC5)cc4OC4CCCC4)CC[C@@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C

Procedure:
A solution of 850 mg. of 8α-estra-1,3,5(10)-triene-1,3,17β-triol (prepared from compound of Example 10 by saponification in 30 ml. of ethanol is heated to the boiling point under N2 with 2.5 ml. of cyclopentyl bromide and 2.5 g. of potassium carbonate for 5 hours. The mixture is then introduced into ice water, taken up in ether, and the organic phase is washed, dried, and evaporated. After purification by chromatography on silica gel, 365 mg. of final product is obtained.