Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl-].[NH4+]>[Fe].CCO.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Yield: 71.2 %

Procedure:
A solution of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g, 0.378 mmol), ammonium chloride (0.0101 g, 0.189 mmol) in 4:1 EtOH/water (2 mL) was treated with iron (0.211 g, 3.78 mmol) and refluxed for 2 hours. The solvent was removed and the residue taken in EtOAc-water and filtered through glass fiber filter paper. The organic phase was separated, dried (phase separator silicone treated filter paper), and concentrated to provide 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (0.076 g, 71% yield) as a yellow gum.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[CH:22]=[C:23]([CH3:27])[C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:29][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1C
Yield: 70.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(2,4,5-trimethylphenyl)piperazine (249 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (337 mg) was obtained.
Reaction SMILES: [C:1]12(OCC[O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH2:2]2.[Li+].[OH-]>C1COCC1.O>[O:18]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:2]1
Reactant: CCOC(=O)CC[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC[C@H]1CC(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a stirred solution of (R)-ethyl 3-(3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-3′-yl)propanoate (2.3 g, 7.92 mmol) in THF (10 mL) and water (1 mL) in round bottom flask. LiOH (1.328 g, 55.4 mmol) was added and reaction mixture was stirred at 25° C. for 2 h. Reaction mixture was concentrated and acidified with dilute HCl, stirred for 1 h at RT. Extracted with ethyl acetate (2×30 mL), dried over sodium sulphate, concentrated to get crude title compound (1.6 g, 93%); m/z 262.7
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([O:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([O:24][C:19]2[CH:18]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[N:22]=[C:21]([CH3:23])[N:20]=2)[CH:34]=1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=C1Nc2ncccc2C12CCNCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)C(=O)Nc2ncccc23)n1

Procedure:
36 mg (0.15 mmol) spiro[piperidin-4.3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 44 mg (0.15 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 91 μL (0.536 mmol) DIPEA in 2.0 mL DMF were stirred for 48 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:17][CH2:16]1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:62][CH:63]3[CH2:67][CH2:66][CH2:65][CH2:64]3)=N2)C=1)(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:63]1([CH2:62][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([S:18][CH:15]3[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:29])=[O:27])[CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(SC2CC2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. 1,1,1,3,3,3-hexamethyldisilazane (1.2 mL, 5.69 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 2.12 mL, 5.32 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of 2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide (900 mg, 2.53 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 min keeping the reaction below −60° C. It was then stirred for 15 min, warmed to 0° C. and stirred for 20 min and then recooled to −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO 2004/052869 A1 Example 1, 798 mg, 3.79 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (643 μL, 5.32 mmol) dropwise. The reaction was then stirred at −78° C. for 30 min and then warmed to 0° C. and stirred for 3 h. The reaction was then diluted with ethyl acetate (30 mL) and washed with a saturated aqueous ammonium chloride solution (3×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organics were then washed with a saturated aqueous brine solution (15 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (719 mg, 65%) as a clear colorless oil: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C27H35NO2S (M+H)+ 438.2462, observed 438.2461.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:19][F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=O)C1C=CC=CC=1.[ClH:21].O>FC(F)(F)C(O)=O>[ClH:21].[NH2:11][C@H:12]([CH2:19][F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)/C=C/[C@@H](CF)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)/C=C/[C@H](N)CF
Temperature: 25 °C
Reaction time: 3 h

Procedure:
690 ml of 26B was stirred in 25 ml of trifluoroacetic acid at room temperature for 10 minutes. Then 5 ml of concentrated hydrochloric acid was added drop-by-drop. The resulting solution was stirred at room temperature for three hours, then 16 ml of water was added, and the resulting solution was stirred at room temperature for 16 hours. Then the solvent was evaporated, the residue was dissolved in 30 ml of 2N hydrochloric acid and the resulting solution was extracted with ether, and the solvent was evaporated at a temperature below 40° C. to give methyl (S)-(E)-4-amino-5-fluoro-2-pentenoate hydrochloride (26C), as a pale yellow paste.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4.8 g, 20.86 mmol) in DMF (100 mL) was added 60% NaH in mineral oil (1.1 g, 45.9 mmol), and the mixture was stirred at 0° C. for 15 min. A solution of 1,2-dibromoethane (3.92 g, 20.86 mmol) in DMF (20 mL) was added and the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (200 and 450 mg) were added sequentially, until conversion was complete. The mixture was poured into EtOAc (1 L) and washed with water (60 mL), dried over Na2SO4 and concentrated in vacuo to give an oil which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])[CH:3]=1.Br[CH2:32][C@@H:33]([CH3:53])[CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:36]([O:35][CH2:34][C@H:33]([CH3:53])[CH2:32][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:23])=[O:24])[C:4]1[CH:3]=[C:2]([C:1]2[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=2)[C:19]([C:20]2[CH:16]=[CH:17][CH:8]=[CH:9][CH:10]=2)=[CH:18][C:5]=1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccccn2)cc1
Reactant: C[C@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2cc(-c3ccccc3)c(-c3ccccc3)cc2N(C[C@@H](C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S(=O)(=O)c2ccccn2)cc1
Reaction time: 4 h
Yield: 139.6 %

