Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([O-:33])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:40]([C:37]1[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:39][CH:38]=1)(=[O:41])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol), diisoproylethylamine (0.084 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (254 mg, 88%) as a foam. H1-NMR (chloroform-D3): 0.90 (m, 6H), 1.60 (m, 7H), 2.90 (m, 5H), 3.68 (m, 2H), 3.87 (m, 4H), 4.17 (m, 1H), 4.83 (d, 1H), 5.02 (m, 1H), 5.64 (d, 1H), 7.23 (m, 5H), 7.99 (d, 2H), 8.38 (d, 2H). MS(ESI): 630(M+Na).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C>C(O)C.O.Cl>[NH:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(OCCOc2ccc(C(N)=O)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(OCCOC2CCNCC2)cc1
Yield: 9.7 %

Procedure:
4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (4.3 g.) in ethanol (60 ml.), water (30 ml.) and 2 N hydrochloric acid (10 ml.) was heated under reflux for 24 hours then the solvent evaporated in vacuo. The residue was taken up in water and extracted three times with chloroform, the aqueous phase was adjusted to pH 12 with sodium carbonate solution and extracted three times with chloroform. The combined chloroform extracts were discarded, the aqueous phase was saturated with sodium chloride and extracted with chloroform, the chloroform layer dried (Na2SO4), and the solvent evaporated in vacuo to give 4-[2-(4-piperidyloxy)ethoxy]benzamide (0.36 g.). The aqueous phase was concentrated in vacuo and the residual solid extracted with refluxing ethyl acetate (200 ml.).
Reaction SMILES: C(OC(=O)[NH:10]/[C:11](/[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:28][CH:29]=2)[CH:24]1[C:43]1([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)=[N:12]\C(=O)OCC1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].Br[CH2:59][CH:60]([O:63][CH3:64])[O:61][CH3:62]>C(O)C>[CH3:62][O:61][CH:60]([O:63][CH3:64])[CH2:59][NH:10][C:11]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:38])=[O:39])=[CH:28][CH:29]=2)[CH:24]1[C:43]1([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)=[NH:12]
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reactant: COC(CBr)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)NCC(OC)OC)CC2
Temperature: 120 °C
Reaction time: 1.33 h

Procedure:
1-[1-(4-Fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-carboximidamide acetate (140 mg, 0.255 mmol, cf. example 72) was suspended in ethanol (2 mL). Sodium methylate (138 mg, 0.142 mmol) and 2-bromo-1,1-dimethoxyethane (65 mg, 0.383 mmol) were added. The reaction mixture was stirred at 120° C. in the microwave (80 W) for 80 min. The solvent was evaporated in vacuo and the crude product was used without further purification for the next step.
Reaction SMILES: O.O.O.[C:4]([C:7]1[CH:8]=[C:9]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)(=[O:6])[NH2:5].[OH:30][CH2:31][S:32]([O-:35])(=[O:34])=[O:33].[Na+:36]>O>[OH2:6].[OH2:30].[C:4]([C:7]1[CH:8]=[C:9]([N:13]([CH2:31][S:32]([O-:35])(=[O:34])=[O:33])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)(=[O:6])[NH2:5].[Na+:36]
Reactant: O=S(=O)([O-])CO
Reactant: COc1ccc(CCNC(=O)CNc2cccc(C(N)=O)c2)cc1OC
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCNC(=O)CN(CS(=O)(=O)[O-])c2cccc(C(N)=O)c2)cc1OC
Yield: 47.8 %

Procedure:
200 g of 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide trihydrate and 65.2 g of sodium hydroxymethanesulfonate were suspended in 400 ml of water, and the suspension was refluxed over night. After cooling, the reaction mixture was washed with chloroform, and an insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of 500 ml of water and 500 ml of ethanol under heating, and then the solution was cooled. The precipitate formed was collected by filtration and recrystallized from a mixture of water and ethanol to give 59.2 g of sodium N-(3-carbamoylphenyl)-N-(2-((2-(3,4-dimethoxyphenyl)ethyl)amino)-2-oxoethyl)aminomethanesulfonate dihydrate as colorless crystals with m.p. 253° to 255° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(Cl)CCl.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH:29]1[C:38](O)=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:38]([CH:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:39])[CH2:4][CH2:5]1)(=[O:13])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of naphthalene-2-sulfonic acid-(4-aminomethyl-trans-cyclohexylmethyl)amide (0.5 g, 1.4 mmol), EDC (0.54 g, 2.8 mmol), and DMAP (0.34 g, 2.8 mmol) in methylene chloride (30 mL) was stirred at room temperature for 0.5 h. 1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (0.24 g, 1.4 mmol) was added to the reaction mixture and stirred at room temperature till the completion of the reaction (by TLC). The reaction mixture was washed with saturated ammonium chloride (3×30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was flash chromatographed over silica gel to afford white solid (0.66 g, 99%); mp 225-6° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.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>[CH:11]([C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH2:12]
Reactant: Brc1nc2ncccc2[nH]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc2ncccc2[nH]1

