Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][NH:19][C:18]3=[O:28])[CH2:16][CH2:15]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH:32]([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34].[ClH:39]>CCCCCCC.CN(C)C=O.O1CCCC1.CCOCC.C(OCC)(=O)C.O>[ClH:39].[CH2:36]([O:35][C:33](=[O:34])[CH:32]([N:19]1[C:18](=[O:28])[C:17]2([CH2:29][CH2:30][N:14]([CH2:13][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH2:15][CH2:16]2)[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20]1)[CH3:38])[CH3:37]
Reactant: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc3ccccc13)CC2
Reactant: CCOC(=O)C(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Reaction time: 0.08 h
Yield: 85 %

Procedure:
Sodium hydride, 60% (0.156 g, 3.9 mmol) was suspended in dry heptane (5 ml) and stirred under nitrogen for 5 minutes. The solvent was decanted and dry dimethyl formamide (2 ml) was added. 8Naphthalen-1-ylmethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1.115 g, 3.0 mmol), dissolved in dry dimethyl formamide (11 ml) was added dropwise under cooling in an ice bath. The mixture was stirred at 0° C. for 1 h. An aliquot of the resulting solution of deprotonated 1-phenyl-8-naphthalen-1-ylmethyl-1,3,8-triazaspiro[4.5]decan-4-one (2.3 ml, 0.5 mmol) was added to ethyl 2-bromopropionate and the mixture was stirred at room temperature overnight. Water (15 ml) and ethyl acetate (15 ml) were added and the mixture was shaken, the organic phase was separated and successively washed with water (2×10 ml) and brine (10 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and dichloromethane 1:4 to give the pure base, which was dissolved in tetrahydrofuran (3 ml) and an excess of a solution of hydrogen chloride in ether was added. Crystallization occurred on the careful addition of ether (6 ml). The precipitate was collected by filtration and dried to give the title compound (217 mg, 85% yield).
Reaction SMILES: BrC(Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.ClCCl.[CH3:29][O:30][CH2:31][O:32][CH3:33]>FC(F)(F)S([O-])(=O)=O.[Ag+].C(O)CO>[O:30]1[CH2:29][CH2:33][O:32][CH:31]1[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: COCOC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: OCCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCCO4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.5 %

Procedure:
A mixture of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g, 10.0 mmol), silver trifluoromethanesulfonate (0.500 g, 19.5 mmol), ethylene glycol (5.00 ml), dichloromethane and dimethoxymethane is stirred three days at room temperature and treated with additional silver trifluoromethanesulfonate (0.300 g, 11.7 mmol). The resultant mixture is stirred one day at room temperature and treated with additional silver trifluoromethanesulfonate (0.400 g, 15.6 mmol) and ethylene glycol (1.00 ml), stirred another day at room temperature and treated again with silver trifluoromethanesulfonate (0.300 g, 11.7 mmol) and ethylene glycol (1.0 ml). After stirring an additional day the mixture is filtered. The filtrate is diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is triturated with hexanes-ethyl acetate to afford the title compound as a white solid (0.070 g, 17.5%, mp 213-216° C.) which is identified by NMR spectral analysis.
Reaction SMILES: CO[C:3](=O)[C@@H:4]([N:6]([C:15](=[O:26])[C@H:16]([NH:18][C:19](OC(C)(C)C)=[O:20])[CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)C.FC(F)(F)C(O)=O>ClCCl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C@@H:4]([CH3:3])[C:19](=[O:20])[NH:18][C@H:16]([CH3:17])[C:15]2=[O:26])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1NC(=O)[C@H](C)N(Cc2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of (2S)-2-[(2R)-(2-tert-butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionic acid methyl ester (43 g, 382 mmol) in dichloromethane (120 mL) at 0° C. was added trifluoroacetic acid (60 mL). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was cooled to 0° C. and slowly quenched by addition of 3 N sodium hydroxide until basic. The resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (22 g).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH2:17][C:18](=O)[CH2:19][CH3:20])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:19]([C:18]1[NH:8][C:9]2[C:10]([CH:17]=1)=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH3:20]
Reactant: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2[nH]1
Yield: 58 %

