Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([S:8]([O-:11])(=[O:10])=[O:9])[C:5]([OH:12])=[CH:4][C:3]=1[S:13]([O-:16])(=[O:15])=[O:14].[K+:17].[K+].C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.S(=O)(=O)(O)O.OO>O>[C:5]1(=[O:12])[CH:4]=[C:3]([S:13]([O-:16])(=[O:15])=[O:14])[C:2](=[O:1])[CH:7]=[C:6]1[S:8]([O-:11])(=[O:9])=[O:10].[K+:17].[K+:17]
Reactant: O=S(=O)([O-])c1cc(O)c(S(=O)(=O)[O-])cc1O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: O=C1C=C(S(=O)(=O)[O-])C(=O)C=C1S(=O)(=O)[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
34.6 g (100 mmol) of dipotassium 2,5-dihydroxybenzene-1,4-disulfonate were dissolved in 500 ml of water at 60° C. After addition of 0.68 g (2 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]-tetraaza[14]annulene, 0.8 g (2 mmol) of diethylenetriaminepentaacetic acid, 1 ml of concentrated sulfuric acid and 1 ml of a commercial antifoam agent, 28.4 g (250 mmol) of 30% by weight aqueous hydrogen peroxide were added dropwise. The mixture was stirred for 15 min at 60° C. The solution was cooled to 5°-10° C. and then the solid was filtered off with suction and recrystallized from water to yield 14.5 g (42%) of dipotassium 1,4-benzoquinone-2,5-disulfonate in the form of reddish brown needles. Melting point >360° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1(C(OC)=O)[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8]1)=[O:5])[CH3:2].[Cl-].[Li+].O>CN(C)C=O>[O:13]=[C:12]1[CH2:11][CH2:10][N:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH:7]1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1CCC(=O)C(CC(=O)OCC)(C(=O)OC)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CN(CC(=O)OCC)CCC1=O
Yield: 48.6 %

Procedure:
Ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidineacetate (1.0 g) and 140 mg of lithium chloride were dissolved in 10 ml of N,N-dimethylformamide and the solution was refluxed for 48 hours. Then, 10 ml of water was added to the reaction liquid, and the mixture was extracted with 100 ml of ethyl acetate. The resulting extract was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give 400 mg of diethyl 4-oxo-1,3-piperidinediacetate as an oily substance.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:9](=[O:22])[N:8]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=O)=O.[NH:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]1=[O:40].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:8]1[C@H:7]([CH2:6][N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]2=[O:40])[C@H:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]
Reactant: O=c1cccc[nH]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2COS(C)(=O)=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ccccc2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.4 %

Procedure:
((2S,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl methanesulfonate (860 mg, 1.80 mmol), pyridin-2(1H)-one (855 mg, 8.99 mmol), K2CO3 (1.74 g, 12.6 mmol) and NaI (746 mg, 4.49 mmol) were slurried in DMF (6.9 mL) and heated to 80° C. with stirring. After 4 h, it was cooled to rt, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford title compound (304 mg, 35%). LCMS: Rt=0.79 min, m/z=478.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, CDCl3) δ 7.39-7.28 (m, 6H), 7.07 (d, J=5.9 Hz, 1H), 6.93-6.85 (m, 1H), 6.55 (d, J=9.0 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 6.35 (dd, J=8.2, 2.4 Hz, 1H), 6.10-6.02 (m, 1H), 5.87 (d, J=7.8 Hz, 1H), 5.10 (s, 2H), 4.93 (br s, 1H), 4.63 (d, J=14.5 Hz, 1H), 4.27-4.10 (m, 1H), 3.97 (d, J=9.0 Hz, 2H), 3.88 (d, J=14.5 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]3[C:17]([C:18]([OH:30])=[C:19]([C:26]([O:28]C)=O)[C:20](=[O:25])[N:21]3[CH3:24])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.BrC1C=C2C([C:36](O)=[C:37]([C:44]([O:46]C)=[O:45])C(=O)N2C)=CC=1.C(OC(C1C=CC(B(O)O)=CC=1)=O)(C)(C)C.[F-].[Cs+]>CCOC(C)=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.CO>[C:44]([CH2:37][CH2:36][C:26]([C:19]1[C:20](=[O:25])[N:21]([CH3:24])[C:22]2[C:17]([C:18]=1[OH:30])=[CH:16][CH:15]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:5])=[O:7])=[CH:9][CH:10]=1)[CH:23]=2)=[O:28])([OH:46])=[O:45]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: COC(=O)c1c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)O)cc3)cc21
Temperature: 80 °C