Procedure:
A solution of bromoimidazo[4,5-b]pyridine (1 eq.), tributyl(vinyl)tin (1.5-3 eq.), and tetrakis(triphenylphosphine)palladium(0) (0.1 eq.) in toluene (deoxygenated with N2, 20 ml/mmol ml) is stirred under reflux for 4 h. Concentration in vacuo and chromatographic purification (EtOAc/hexane gradient) yields the corresponding vinylimidazo[4,5-b]pyridine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH2:33](O)[CH3:34]>>[CH2:33]([O:29][C:28](=[O:30])[C:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=2)[CH:22]=1)([F:31])[F:32])[CH3:34]
Reactant: CCO
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C(=O)O)c2)n1
Agent: Cl
Product: CCOC(=O)C(F)(F)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 52 μL, 2.1 mmol) is added to a solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid [65 mg, 0.14 mmol, Example 81(a)] in ethyl alcohol (6 mL) and the reaction mixture is stirred overnight at 65° C. The reaction is cooled to room temperature, quenched with water, extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid ethyl ester [18 mg, Example 81(c)]. LCMS: RT=3.19 minutes; MS: 496, 498 (M+H); 1H NMR [300 MHz, CDCl3]: □8.18 (2H, d, J=3.5 Hz), 7.7 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.4 (1H, s), 7.42 (1H, s), 7.18 (2H, s), 6.45 (1H, s), 5.08 (1H, b), 4.3 (2H, q, J=4 Hz), 4.05 (3H, s), 3.72 (2H, b), 3.08 (2H, t, J=3.5 Hz), 1.3 (3H, t, J=4 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:26][CH2:27][CH3:28])[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:4]1[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:3]=1)[CH3:28]
Reactant: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12

Procedure:
1.0 g (2.4 mmol) 2-chloro-4-ethoxy-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.83 g (9.6 mmol) piperazine are refluxed in 20 ml toluene for 4 h. Then, the solvent is removed and the residue is suspended in dichloromethane. The organic phase is washed with saturated sodium carbonate solution, dried on sodium sulfate and the solvent is removed. The residue is purified by flash chromatography (ethanol/chloroform 1:5). 0.98 g (87%) of the title substance is obtained.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([F:26])[CH:25]=1.O>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:27][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Oc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
5-Fluoro-2-nitro-benzonitrile (5 g, 30.1 mmol) in dry DMF (60 mL) was treated first with cesium carbonate (11.7 g, 36.12 mmol) followed by 3,5-difluoro-phenol. The reaction was stirred at room temperature for 1 hour and then poured into iced water (600 mL). After stirring for 2 hours, a pale yellow solid was filtered with suction, washed with water furnishing, after drying at 50° C. under vacuum, 7.73 g of title compound in 93% yield.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:15][C:16]1([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:20][CH2:19][O:18][C:17]1=[O:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:17](=[O:21])[C:16]([CH3:15])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH2:20][CH2:19][OH:18])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: CC1(S(=O)(=O)C2CCOCC2)CCOC1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)C2CCOCC2)on1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a solution of 3-tert-butyl-isoxazol-5-ylamine (0.421 g; 3.00 mmol) in methylene chloride (10 mL) was added dropwise the trimethylaluminum (1.50 mL of a 2.0 M solution in toluene; 3.0 mmol). The mixture was stirred 15 minutes and 3-methyl-3-(tetrahydro-pyran-4-sulfonyl)-dihydro-furan-2-one (0.596 g; 2.40 mmol) was added. The mixture was heated to 45° C. overnight, cooled to room temperature, carefully quenched with 0.5 mL methanol, applied to a plug of silica gel and eluted with ethyl acetate. Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide 0.646 g of the desired product. 1H NMR (CDCl3) δ 9.92 (bs, 1H), 6.29 (s, 1H), 4.11-3.92 (m, 4H), 3.86 (m, 1H), 3.60 (m, 1H), 3.40 (m, 2H), 2.57 (m, 1H), 2.36 (m, 1H), 2.12-1.90 (m, 4H), 1.80 (s, 3H), 1.32 (s, 9H). MS (ESI): m/e 389 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH:31]([NH2:30])[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To 210 mg of N,N-dimethylformamide were added 50 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour, and concentrated under reduced pressure. The procedure of adding 2 ml of diisopropylether to the residue, stirring and decanting was repeated twice. 2 ml of ethanol and 40 mg of N-methylpyrrolidine were added to the residue, and the mixture was allowed to stand overnight, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 26 mg of the title compound as a pale yellow powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[N+:11]([O-:12])=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>>[CH3:5][C:6]1[N+:11]([O-:12])=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c([N+](=O)[O-])c2c([n+]([O-])c1C)CCCCC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Fuming nitric acid (27.0 ml) was added dropwise to ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (3.10 g, 12.4 mmol) at 0° C., and the mixture was stirred at 90° C. for 2 hours. After cooling, the reaction solution was poured into ice water, mixed with 2 N sodium hydroxide aqueous solution and extracted with chloroform, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=40:1) to obtain the title compound (3.38 g, 92.4%) as pale yellow powder.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-:15].[K+].CN(C)C=O>O>[F:15][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [F-]
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(F)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 25.8 %

