Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I.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>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 70 °C
Yield: 85.7 %

Procedure:
A mixture of (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (364 mg, 0.81 mmol), Ethynyl-trimethyl-silane (0.68 mL, 4.9 mmol), Copper(I) iodide (154 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium (94 mg, 0.08 mmol) and triethylamine (0.67 mL, 4.9 mmol) in 5 ml DMF was heated to 70° C. overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) and followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA) to give (2-Methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (324 mg). LCMS-ESI−: calc'd for C25H34BN4O3Si: 466.65; Found: 467.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:2]1
Reactant: OC1(c2ccoc2)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=CC(c2ccoc2)c2ccccc21
Yield: 61.7 %

Procedure:
To a mixture of 5 g (0.024 mol) of 1-(3-furyl)-indan-1-ol in 500 mL of toluene was added 50 mg of p-toluenesulfonic acid monohydrate and the solvent was distilled in vacuo (40 mm) until a residue was obtained. The residue was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 2.7 g (61.3 %) of 1-(3-furyl)-indene as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([N:8]=[C:9]=[O:10])[CH:5]([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23].CCN(CC)CC>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:9](=[O:10])[NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:11]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-methyl-2-isocyanato-3-methylbutanoate (4.46 mL, 29.9 mmol) in CHCl3 (50 mL) was added drop-wise to a solution of (2,4-dimethoxyphenyl)-methanamine (5.00 g, 29.9 mmol) and NEt3 (8.34 mL, 59.8 mmol) in CHCl3 (100 mL) at ambient temperature. The resultant mixture was heated at 60° C. for 12 hours, then cooled to ambient temperature. The cooled reaction mixture was concentrated to provide (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate as a white solid, 1.25 g (13%). LCMS (APCI+) m/z 325 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:16](O)[CH3:17]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
23.3 g of the crude 2-(4-nitrophenyl)propionic acid was dissolved in 100 ml of 22% hydrochloric acid-ethanol solution, and the solution was refluxed on an oil bath for two hours. After ethanol was distilled off under reduced pressure, the residue was neutralized with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off ethyl acetate under reduced pressure, the residue was subjected to silica gel chromatography with chloroform solvent to give 55 g of ethyl 2-(4-nitrophenyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C[CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1.[CH3:36]CN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[CH2:33][CH2:34][O:35][CH2:30][CH:31]3[CH3:36])=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:27])([F:26])[F:28]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1CNCCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N1CCOCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 50.6 %

Procedure:
To a mixture of 112 mg (0.244 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid, 70 mg (0.70 mmol) of 2-methylmorpholine and 0.174 mL (1.0 mmol) of DIEA in CH2Cl2 (2.5 mL) was added 0.19 mL 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3 h the reaction mixture was directly purified via flash column (50% EtOAc in hexane) to afford 67 mg of 4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as a white powder. MS m/z: 542.36 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:22])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C(O)=O)(C)(C)C.C([N:26](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:5][C:6](=[O:23])[CH2:7][C@@H:8]([NH2:26])[CH2:12][C@H:13]([CH3:22])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[C@H](CCC1CCCCC1)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H](N)C[C@H](C)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 2.19 g (6.71 mmol) of (S)-2-((R)-4-cyclohexyl-2-methyl-butyl)-succinic acid 4-tert-butyl ester, 40 mL of toluene, 0.935 mL (6.71 mmol) of triethylamine, and 1.45 mL (6.71 mmol) of diphenylphosphorylazide. The mixture was stirred for 15 minutes at room temperature and then heated to 110° C. and stirred for 6 hours. The toluene was removed under reduced pressure, and the residue was taken up in diethyl ether. The ether layer was washed with 3M HCl aq., water, and brine. The ether was removed under reduced pressure, and the crude isocyanate was taken up in 3 M HCl aq. and heated at reflux for 8 hours. The water was removed under reduced pressure, and the residue was triturated with ether. This provided 1.45 g of an impure white solid. A portion of the white solid was dissolved in methanol, and HCl gas was bubbled through for 15 minutes. The acidic solution was stirred 2 hours. The methanol was removed under reduced pressure, and the crude ester was purified by column chromatography (4:1 dichloromethane:methanol). This gave 0.356 g of the pure ester: 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (m, 2H) 0.88 (d, J=8.00 Hz, 3H) 1.15 (m, 6H) 1.26 (m, 1H) 1.36 (ddd, J=13.73, 9.21, 4.64 Hz, 1H) 1.51 (m, 1H) 1.65 (m, 7H) 2.28 (dd, J=15.86, 8.78 Hz, 1H) 2.43 (dd, J=16.0, 4.00 Hz, 1H) 3.28 (m, J=8.97, 8.97, 4.39, 4.27 Hz, 1H) 3.69 (s, 3H). MS (APCI) m+1/z=256.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]([CH3:29])[CH2:26][C:27]#[CH:28].CO>C(N(CC)CC)C.C1C=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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:28]#[C:27][CH2:26][N:25]([CH3:29])[CH3:24])[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3cc(C#CCN(C)C)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 1-dimethylamino-2-propyne (90 μL, 0.84 mmol), 7.5 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are brought to pH 8 by adding 2 N sodium hydroxide. The aqueous layer is extracted with chloroform, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 225 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile as red crystals, mp 164-166° C.; 1H NMR (DMSO-d6) δ 2.21 (s, 6H), 3.53 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.77 (s, 1H); MS 429.3, 431.2 (M−H)−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=3)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].Cl>O1CCOCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][OH:40])=[CH:37][CH:38]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 34D (0.14 g) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (2 mL) and MeOH (0.5 mL). The solution was stirred for 1 hour at rt, concentrated under reduced pressure, and added 1.0 N LiOH (2 mL) in 1,4-dioxane (2 mL). The solution was stirred at 60° C. for 1 hour, concentrated under reduced pressure and purified by Prep HPLC to provide the desired product 34: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.69 (d, J=7.36 Hz, 1H), 7.29-7.49 (m, 8H), 4.90 (s, 2H), 4.50 (s, 2H), 3.78 (t, J=5.98 Hz, 2H), 3.98 (t, J=5.98 Hz, 2H); MS (ESI(+)): m/z 543 (M+H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[C:5]1([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:11]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]1)([O-:4])=[O:2].[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: O=[N+]([O-])O
Product: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=C(O)C1(c2ccccc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of fuming nitric acid (1.6 mL), at −30° C. and under nitrogen, was treated portionwise with 1-phenyl-cyclopropanecarboxylic acid (10 g). The reaction mixture was allowed to warm to 0° C., then stirred at this temperature for 2 hours and then poured into ice(100 g). The resulting solid was filtered, then washed well with water, then dried at 60° C. under vacuo and then recrystallised from toluene to give 1-(2-nitro-phenyl)-cyclopropanecarboxylic acid and 1-(4-nitro-phenyl)-cyclopropanecarboxylic acid (11.35 g). MS(ES−): 206 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[Zn][CH2:23][CH:24]([CH3:26])[CH3:25]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:23][CH:24]([CH3:26])[CH3:25])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)C[Zn]Br
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Yield: 22.1 %