Procedure:
596 mg of methyl 4-({4,5-dimethyl-2-[(pyridin-2-ylsulfonyl)amino]phenoxy}methyl)benzoate was dissolved in 5.96 mL of DMF, and 820 mg of {[(2S)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane and 1.37 g of cesium carbonate were added thereto, followed by stiffing at 80° C. for 4 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 840 mg of methyl 4-[(2-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-diphenylphenoxy)methyl]benzoate.
Reaction SMILES: [CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:27])([CH3:26])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](OC)=[O:12])(=[O:5])=[O:4])[CH3:2].[NH3:28]>CO>[CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:27])([CH3:26])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:28])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: N
Reactant: CCS(=O)(=O)N(CCCCC(=O)OC)C1CC(C)(C)Oc2ccc(C)cc21
Solvent: CO
Product: CCS(=O)(=O)N(CCCCC(N)=O)C1CC(C)(C)Oc2ccc(C)cc21
Reaction time: 216 h

Procedure:
A solution of 0.4 g (1 mmol) of methyl 5-[ethylsulfonyl-(2,2,6-trimethyl-chroman-4-yl)amino]pentanoate and 1.5 ml of liquid ammonia in 10 ml of methanol is allowed to stand at RT for 9 days. After concentrating in vacuo, the residue is treated with water and extracted with EA. 0.37 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanamide is obtained; m.p. 127-129° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:45])[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>>[OH:45][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]1=[O:42]
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2ccccc21
Agent: Cl
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(O)c3c2OCC(=O)N3)c2ccccc21

