Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:15]#[N:16])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[NH:12][C:15]=1[NH2:16])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C#N)c1ccncc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)[nH]c2cnccc12
Temperature: 95 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A solution of cyano-(3-nitro-pyridin-4-yl)-acetic acid ethyl ester (2.50 g, 10.6 mmol) in 20 mL acetic acid was heated to 80° C. under nitrogen. Zinc powder was added in 500 mg portions over 20 minutes and the reaction mixture was then heated to 95° C. and stirred for 1 hour. Upon cooling, the insoluble material was removed by filtration and washed with acetic acid. The resulting filtrate was concentrated in vacuo and the residue treated with saturated sodium bicarbonate solution to give a light brown solid which was collected by filtration and dried in vacuo to a constant weight to give the title compound (2.02 g, 93%). 1H NMR (DMSO) δ 11.0 (1H, s, br), 8.31 (1H, br), 8.0 (1H, br), 7.41 (1H, d, J=4.7), 7.0 (2H, br s), 4.23 (2H, q, J=7.1), 1.32 (3H, t, J=7.1).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1SC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CS>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Reactant: C1COCCN1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1

Procedure:
4.1 g of 1,3-bis(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate in 25 ml of absolute acetonitrile are treated under an argon atmosphere with 1.45 g of absolute morpholine, whereby the evolution of methylmercaptan sets in immediately and solution occurs. The solution is left to stir overnight at room temperature until the cleavage of methylmercaptan is complete. The resulting colorless precipitate is removed by filtration. The filtrate is treated with 30 ml of diethyl ether and again filtered. The two filter residues are combined and reprecipitated from acetonitrile/ether. There is obtained 1,3-bis(benzylideneamino)-2-morpholinoimidazolium tetrafluoroborate in the form of colorless crystals of m.p. 244°-247° (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[NH4+].[Cl-].[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: CC(=O)Nc1cc(Cl)nc(C)n1
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2ccncc2Cl)nc(C)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of N-(6-chloro-2-methylpyrimidin-4-yl)acetamide (228 mg, 1228 μmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (294 mg, 1228 μmol, Combi-Blocks, Inc., San Diego, Calif.), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (100 mg, 123 μmol), cesium carbonate (197 μl, 2457 μmol), dioxane (4 mL) and water (0.5 mL) was stirred at 100° C. for 30 min. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give N-(6-(3-chloropyridin-4-yl)-2-methylpyrimidin-4-yl)acetamide (102 mg, 31.6% yield). 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H); 8.56 (d, J=5.41 Hz, 1H); 8.34 (s, 1H); 7.94 (s, 1H); 7.44 (d, J=5.26 Hz, 1H); 2.69 (s, 3H); 2.25 (s, 3H). m/z (ESI, +ve ion) 263 (M+H)+.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]1([CH2:19][CH2:18][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)C1CCN(C(=O)CCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCN(C(=O)CCc2ccccc2)CC1
Yield: 59.7 %