Procedure:
To methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D19) (1.5 g, 4.85 mmol) was added bromo(2-methylpropyl)zinc (48.5 ml, 24.25 mmol) in tetrahydrofuran (50 ml) under argon. To the solution was then added 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.355 g, 0.485 mmol) and the reaction heated to reflux for 6 h. The mixture was quenched with water (2 mL) and then filtered through celite, washing with ethyl acetate. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the organic phase dried (phase separator) and the solvent removed in vacuo. The residue was purified by silica chromatography, eluting 0-15% EtOAc in iso-hexane over 40 min. Two batches were collected, one of which was the title compound as a colourless oil (233 mg, 1.072 mmol). δH (CDCl3, 400 MHz): 8.28 (1H, d), 8.15 (1H, dd), 7.38 (1H, d), 3.94, 3H, s), 2.78 (2H, d), 2.02 (1H, m), 0.96 (6H, d).
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C:9]1[C:14]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]3[CH2:24][CH:23]([C:25]([O:27]C)=[O:26])[NH:22][C:21]3=[O:29])=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>O.O1CCCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH:20]([C:21]([OH:29])=[O:1])[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:22])=[CH:30][CH:31]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCc1ccccc1-c1ccc(OC2CC(C(=O)OC)NC2=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc(CCCCCCc2ccccc2)cc1)C(=O)O)C(=O)O
Temperature: 58 °C
Reaction time: 3.8 h
Yield: 27.3 %