Procedure:
1-[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl]-2-butanone (7.33 g, 0.025 mol) in 120 mL of CH2Cl2 and 20 mL of trifluoroacetic acid was stirred for 20 hours, washed with water, NaHCO3 solution and the product chromatographed on silica (eluted with 20% EtOAc/hexane) to give 2.54 g (58% yield) of 2-ethyl-5-methoxy-1H-indole as a white solid, mp 49°-50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]3[O:18][CH2:19][C:20](=[O:22])[NH:21][C:16]=3[N:15]=[C:14]([CH3:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([NH2:34])=[O:33]>C(C(C)=O)C>[NH2:34][C:32]([CH2:31][N:21]1[C:20](=[O:22])[CH2:19][O:18][C:17]2[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[N:13][C:14]([CH3:23])=[N:15][C:16]1=2)=[O:33]
Reactant: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3CC(N)=O)CC1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A suspension containing 0.96 g of 4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Example 1), 25 ml of methyl ethyl ketone, 0.5 g of anhydrous potassium carbonate and 0.31 g of chloroacetamide is boiled under stirring for 8 hours, filtered as hot, washed with methyl ethyl ketone and this filtrate is set aside. The precipitate is washed with water, then with ether and dried to give 0.65 g of the product, m.p.: 225°-227° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].[C:24]([C:27]1[CH:28]=[C:29]([C:32](O)=[O:33])[NH:30][N:31]=1)(=[O:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][C@H:7]([NH:21][C:32]([C:29]1[NH:30][N:31]=[C:27]([C:24](=[O:26])[CH3:25])[CH:28]=1)=[O:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(C)=O)n[nH]1
Reaction time: 0.03 h
Yield: 66.7 %

Procedure:
(2R,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 500 mg, 1 mmol, 1.0 eq.), 5-acetyl-2H-pyrazole-3-carboxylic acid (330.4 mg, 2.1 mmol, 1.5 eq.), and HATU (820 mg, 2.1 mmol, 1.5 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. DIPEA (750 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum, and the product was purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield the title compound (300 mg, purity 98%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H27N3O5, 450.20. found 450.2.
Reaction SMILES: N1C=CC=C(C=O)C=1.Cl.N12CCC(CC1)C(=O)C2.[OH-].[K+].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[C:28]2[C:33](=[O:34])[CH:32]3[CH2:35][CH2:36][N:29]2[CH2:30][CH2:31]3)[CH:22]=1>CO.[Ni]>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]2[CH:33]([OH:34])[CH:32]3[CH2:31][CH2:30][N:29]2[CH2:36][CH2:35]3)[CH:22]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [Ni]
Agent: Cl
Agent: O=C1CN2CCC1CC2
Solvent: CO
Product: OC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
The manner in which 3-(phenylmethoxy and 2-phenylethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octanes of the present invention are synthesized can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968). This aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3one, is then dissolved in methanol and hydrogenated in the presence of Raney nickel catalyst to afford 2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. Treatment of the alcohol with sodium hydride followed by benzyl bromide in a suitable solvent affords the desired product, 3-(phenylmethoxy)-2-(3-pyridylmethyl)-azabicyclo[2.2.2]octane. 3-(2-Phenylethoxy)2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane can be synthesized by substituting benzyl bromide with 2-bromoethylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7].[O-]S(C(F)(F)F)(=O)=O.[C:30]1(C(C2C=CC=CC=2)=C[SH2+])C=CC=C[CH:31]=1.C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([CH:6]([CH3:8])[CH3:7])[O:9][CH2:31][CH2:30][N:10]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:21]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(C)cc1)[C@H](O)C(C)C
Reactant: [SH2+]C=C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@@H](C(C)C)OCCN1S(=O)(=O)c1ccc(C)cc1
Reaction time: 12 h

Procedure:
A mixture of (2S,3R)-3-hydroxy-4-methyl-2-(toluene-4-sulfonylamino)-pentanoic acid methyl ester (0.4 g, 1.27 mmol) and diphenylvinylsulfonium triflate (0.5 g, 1.4 mmol) in dichloromethane (10 mL) was added triethylamine dropwise at 0° C. After stirring for 12 hours, the mixture was diluted with water, and then extracted with ethyl acetate, then dried over sodium sulfate. After removal of solvent, the residue was purified by flash chromatopraphy (eluented with ethyl acetate/hexane=1:4) to afford the product as a white solid. MS: calc'd (MH+) 342, measured (MH+) 342.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH4+].[OH-]>C(O)C.C(OCC)(=O)C.[Zn]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Clc1ncc2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 3.56 mmol) and zinc dust (2.34 g, 35.6 mmol) were combined and stirred in ethanol (10 mL). NH4OH (1 mL) was added and the reaction heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was washed with water (100 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 90/10 petroleum ether/ethyl acetate to afford 2-chloro-5-phenyl-thieno[2,3-d]pyrimidine (260 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([O:24]CC)=[O:23])[O:8][C@H:7]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:18])([CH3:19])[CH2:14][N:15]([CH3:16])[CH3:17])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([OH:24])=[O:23])[O:8][C@H:7]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:37]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CN(C)C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl trans-7-chloro-5-(1-naphthyl)-1-(2,2-dimethyl-3-dimethylamino-propyl)-2- oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (212 mg, 0.41 mmol) and potassium carbonate (112 mg, 0.83 mmol) were stirred in a mixture of MeOH (8 ml) and water (2.5 ml) for 18 hours at 60° C. The mixture was cooled to room temperature, acidified to pH 2 with 2N HCl and extracted several times with ethyl acetate. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure to give the title compound (156 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Solvent: CCCCO
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)n1
Temperature: 160 °C
Reaction time: 48 h
Yield: 26.9 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methoxypicolinamide (228 mg, 0.624 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (375 mg, 1.87 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(6-methoxypicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (91.5 mg, 27% yield) as a solid. LCMS (APCI+) m/z 445.1, 447.1, 454.1 (M+H)+, Retention time=4.03 minutes (Method 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=1)[CH:9]=2)=[O:5])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][N:17]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Oc3ccc(N)cn3)cc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2ccc(Oc3ccc(NC(C)=O)cn3)cc2[nH]1
Reaction time: 2 h
Yield: 29.1 %