Procedure:
Methyl 7-(4-(tert-butoxycarbonyl)phenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate. To a mixture of methyl 7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (Method 7) (3.82 g, 12.2 mmol), 4-(tert-butoxycarbonyl)phenylboronic acid (2.72 g, 12.2 mmol), cesium fluoride (5.58 g, 36.7 mmol), and tetrakis(triphenylphosphine)palladium [0] (0.424 g, 0.367 mmol) in a vial, was added MeOH (61 mL). The vial was sealed and heated at 80° C. for 2 hours. The reaction mixture was then cooled, diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotary evaporation to give the product. The resulting product was purified via flash chromatography (silica gel) to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]([C:13]([O:15]CC)=[O:14])[C:6]2=[O:18].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]2=[O:18]
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Yield: 87.4 %

Procedure:
A mixture of ethyl 6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylate (1.22 g, 4.96 mmol), 1N NaOH (25 mL), and ethanol (5 mL) is heated at reflux for 1.5 h. The reaction mixture is cooled in an ice bath, acidified with aqueous HCl, and the precipitate is collected, rinsed with water and dried to give 0.95 g of 6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Yield: 63.2 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-phenoxypropionate (2.10 g), which is the product of Reference example 4(b) and palladium on carbon (5%, 0.32 g) and the reaction mixture was treated to afford the desired compound (1.01 g) as a syrup.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([C:14]1[N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:16]2[C:25]3[CH:24]=[CH:23][C:22]([O:26][CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:36]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[N:15]([CH2:37][CH:38]([CH3:39])[CH3:40])[C:16]2[C:25]3[CH:24]=[CH:23][C:22]([O:26][CH2:27][C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])=[CH:21][C:20]=3[N+:19]([O-:9])=[CH:18][C:17]=2[N:36]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cnc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
Over a period of 30 minutes, mCPBA (1.85 g, 5.47 mmol, 50% pure) was added in four portions to a solution of 2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinoline (2.13 g, 5.47 mmol) in chloroform (200 mL). The reaction was stirred overnight at ambient temperature, washed twice with 1% aqueous sodium carbonate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 0.53 g of 2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C@@H:10]1[CH2:14][NH:13][CH2:12][C@H:11]1[CH2:15][NH:16][C:17]([C:19]1[S:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:18].[N+](C1C=CC([O:34][C:35](=O)[NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]3=[O:49])=[CH:39][C:38]=2[F:50])=CC=1)([O-])=O>>[F:50][C:38]1[CH:39]=[C:40]([N:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]2=[O:49])[CH:41]=[CH:42][C:37]=1[NH:36][C:35]([N:13]1[CH2:14][C@@H:10]([O:9][CH3:8])[C@H:11]([CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:12]1)=[O:34]
Reactant: CO[C@@H]1CNC[C@H]1CNC(=O)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
80.6 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-methoxy-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methoxy-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 505.1 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[C:14](=O)([O-])[O-].[Cs+].[Cs+].BrCCl>CN(C=O)C>[CH2:14]1[O:12][C:11]2[C:2](=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:13])[CH2:6][CH2:5][CH2:4]3)[O:1]1
Reactant: O=C1CCCc2c1ccc(O)c2O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc1c2OCO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of the product of Example 177 (30 g) in DMF (390 ml) was added cesium carbonate (83 g) followed by bromochloromethane (33 g) and the resulting mixture heated to 100 ° C. and mechanically stirred for 2 hours. The reaction was cooled, filtered and the solids washed with ethyl acetate. The filtrate concentrated and the residue taken up into water and toluene. The layers were separate and the aqueous layer reextracted with toluene. The extracts were combined, dried (MgSO4), filtered, treated with charcoal, refiltered and concentrated to provide 29.9 g of the desired product, m.p. 132°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].C(O)C.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([OH:16])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)O)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 99.7 %

Procedure:
A mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro -1-methyl-2-oxoquinoline-3-carboxylate (1.3 g), ethanol (6.0 ml) and potassium hydroxide (0.6 g) was refluxed for 15 minutes. The mixture was diluted with water and acidified by addition of 2N-hydrochloric acid. The precipitated crystals were collected and recrystallized from ethanol to obtain colorless plates of 6-chloro-4-(2-chlorophenyl) -1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid (1.20 g, 85.0%). mp 197°-198° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N2CCNCC2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of t-butyl 4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1.06 g, 3.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and trifluoroacetic acid (6 mL) was placed in a 50-mL round-bottom flask and stirred for 2 h at 30° C. in an oil bath. The pH value of the solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with 4×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate, followed by filtration to remove the solids. The resulting solution was concentrated under vacuum, resulting in 740 mg (crude) of 1-(4-(trifluoromethyl)phenyl)piperazine as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>C(Cl)Cl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH2:48][CH3:49])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and ethylamine (0.19 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (17 mg, 40%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].[NH2:7][S:8]([C:11]1[C:12]([Cl:27])=[CH:13][C:14]([NH:20][CH2:21][C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])(=[O:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:7][S:8]([C:11]1[C:12]([Cl:27])=[CH:13][C:14]([NH:20][CH2:21][C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:19]=1)[C:16]([O:4][CH2:3][C:2]([Cl:6])([Cl:5])[Cl:1])=[O:17])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl

