Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=[O:38])[CH3:37]>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:36](=[O:38])[CH3:37])[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-2,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.64 g) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (411 mg).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(O)ccc1OCc1ccccc1

Procedure:
Methyl 5-{[(4-methylphenyl)sulfonyl]oxy}-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 37; 2.5 g, 6.06 mmol) was boiled with potassium hydroxide (2.38 g, 42.4 mmol) in a mixture of ethanol (60 ml) and water (15 ml) for 4 h. After the ethanol had been evaporated, the aqueous solution was washed with ethyl acetate (20 ml) and acidified with concentrated HCl. The mixture was extracted with ethyl acetate (3×30 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo to yield the title compound as a yellow oil. 1.35 g.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:33])([O:30]CC)[O:27]CC)[C@@H:21]([OH:34])[C@H:20]3[OH:35])[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si](I)(C)(C)C>CC#N>[C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:30])[OH:33])[C@@H:21]([OH:34])[C@H:20]3[OH:35])[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: O=C(Nc1ncnc2c1cnn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Compound 25.1 (62.2 mg, 0.124 mmol) in CH3CN (1.25 mL, 0.1 M) was treated with 2,6-lutidine (215 μL, 1.85 mmol) and TMSI (176 μL, 1.24 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The residue was treated with concentrated NH4OH (2 mL) and the solvent was removed in vacuo (×3). The residue was treated with 1% AcOH (2 mL) and treated to reverse phase HPLC to afford compound 25.2 (19.3 mg, 35% yield) as a white solid: MS (ESI) m/z 448 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Clc1ncccc1Br
Product: Brc1cccnc1N1CCNCC1

Procedure:
Alternatively, 3-bromo-2-chloropyridine may be used as shown in Scheme VIII. Thus, 3-bromo-2-chloropyridine (27) is heated with piperazine to provide 1-(3-bromopyridin-2-yl)piperazine (28), followed by Suzuki coupling of the phenyl moiety to provide the phenylpiperazine intermediate (25).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([CH:4]([CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[C:3]([OH:26])=[O:2])[C:13](=[O:25])[CH:14]=1
Reactant: COC(=O)C(CC(C)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid methyl ester (614 mg, 1.56 mmol) dissolved in tetrahydrofuran (10 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (131 mg, 3.13 mmol) in water (10 mL). The mixture was then stirred for 2 h at 25° C. After such time, the mixture was treated with a 1N aqueous hydrochloric acid solution until pH=2 and extracted with ethyl acetate (3×20 mL). The organics were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid (575 mg, 98%) as a yellow-orange solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 78.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (55 mg, 0.053 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (63 mg, 0.106 mmol) and cesium carbonate (1.3 g, 3.99 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-quinoline (compound of example 2) (1 g, 2.66 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.28 g, 3.19 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 80:20 to give a yellow solid (800 mg, 78%). MS: m/z=383 (M+H).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18]>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:18][C:17]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:16]=2[CH3:15])=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cc(C)ccc2C)[nH]c1=O
Reaction time: 17 h
Yield: 45.5 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5pyrimidinecarboxylate (10 g) and 2,5-dimethylaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-6-oxo-2-(2,5-dimethylanilino)-5-pyrimidinecarboxylate (6.1 g). M.p. 252°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(C)(C)Oc2cc(F)c(Br)cc21
Temperature: 50 °C
Yield: 93.2 %

Procedure:
Methyl 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (187 mg, 0.785 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (154 mg, 0.863 mmol). The reaction was heated at 50° C. for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (232 mg, 93.2% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@@H:24]1[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred solution of 325.5 mg (0.64 mmol) of tert-butyl cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 4 mL of N,N-dimethylformamide was added 353.8 mg of potassium carbonate, followed by 184.9 mg (1.28 mmol) of iodomethane. The suspension was stirred at room temperature overnight. After removal of the volatile material, 80 mL of ethyl acetate was added. The organic phase was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane (3:7) to give 292.1 mg of tert-butyl cis-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 87% yield. MS: 523.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
In a 15 mL round-bottomed flask, 3-(tert-butoxycarbonylamino)pyrrolidine (0.50 g, 2.68 mmol) was dissolved in CH2Cl2 (5 mL). Triethylamine (0.45 mL, 3.22 mmol) was added and the reaction mixture was cooled to 0° C. Methanesulfonyl chloride (0.25 mL, 3.22 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was diluted with CH2Cl2 (20 mL) and quenched with 1.0 M aqueous HCl (5 mL). The aqueous layer was extracted with CH2Cl2 then the combined organics were dried over Na2SO4, filtered and concentrated to afford 0.90 g of (1-methanesulfonyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a light brown solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:15]([NH:17][NH:18][C:19]([CH:21]2[CH2:24][N:23]([C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:22]2)=[O:20])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:15]2[O:20][C:19]([CH:21]3[CH2:22][N:23]([C:25]([O:27][CH2:28][CH:29]4[C:41]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[C:35]5[C:30]4=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:26])[CH2:24]3)=[N:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC(=O)C2CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c2ccccc2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)o2)CC1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-phenyl-1-(2-(N-(9-fluorenylmethoxycarbonyl)-3-azetidinecarbonyl)-hydrazinocarbonyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.411 g, 0.645 mmol), iPr2NEt (0.775 mL, 4.448 mmol) and PPh3 (0.693 g, 2.643 mmol) in CH3CN (8 mL) was added hexachloroethane (0.351 mg, 1.483 mmol). The mixture was allowed to stir for 1 h and then it was worked up as in Method A above and the crude product purified by flash chromatography (SiO2/EtOAc-hexane, 1:1) to give the title compound (0.299 g, 75%) as a colorless solid:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+:12].C(O)C>O>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:10])=[O:9].[Na+:12]
Reactant: CCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCC(=O)[O-]