Procedure:
To a solution of 6-(5-aminopyridin-2-yloxy)-1H-indole-2-carboxylic acid ethyl ester (2.6 g, 8.6 mmol) in pyridine (13 mL) was added acetic anhydride (2.2 g, 21 mmol) under ice cooling and the mixture was stirred for 2 hours. Water (30 mL) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with 2 M HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized with 2-propyl alcohol and filtrated to give 0.85 g of the title compound. The filtrate was evaporated and the residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:3) to give 1.26 g (total of 2.11 g) of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[Na+].BrC(F)(F)C(F)(F)CCO>CO>[OH:1][CH2:2][CH2:3][C:4]([F:13])([F:12])[C:5]([F:10])([F:11])[S:6]([OH:9])(=[O:7])=[O:8]
Reactant: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Agent: OCCC(F)(F)C(F)(F)Br
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(O)C(F)(F)C(F)(F)CCO

Procedure:
The solid from above which contained sodium 4-hydroxy-1,1,2,2-tetrafluorobutane-1-sulfonate was extracted with methanol (100 mL) and filtered. The resulting pale yellow solution was passed through a short column (2.5 cm diameter) which was packed with 7.5 cm of Amberlite 120H acid ion exchange resin to give a light brown solution. Additional methanol was used to flush any remaining sulfonic acid. The volatiles were removed under reduced pressure to give a dark brown oil. The yield was 15.453 g, 77% based on starting 4-bromo-3,3,4,4-tetrafluoro-1-butanol.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:16][CH:17]=3)=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (475 mg), ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (657 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[CH:18]=[CH:17][C:11]3[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[CH:18]=[CH:17][C:11]3[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ccc3c(c2)OCC(=O)N3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1COc2cc(Nc3ccc(O)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of 7-(4-methoxyanilino)-2H-1,4-benzoxazin-3(4H)-one (135 mg; 0.5 mmol) in CH2Cl2 (2 ml) was treated with BBr3 (350 mg; 1.5 mmol). The mixture was stirred at room temperature for overnight. After evaporation to dryness the residue was taken up in EtOAC and saturated aqueous NaHCO3. The organic phase was washed with water, brine and dried over MgSO4. The residue (147 mg) was triturated with EtOAc, filtered and dried to give 7-(4-hydroxyanilino)-2H-1,4-benzoxazin-3-(4H)-one as a magenta solid (120 mg), Melting point 270-275° C. Yield: 94% 1H NMR spectrum (DMSO d6): 4.48(s, 2H); 6.46 (d, 1H); 6.48 (dd, 1H); 6.68-6.72 (m, 3H); 6.89 (m, 2H); 7.56 (s, 1H); 8.98 (s, 1H); 10.42 (s, 1H). LCMS-ESI: 256 [MH]+
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:25]([NH:24][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[O:26])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 44.9 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2,3-dichlorophenylisocyanate (50 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (63 mg, 45%). 1H NMR (DMSO-d6): δ 10.51 (s, 1H), 9.34 (s, 1H), 9.27 (s, 1H), 8.29 (d, 1H), 7.32 (m, 2H), 7.16 (d, 1H), 2.87 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=2)[CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:14][C:12]1[CH:13]=[C:8]([N:4]2[CH:3]=[C:2]([F:1])[C:6]([F:7])=[CH:5]2)[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-(3,4-difluoro-1H-pyrrol-1-yl)-2-nitrophenol (6.39 g), benzyl bromide (3.48 mL) and potassium carbonate (5.51 g) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (8.57 g).