Procedure:
Benzene (30 mL) (or toluene) and 2,2,2-trichloroethanol (0.024 mole) are added to a round-bottomed flask. Furosemide (10) (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid, Aldrich) (0.025 mole), benzene (30 mL), and p-toluenesulfonic acid (0.001 mole) catalyst are added to the flask. A Dean-Stark trap is filled with benzene, and the contents of the flask are refluxed with stirring for several hours or until no additional water is collected in the trap. The reaction is cooled, extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give 2,2,2-trichloroethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate. See Sandler et al., Organic Functional Group Preparations, (1968) p. 249.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3](Cl)([C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:28][CH3:29])=[C:22]([F:30])[CH:21]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:32][C:2]([F:1])([F:33])[CH:3]([C:20]1[CH:21]=[C:22]([F:30])[C:23]([O:27][CH2:28][CH3:29])=[C:24]([F:26])[CH:25]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1
Reactant: CCOc1c(F)cc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOc1c(F)cc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1F
Temperature: 95 °C
Yield: 75.3 %

Procedure:
(RS)-1,1,1-Trifluoro-2-chloro-2-(3,5-difluoro-4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.2 g), α,α'-azoisobutyronitrile (0.01 g) and tri-n-butyltin hydride (0.13 g) were mixed in toluene (10 cm3), and the reaction mixture heated at 95° C. for 8 hours. Analysis by gas liquid chromatography then showed no starting material remaining. The solvent was evaporated under reduced pressure, and the residual oil purified by chromatography on a silica gel support, eluting with n-hexane contaning 5% by volume ethyl acetate, to give 1,1,1-trifluoro-2-(3,5-difluoro-4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)-propane (0.14 g) as a colourless oil (97% pure).
Reaction SMILES: Cl.[F:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:5]([C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([CH:34]=[O:35])=[C:27]3[N:26]=2)[CH:4]=1>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:18]=[CH:19][C:3]([F:2])=[CH:4][C:5]=1[C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([CH:34]=[O:35])=[C:27]2[N:26]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Agent: Cl
Solvent: ClCCl
Product: NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
An HCl (4N dioxane, 80 μl, 0.32 mmol) was added to a DCM (2 mL) solution of (R)-tert-butyl 2-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 0.422 mmol), and the reaction was purged with N2 and stirred at ambient temperature overnight. After removal of solvent, NaOH (5 mL×1N) was introduced and the reaction mixture was extracted with several portions of DCM in a phase separator tube. The combined organic extracts were concentrated to provide (R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (155 mg, 99.5% yield), which was used immediately in the next step. MS (apci) m/z=352.3 (M+H−H2O).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=C([O:30][C:31]([F:34])([F:33])[F:32])C=CC=1C=O>>[CH3:19][O:18][C:5]1[CH:4]=[C:3]([O:30][C:31]([F:34])([F:33])[F:32])[CH:2]=[CH:7][C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(OC(F)(F)F)ccc1C(O)C#Cc1ccccc1
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-4-trifluoromethoxy-benzaldehyde was reacted to give the title compound as a pale yellow oil (650 mg, 100%). LCMS (Method B): RT=4.13 min, [M−H2O+H]+=305.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][CH2:8]2.[H-].[Na+].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:15][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][OH:1])[CH2:8][CH2:9][CH2:10]1
Reactant: OCc1cccc2c1NCCC2
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCCc2cccc(CO)c21
Reaction time: 2 h

Procedure:
To 8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (8.03 g) and sodium hydride (60% in oil) (1.97 g) was added tetrahydrofuran (100 ml) under ice-cooling and argon atmosphere, and the mixture was stirred for 2 hours at 70° to 75° C. At -70° C., n-butyllithium (20 ml) was added to the reaction mixture by use of a syringe, and 30 minutes after addition, a solution of methyl iodide (6.98 g) in tetrahydrofuran (30 ml) was added thereto, and the mixture was stirred for 20 hours at room temperature. After distilling off tetrahydrofuran, the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4:1)]to give 1-methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (5.00 g).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[C:36]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11]
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Yield: 66.4 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.00 g, 9.08 mmol, RN-59216-82-9), oxalyl chloride (0.871 mL, 9.99 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.17 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (2.41 g, 9.08 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 2.82 g (66%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.40-1.44 (m, 2 H), 1.57-1.73 (m, 4 H), 1.79 (s, 3 H), 1.87-1.93 (m, 2 H), 2.16 (s, 3 H), 3.21 (quintet, 1 H), 3.86 (s, 3 H),3.93 (s, 2 H), 7.04 (d, 1 H), 7.11-7.18 (m, 2 H), 7.29 (t, 1 H), 7.51 (dd, 1 H), 7.54-7.60 (m, 2 H).