Procedure:
Pd/c (528 mg) was added to a stirred solution of 1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid benzyl ester (2.64 gm, 7.5 mmol) in MeOH (52.8 mL) and continued the stirring under hydrogen atmosphere for 3 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure to afford 1.17 g (59.6% yield) of 1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid. LCMS Purity: 93.56%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1([C:17](O)=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1>CCOCC>[NH2:7][C:8]1([CH2:17][OH:18])[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC1(CO)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (1 M solution in ether, 23.7 ml, 23.7 mmol) is added to a solution of 2-aminoindan-2-carboxylic acid (J. Med. Chem. 1991, 34, 3125; 2.26 g, 12.8 mmol) in ether (150 ml). The reaction is stirred for 2 hours at ambient temperature and quenched sequentially with water (0.9 ml), 2 M NaOH (0.9 ml) and further water (0.9 ml). MgSO4 is added and the resultant suspension is filtered. The filtrate is evaporated to afford (2-aminoindan-2-yl)methanol, MH+164.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[NH3:22]>CO.[Cu]Br>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:4]=[N:3][C:2]([NH2:22])=[CH:7][CH:6]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Reactant: N
Agent: [Cu]Br
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
3-Iodo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (example 15a) (200 mg, 0.5 mmol) was dissolved in a solution of ammonia in methanol (7 M, 3 mL). After addition of copper(I) bromide (88 mg, 0.6 mmol) the mixture was stirred for 16 h at room temperature. The precipitate was filtered and the organic phase was adsorbed on silica. Chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (66 mg, 46%) as a light yellow solid. MS: m/e=283.1 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@H](O)C(C)C
Reactant: Cc1ccc(Cl)c(O)c1
Product: COC(=O)[C@@H](Oc1cc(C)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:15][Si]([Cl:19])(C)C>CO>[ClH:19].[NH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O:8][CH3:15])=[O:7]
Reactant: C[Si](C)(C)Cl
Reactant: NCCC(C(=O)O)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCN)c1ccccc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of 1 g (4.64 mmol) of 4-amino-2-phenylbutyric acid hydrochloride and 0.67 ml (5.1 mmol) of trimethylsilyl chloride in 50 ml of methanol is heated at reflux for 2 hours. The mixture is subsequently stirred at 20° C. for 12 hours and then concentrated under reduced pressure, triturated in 50 ml of ethyl ether and then filtered. This gives 0.9 g of the expected product in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][C:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28](O)[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (9.6 ml) was added to a solution of 2-(tert-butyloxycarbonyl)-5-hydroxy-2,3-dihydro-1H-isoindole (12.2 g) and triethylamine (8.7 ml) at −20° C. under argon. The reaction was stirred overnight at room temperature, then the crude product isolated by extraction and chromatographed to give 2-(tert-butyloxycarbonyl)-5-trifluoromethanesulfonyloxy-2,3-dihydro-1H-isoindole (12.7 g), which was dissolved in DMF (180 ml). To this solution was added zinc cyanide (3.7 g) and tetrakis-triphenylphosphine palladium (0) (3.7 g) and the mixture was heated at 100° C. for 4 h. Work-up and chromatography on silica gel gave the title compound as a solid (7.6 g, 83%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2]>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(N)cc1C#N
Yield: 95.5 %

Procedure:
A solution of 6A (0.554 g, 2.31 mmol) in MeOH (60 mL) was hydrogenated (60 psi) over 10% palladium on carbon (99 mg) for 3 h at rt. The reaction mixture was filtered and concentrated under reduced pressure to give 6B (464 mg, 96%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.25 Hz, 3H), 3.30 (q, J=7.47 Hz, 2H), 4.62 (s, 2H), 6.89 (dd, J=8.79, 2.64 Hz, 1H), 7.04 (d, J=2.20 Hz, 1H), 7.83 (d, J=8.79 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C.Cl.[CH2:39]([C:41]1[C:42]([NH:51][C@H:52]2[CH2:56][CH2:55][CH2:54][C@@H:53]2[NH2:57])=[N:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=1)[CH3:40]>C(Cl)Cl>[CH2:39]([C:41]1[C:42]([NH:51][C@H:52]2[CH2:56][CH2:55][CH2:54][C@@H:53]2[NH:57][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=1)[CH3:40]
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1cc(F)ccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 88 h

Procedure:
To a solution of 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 53 mg, 0.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (33 mg, 0.24 mmol), EDC (46.3 mg, 0.241 mmol) and triethylamine (0.067 ml, 0.48 mmol) in DCM (5 ml) was added (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 50 mg, 0.161 mmol). The reaction mixture was stirred at room temperature for 88 hours and then partitioned between DCM and a saturated solution of sodium bicarbonate, passing through a hydrophobic frit. The organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. This was then purified by reverse phase chromatography (C18 silica, 0-100% acetonitrile/water with 0.1% ammonia). The resulting aqueous was concentrated in vacuo and extracted with DCM. The organics were concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 81.1 %

Procedure:
4-Fluorotoluene (14 g) is added slowly with stirring to a solution of fuming nitric acid (18 g) and concentrated sulfuric acid (30 g) over 30 minutes and alternately warmed and cooled to keep the temperature between 40 and 50° C. This is followed by heating at 100° C. for 30 minutes more. The organic material is cooled and extracted with methylene chloride to give 16 g of 4-fluoro-2-nitrotoluene.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]I)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C-:30]#[N:31].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][C:30]#[N:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-iodomethyl-4-benzoyloxypyrrolidine (5.24 g) was dissolved in 26 ml of dry dimethylformamide, and 539 mg of sodium cyanide was added thereto, followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-cyanomethyl-4-benzoyloxypyrrolidine
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17](I)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36](B4OC(C)(C)C(C)(C)C4)=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17]([C:36]4[CH:35]=[C:34]5[C:39]([CH:40]=[CH:41][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:33]5)=[CH:38][CH:37]=4)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](CN2CCC2)C1
Temperature: 80 °C