Procedure:
A mixture of ethyl α-bromo-4-chlorophenylacetate (37.3 g), anhydrous potassium fluoride (9.7 g) and dry dimethylformamide (75 ml) was heated with stirring at a temperature of 140°-150° C. for a period of 6 hours. The reaction mixture was poured into water and the aqueous mixture extracted with methylene dichloride. The organic extract was washed with aqueous sodium carbonate, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The product was distilled using a spinning band column to give ethyl α-fluoro-4-chlorophenylacetate (7.5 g; 29%) b.p. 67° C. at 0.06 mm Hg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([N:20]1[C:24]2[NH:25][C:26](=O)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:19])[CH3:18]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][C:17]([N:20]1[C:24]2[N:25]=[C:26]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:16])[CH3:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(=O)[nH]c2c1c(C)nn2C(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1c(C)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (0.457 mL, 2.70 mmol) was added dropwise to a solution of ethyl 1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (500 mg, 1.803 mmol) in pyridine (10 mL), and the reaction mixture was stirred at room temperature for 16 h. The contents were diluted with EtOAc and washed with saturated NaHCO3, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0% to 100% DCM:Hex) to afford the final product as a solid, 670 mg (91%). LCMS E-S (M+H)=410.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.71 (s, 9H), 2.58 (s, 3H), 4.46 (q, J=7.07 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:14]([CH2:23][CH2:24][F:25])[N:13]=[N:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nnnn1CCF
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution comprising [2-(1H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (EP 449523) (0.125 g, 0.586 mmol) in DMF (5 ml) is added caesium carbonate (0.23 g, 0.703 mmol) followed by 1-bromo-2-fluoroethane (0.174 ml, 2.344 mmol) and the reaction mixture is left to stir at room temperature for 3 days. The solvent is removed in vacuo and the crude residue is purified by flash silica chromatography (elution 3:2 increasing to 1:4 hexane/ethyl acetate) to afford the titled compound and {2-[1-(2-Fluoro-ethyl)-1H-tetrazol-5-yl]-ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:38][C:36]2[S:37][C:33]4[CH:32]=[C:31]([F:30])[CH:40]=[CH:39][C:34]=4[N:35]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc3ccc(F)cc3s2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 6-fluoro-1,3-benzothiazol-2-amine (44 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol), DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 15 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.59 (s, 2H), 7.19 (t, J=74.7 Hz, 1H), 7.21-7.28 (m, 1H), 7.32-7.38 (m, 1H), 7.42-7.48 (m, 2H), 7.57-7.62 (m, 1H), 7.70-7.76 (m, 1H), 7.84-7.93 (m, 2H), 8.05-8.12 (m, 1H), 8.47-8.53 (m, 1H), 13.48 (br s, 1H); ESI-MS (m/z) 573.46 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:41]([Mg]Br)[CH:42]([CH3:44])[CH3:43]>C1COCC1>[OH:16][C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:41][CH:42]([CH3:44])[CH3:43]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)(CC(C)C)c3c[nH]cn3)ccc2c1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (500 mg) and isobutyl-magnesium bromide in THF (1M; 5 mL) to give the titled compound (188 mg) as colorless powder.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C[C@@]12C(=[O:40])CC[C@H]1[C@H]1[C@@H](C3C=CC(O)=CC=3CC1)CC2>>[CH3:1][C@@:2]12[C:3](=[O:4])[CH2:5][CH2:6][C@H:7]1[C@@H:8]1[CH2:9][CH2:10][C:11]3[C@@:17]([CH:18]=[O:40])([C@H:19]1[CH2:20][CH2:21]2)[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=3
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
This compound is the postulated reaction intermediate of the second hydroxylation step of androstenedione-to-estrone catalysis by Aromatase.