Procedure:
The sodium octoate was prepared by stirring 3.60 g of octanoic acid in 3 g of water and neutralizing with 2.00 g of aqueous sodium hydroxide (50%). 5 g of water was used for dilution and rinse. A waxy solid formed which was dissolved by adding about 10 ml of ethanol. pH paper indicated a pH of about 8. The total solution was evaporated on a watch glass on a steam bath under a flow of nitrogen to give 4.04 g white solid. The solid was titrated in ethanol with aqueous HCl: the titer was 5.88 mmol/g. Estimated purity was 97.6%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cn(C)c3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc(C(F)(F)F)cc2Cl)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Reaction time: 0.25 h
Yield: 105.7 %

Procedure:
3-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.020 g, 0.032 mmol) was dissolved in 0.5 mL of DCM, and TFA (0.5 ml, 6.49 mmol) was added. The reaction was stirred for 15 minutes. The reaction was concentrated, dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 3-(2-chloro-4-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.016 g) as a tan solid. (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=8.43 (s, 7 H), 8.03 (s, 1 H), 8.01-7.97 (m, 2 H), 7.79 (d, J=1.1 Hz, 2 H), 7.67 (d, J=8.6 Hz, 4 H), 7.55 (dd, J=1.7, 8.5 Hz, 1 H), 3.98 (s, 3 H). m/z (ESI) 473.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH:30]=O)[CH2:21][C:20]2=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH2:30][NH:1][CH:2]3[CH2:14][O:13][C:12]4[CH:11]=[CH:10][C:9]5[CH2:8][NH:7][C:6](=[O:15])[C:5]=5[C:4]=4[CH2:3]3)[CH2:21][C:20]2=1
Reactant: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCC1CCc2[nH]c4ccc(F)cc4c2C1)CO3
Reaction time: 0.67 h

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carbaldehyde ((28), 64 mg, 0.294 mmol) in acetic acid (38 mg, 0.588 mmol) and methanol (3 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. The resulting mixture was stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. The concentration of organic solution in vacuo gave crude (27), which was purified on silica gel eluting with 80% EtOAc/Hexane to give a white solid (71 mg, 60%). MS (ES) m/z 406.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
3-Chloro-4-methoxycarbonylbenzoic acid (0.24 g) was dissolved in DMF (2.5 mL) under N2 then CDI (0.36 g) was added and the resulting mixture was stirred at 40° C. for 2 h. t-BuOH (0.54 mL) and DBU (0.33 mL) were added and the resulting mixture was stirred at 40° C. for 2 days. The mixture was evaporated and the residue was taken up with AcOEt, washed with 1N HCl and sat NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: toluene) to give 2-chloro-4-(tert-butoxycarbonyl)benzoic acid methyl ester (216 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:20]([O-])=O.[H][H]>CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[C:8]([NH2:20])=[CH:9][C:10]([C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N, N′-Trimethyl-N′-(2-nitro-4-pentafluoroethyl-phenyl)-propane-1,3-diamine (Step 2, 800 mg, 2.25 mmol) was dissolved in 15 mL MeOH. Palladium (120 mg, 0.307 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding viscous brown oil. The crude mixture was purified using reverse phase chromatography to give the title compound as reddish-brown oil. MS (M+H)+=326; Calc'd 325.32 for C14H20F5N3.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=O)[C:25]#[C:26][CH2:27][O:28]C)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:27](=[O:28])[CH:26]=[C:25]([CH2:24][O:23][CH3:21])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CCOC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-methoxy-but-2-ynoic acid ethyl ester (Larock, J Org Chem 2002, 67, 9318) employing the procedure described in Example 105. [α]D25 −17.80 (c 0.5, CHCl3).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>S(Cl)(Cl)=O.ClCCl>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: Nc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A solution of 2-azido-4,5-difluoro-benzoic acid (26.2 g, 132 mmol; Grieder A.; Thomas, A. W., Synthesis (2003), (11), 1707-1711) in thionyl chloride (216 ml) was stirred under reflux conditions for 1.5 h. The solvent was removed under reduced pressure to give the corresponding crude acid chloride which was suspended in dichloromethane (200 ml). 4-Chloroaniline (16.8 g, 132 mmol) was added and the mixture was stirred at ambient temperature for 14 h. Under ice cooling saturated NaHCO3 solution was added until pH 8 was reached. The mixture was extracted two times with dichloromethane, the combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from dichloromethane/n-heptane to give the title compound (18.5 g, 60 mmol; 46%) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][CH2:17]N(C(C)C)C(C)C.C(OS(C(F)(F)F)(=O)=O)C.N1CCOCC1>>[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCOS(=O)(=O)C(F)(F)F
Solvent: C1COCCN1
Product: CCN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Nitrophenyl)piperidine (255, 500 mg g, 2.4 mmol) was dissolved in 30 mLMeCN. To it were added DIEA (830 μL, 4.8 mmol) and then EtOTf (460 μL, 3.6 mmol). The mixture was stirred at RT for 10 min, and to it was added 0.5 mL morpholine. It was concentrated in vacuo and subjected to silica flash column using 0 to 7% MeOh in DCM to isolate 1-ethyl-4-(4-nitrophenyl)piperidine (259). It was dissolved in 40 mL EtOAc. To it was added 10% Pd/C (0.3 g), and the mixture was hydrogenated using a H2 balloon at RT for overnight. The mixture was filtered through celite, and concentrated in vacuo to give 4-(1-ethylpiperidin-4-yl)aniline (260) (410 mg, 83% overall) as a white solid.