Procedure:
To the DMF solution from the preparation of cis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine were added 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (40 mg, 0.12 mmol), Na2CO3 (27 mg, 0.25 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and water (0.6 mL). The solution was purged with nitrogen for 10 min and heated to 80° C. for 16 h. To the cooled reaction solution was added sat. Na2CO3 solution (10 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (3×15 mL) and brine, dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by HPLC gave the title compound as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.06-2.26 (m, 5H), 2.56-2.57 (d, 2H, J=6.2), 2.71-2.77 (m, 2H), 3.21-3.24 (m, 4H), 5.17 (brs, 2H), 5.19-5.26 (m, 1H), 7.31 (s, 1H), 7.46-7.56 (m, 3H), 7.69-7.71 (dd, 1H, J=1.6 & 8.4 Hz), 7.90-7.94 (m, 2H), 8.18-8.20 (m, 2H), 8.26-8.29 (m, 2H), 8.35 (s, 1H). MS (ES+): 461.2 [MH+]. HPLC: tR=2.0 min (polar—5 min).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=1)[CH3:7].N1C(C)=CC=CC=1C.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=1[NH2:40]>CC(N(C)C)=O>[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=2[C:37]([F:36])([F:45])[F:46])=[O:17])=[CH:13][N:12]=1)[CH3:7]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
An ice-cold solution of methane sulfonyl chloride (18 μL, 0.23 mmol) in DMA (2.0 mL) was stirred for 10 min followed by sequential drop wise addition of a solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol) in DMA (5.0 mL) and 2,6-lutidine (55 μL, 0.46 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min followed by addition of a solution of 2-trifluoromethyl aniline (31 μL, 0.25 mmol) in DMA (1.0 mL). The reaction mass was further stirred at RT ° C. for 10 min and then heated at 50° C. for 4 h. The reaction mass was then cooled to 0-5° C. and quenched with H2O (5.0 mL), followed by addition of conc. HCl (0.50 mL). The resulting solution was stirred for 5 min followed by extraction with EtOAc (3×50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via preparative TLC to obtain Compound 11 (5.0 mg, 8%). 1H NMR (300 MHz, DMSO-d6): δ 10.23 (br s, 1H), 10.07 (br s, 1H), 9.12 (br s, 1H), 8.61 (s, 1H), 7.89 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74 (m, 1H), 7.57 (m, 2H), 7.38-7.43 (m, 2H), 7.31 (s, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 3.14 (m, 2H) and 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=444.17.
Reaction SMILES: [CH:1](=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[C:7]1([S:13]([C:16]#[N:17])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.B(O)(O)O>C(O)CCC>[C:7]1([S:13]([C:16]2[CH:4]=[C:3]([CH3:5])[CH:2]=[CH:1][N:17]=2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=CC=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: OB(O)O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1ccnc(S(=O)(=O)c2ccccc2)c1
Temperature: 119 °C
Yield: 72.9 %

Procedure:
First, 9.00 g (107 mmol) of senecialdehyde (3-methyl-2-butenal) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.30 g (4.85 mmol) boric acid were added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.50 g of 2-benzenesulfonyl-4-methylpyridine with the following properties as colorless crystals (purity of 99%, yield of 72% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:15]([F:18])([F:17])[F:16])[OH:12]
Reactant: COc1cccc2c1CCC2=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1CCC2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59522.8 %

Procedure:
To an ice-cold suspension of 4-methoxy-indan-1-one (200 mg, 1.23 mmol) and trimethyl(trifluoromethyl)silane (218 mg, 1.48 mmol) in THF (4 mL) was added 1M-TBAF (615 mL, 0.615 mmol) at 0° C. The mixture was stirred overnight at room temperature, and then diluted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated tinder reduced pressure. The crude residue was purified by column chromatography to give 4-methoxy-1-trifluoromethyl-indan-1-ol (170 g, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(SC)c2ccc(Cl)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added MeI (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.