Procedure:
The product is prepared analogously to Example 12b starting from 1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one. Yield: 30 mg (19%, hydrochloride); HPLC-MS: Rt=13.0 min. (method A); ESI-MS: [M+H]+=526.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[N:1]1[O:11][C:9]([O-:10])=[C:4]2[N+:3]=1[CH2:8][CH2:7][O:6][CH2:5]2
Reactant: O=NN1CCOCC1C(=O)O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-]c1on[n+]2c1COCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The crude 4-nitrosomorpholine-3-carboxylic acid (11.0 g) from step 1 was dissolved in THF (250 ml) and cooled to 0° C. A solution of trifluoroacetic anhydride (7.4 ml, 52 mmol) in THF (20 ml) was added with stirring over 10 min. The resulting mixture was stirred at 0° C. for 5 hr, and warmed to room temperature for 16 hr. The solvent was evaporated and the residue was diluted with 250 ml of ethyl acetate and stirred with 30 g of anhydrous potassium carbonate. The mixture was filtered through a pad of silica gel and the filtrate evaporated. The residue was washed with a mixture of ethyl acetate-ether to give 3.80 g of a white solid; mp 132-133° C.; MS (ESI) m/z 143.1 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>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.C1(C)C=CC=CC=1>[S:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])=[CH:14]1
Reactant: Brc1csc2ccccc12
Reactant: O=Cc1cccc(B(O)O)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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cccc(-c2csc3ccccc23)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
(3-Formylphenyl)boronic acid (1.7 g, 11.3 mmol), 3-bromo-1-benzothiophene (2.0 g, 9.39 mmol) and cesium carbonate (4.6 g, 14.1 mmol) were added to a mixed solvent of ethanol (10 mL) and toluene (50 mL). After argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hr. The reaction mixture was cooled, and the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (2.1 g, yield 94%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:60]1[CH2:65][CH2:64][CH:63]([N:66]2[C:74]3[C:69](=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]2=[O:75])[CH2:62][CH2:61]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:60]4[CH2:61][CH2:62][CH:63]([N:66]5[C:74]6[C:69](=[N:70][CH:71]=[CH:72][CH:73]=6)[NH:68][C:67]5=[O:75])[CH2:64][CH2:65]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
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(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (51 mg, 0.102 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (90 μl, 0.517 mmol) was added to the mixture followed by TBTU (36.1 mg, 0.112 mmol). 1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (36.5 mg, 0.125 mmol) was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Reaction was quenched with 50% acetonitrile-water. Mixture was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fraction by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 34% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.92 (s, 1H) 11.56 (d, J=6.41 Hz, 1H) 7.90 (d, J=5.19 Hz, 1H 7.65 (dd, J=69.89, 7.93 Hz, 1H) 7.49 (s, 1H) 6.81-7.06 (m, 1H) 5.54-5.68 (m, 1H) 5.35-5.50 (m, 1H) 4.49-4.63 (m, 1H) 4.32-4.42 (m, 1H) 4.20-4.49 (m, 1H) 4.13-4.20 (m, 1H) 3.93-4.14 (m, 1H) 3.22 (d, J=16.17 Hz, 2H) 2.97-3.12 (m, 1H) 2.86-2.97 (m, 1H) 2.67-2.79 (m, 1H) 2.52-2.66 (m, 1H) 2.42-2.48 (m, J=17.09 Hz, 1H) 2.34-2.42 (m, 1H) 1.93-2.32 (m, 1H) 1.74-1.85 (m, 1H) 1.65-1.74 (m, 1H). High resolution MS m/e (M+H)+=698.0314.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C[C@@]12[C@@H]([OH:40])CC[C@H]1[C@H]1[C@@H](C3C=CC(O)=CC=3CC1)CC2>>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH2:21][OH:40])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
This compound is the postulated reaction intermediate of the first hydroxylation step of testosterone-to-estradiol conversion by Aromatase.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](N)[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2.N([O-])=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:26])[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2
Reactant: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCc1cc(O)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-Methoxymethyl-3-(3-trifluoromethyl-pyridin-2-yl)-pyrido-[2,3-b]pyrazin-8-ylamine (252 mg, 0.751 mmol) is dissolved in a solution of acetic acid (2 mL) and water (5 mL). The mixture is heated to 50° C. and sodium nitrite (362 mg, 5.26 mmol) is added in portions over 1 hour. The solution is warmed to 70° C. and stirred overnight. Water (20 mL) is added and the aqueous mixture is extracted with EtOAc (4×50 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure. The crude product is chromatographed on silica gel eluting with hexanes/acetone (1:1) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13](=[O:33])[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19](=[O:31])[C:18]2=[O:32])[CH3:11]>O1CCCC1>[C:27]([O:26][C:24]([NH:20][C:21]1[CH:22]=[CH:23][C:15]([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:33])=[CH:16][C:17]=1[C:18](=[O:32])[C:19]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:31])=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: CCOC(=O)Cc1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
2.2 g of isoindoline are added to 5.9 g of tert-butyl 5-(2-ethoxy-2-oxoethyl)-2,3-dioxoindoline-1-carboxylate in 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The solvent is removed in vacuo, and the residue is purified by column chromatography, giving 4.9 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]acetate;
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9](=[S:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)o1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: S=c1cc(-c2ccccc2)cc(-c2ccccc2)o1
Yield: 134.2 %

Procedure:
Under an inert atmosphere, 2.1 g of the product of Step A 45 ml of benzene and 7.5 g of phosphorus pentasulfide were mixed together and refluxed under inert atmosphere for 5 hours. Then the supernatant solution was decanted hot and concentrated to dryness by distilling under reduced pressure. This operation was repeated hot on the reaction medium four times, each time with 30 ml of benzene. The concentrates were put together and dried under a good vacuum to obtain 3 g of product which was chromatographed on silica and eluted with methylene chloride to obtain 2 g of the product sought melting at 122°-123° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([Cl:20])=[CH:12][CH:11]=3)[CH2:7]1)=[O:5])C.O.[OH-].[Na+]>C(O)C>[OH2:3].[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:8]1[C:17]([CH2:18][CH2:19][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[N:16]2.[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:8]1[C:17]([CH2:18][CH2:19][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[N:16]2
Reactant: CCOC(=O)C1CCc2nc3cc(Cl)ccc3c(NNc3ccccc3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2nc3cc(Cl)ccc3c(NNc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
A mixture of 2.0 g (0.0051 mol) of the compound of Example 10, 6.4 ml of water, 6.4 ml of ethanol, and 0.4 g of NaOH is stirred at ambient temperature overnight, then concentrated in vacuo. The residue is dissolved in water and extracted with ethyl acetate. The aqueous phase is acidified using acetic acid and extracted with methylene chloride. The organic extracts are dried over Na2SO4, and concentrated in vacuo. The resulting powder is triturated with petroleum ether to give 42 mg of the title compound: IR (KBr) 3250 (br), 2940 (br), 2500 (br), 1700 , and 1600 cm-1 ; NMR (DMSO-d6) δ8.18-7.58 (m, 11H), 3.24-2.90 (m, 5H), 2.38-2.22 (m, 1H), and 2.10-1.98 (m, 1H).