Procedure:
A mixture of lithium hydroxide (0.712 g) in water (9.3 ml) and tetrahydrofuran (29 ml) was treated with methyl 3-[4-(6-hexylphenyl)phenoxy]-2-pyrrolidone-5-carboxylate (3.91 g), and heated to 58° C. After about 3.8 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was then treated with 5N HCl (5.94 ml). The resulting light suspension was sonicated then stirred at room temperature for fifteen minutes . Insolubles were collected by filtration, washed with 1:1 tetrahydrofuran:water (10 ml), then tetrahydrofuran (10 ml) and finally water (10 ml). The title compound crystallized out from the filtrate and was collected by filtration. This material was dried in vacuo to give 1.077 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5](=C=O)[C@H:6](OC)[NH:7]2.[OH2:22].[OH-].[Li+].[O:25]1[CH2:29]CCC1>>[C:29]([C@H:6]1[CH2:5][C@H:4]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:25])=[O:22]
Reactant: O
Reactant: C1CCOC1
Reactant: CO[C@@H]1Nc2cc(Cl)cc(Cl)c2[C@@H](NS(C)(=O)=O)C1=C=O
Agent: [Li+]
Agent: [OH-]
Product: CS(=O)(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of trans-5,7-dichloro-2-methoxy-carbony-4-methylsulphonylamino-1,2,3,4-tetrahydro-quinoline (0.127 g, 0.36 mmol) in tetrahydrofuran (10 ml) was added water (5 ml) and aqueous lithium hydroxide (0.80 ml of a 0.5 M solution, 0.40 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. The organic solvent was removed in vacuo and to the aqueous residue was added dilute sodium hydrogen carbonate solution (40 ml). The mixture was washed with ethyl acetate (30 ml), the pH of the aqueous layer was adjusted to 1 with dilute hydrochloric acid and extracted with ethyl acetate (2×40 ml). The combined organic extracts were washed with brine (40 ml), dried (Na2SO4) and evaporated to give the crude product which was triturated with diethyl ether to give the title compound as colourless crystals (0.08 g, m.p. 194°-195° C.); δ (360 MHz, DMSO) 1.60 (1H, m, CHACHBHCCHD), 2.47 (1H, m, CHACHBHCCHD), 3.04 (3H, s, CH3), 4.00 (1H, m, CHACHBHCCHD), 4.65 (1H, m, CHACHBHCCHD), 6.64 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.76 (1H, br, s, ArNH), 6.84 (1H, d, J=1.9 Hz, 6-H or 8-H), 7.43 (1H, d, J=5.8 Hz, CHNHSO2CH3); m/e (FAB) 337 (M-1); Found: C, 39.13; H, 3.60; N, 8.02; C11H12Cl2N2O4S requires C, 38.95; H, 3.57; N, 8.26%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11]([O:14]C(=O)C)(=O)[CH3:12].[N+:18]([O-])([OH:20])=[O:19]>>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:18]([O-:20])=[O:19])[CH2:7][CH2:6][CH2:5]2)(=[O:14])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Amino-indan (3.00 g, 22.53 mmol) was added slowly to acetic anhydride (10 mL) cooled by an ice water bath. After 15 min., 70% HNO3 (3 mL, 46.99 mmol) was carefully added dropwise so that the temperature remained below 26° C. The mixture was allowed to slowly warm to room temperature and stirred for 2 days. It was then treated with ice water (60 mL) and extracted with EtOAc (3×20 mL). The extract was washed with water, Na2CO3 solution, dried (MgSO4), filtered and concentrated to give a dark oil (3.51 g). It was dissolved in CHCl3 and flash chromatographed over silica gel (180 g) eluting with EtOAc/hexane (1:10) to afford a yellowish orange solid (1.43 g, 29% yield): mp 100-104° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+].O1CCCC1>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.C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(F)cc4)nc23)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.412 mmol), 4-fluorophenylboronic acid (87 mg, 0.619 mmol), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.041 mmol), 4 mL of 2M aqueous sodium bicarbonate, and 30 mL of tetrahydrofuran were placed in a round bottom flask. The mixture was heated to reflux (about 75° C.) and allowed to stir for about 18 hours. The reaction was poured into 3:1 chloroform:isopropyl alcohol, extracted three times each with 1N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 0-10% methanol/dichloromethane) to give 87.9 mg of the title compound. (79%). MS(FD) m/e 309.6 (M+). EA calculated for C19H20FN3: C, 73.79; H, 6.47; N, 13.59. Found: C, 73.69; H, 6.73; N, 13.40.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:13]O.C([O-])=O.[Na+].O>C(O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: NO
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1c[nH]c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97 g) in 90% formic acid (25 mL) were added hydroxylamine (0.65 g) and sodium formate (0.81 g), and this mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, water was added to this reaction mixture and the precipitated solid was collected by filtration, and washed with water, dried to give the title compound (0.57 g).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:26])([F:25])[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:11]=[C:10]([NH2:24])[CH:9]=1.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>>[N+:27]([C:9]1[C:10]([NH2:24])=[N:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:21])[F:23])=[CH:13][C:8]=1[C:7]([F:6])([F:25])[F:26])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(C(F)(F)F)cc(-c2ccccc2C(F)(F)F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (10 mL) was placed in a 100 mL two-necked round-bottomed flask fitted with a magnetic stir bar and an internal thermometer and cooled to 0° C. 4-Trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (720 mg, 2.35 mmol, prepared as described in STEP C above) was added portion wise so that the internal temperature did not exceed 5° C. The resulting mixture was stirred at 0° C. for 1 h. Nitric acid (106 μL, 2.35 mmol) was added slowly, keeping the internal temperature below 10° C. The mixture was stirred an additional 2 h at 0° C., poured over ice water (100 mL), treated with 6 M aqueous NaOH to pH 10, and extracted twice with EtOAc (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a bright yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C13H7N3O2F6: 352.0 (M+H); Measured: 352.0.