Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of 2-methylpiperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained is poured, at this temperature, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. 5 g of potassium carbonate are added at about 20° C. and the mixture is extracted with 3 times 50 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 30 cm3 of ethanol. 1.6 g of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 240° C.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[C-]#N.[K+].[C:25]([Cu])#[N:26]>Cl.O.[O-]S([O-])(=O)=O.[Cu+2].CCOC(C)=O.C1(C)C=CC=CC=1>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:25]#[N:26])[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: N#C[Cu]
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)cc1C#N
Temperature: 60 °C

Procedure:
A suspension of methyl 2-amino-4-bromobenzoate (500 mg, 2.2 mmol) in 2 mL of conc. HCl was added 5 mL of water and a solution of NaNO2 (159 mg, 2.3 mmol) in water (1 mL) was added over a 10-minute period at 0° C. This diazonium solution was then brought to pH 6 with aqueous NaHCO3. In a separated vail, a solution of CuSO4 (660 mg, 2.75 mmol) in water (2 mL) was added dropwise to a solution of KCN (657 mg, 10.11 mmol) in water (2 mL) at 0° C., then toluene (5 mL) was added and the mixture was stirred and heated to 60° C. The previously prepared diazonium solution was added dropwise to the brown CuCN solution at 60° C. over 40 min. The reaction mixture was heated to 70° C. for 1 hour and cooled to room temperature, and EtOAc (100 mL) was added. The organic phase was washed with brine (20 mL) and concentrated. The crude product was purified via cprep-TLC to afford the methyl 4-bromo-2-cyanobenzoate. 1H-NMR (400 MHz, CDCl3) δ 7.75-7.95 (m, 3H), 3.93 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([NH:22][C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:12]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Product: O=C(NN1CCCCC1)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): 288.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.CS([Cl:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Cl:16])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc2c(c1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(c1)CCCC2Cl
Yield: 31.6 %

Procedure:
To 7.02 g of 3-methyl-5,6,7,8-tetrahydroquinoline was added dropwise 9.62 g of methanesulfonyl chloride under ice-cooled condition. The reaction mixture was stirred under ice-cooling condition for 2 hours, then further stirred at 80° C. for 3 hours. To the reaction mixture was added water, and this solution was made alkaline by adding sodium carbonate, then extracted with diethyl ether. The diethyl ether layer was washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, then thus obtained residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain 2.74 g of 3-methyl-8-chloro-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1([CH3:40])[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH2:22]([C:21]1[N:36]2[N:37]=[CH:38][N:39]=[C:35]2[N:34]([CH:32]2[CH2:31][CH2:30][O:29][C:28]([CH3:40])([CH3:27])[CH2:33]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)CC(Nc2nnc[nH]2)CCO1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (0.89 g) and N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 71%).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2].[Br:23]Br>C(Cl)Cl.BrBr>[CH2:1]([S:3]([CH:6]([Br:23])[C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2]
Reactant: BrBr
Reactant: CCS(=O)(=O)CC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)(=O)C(Br)C(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 66.6 %

Procedure:
N-(3'-Ethylthio-1',1'-dimethylacetonyl)-3,5-dichlorobenzamide (5.0 gm, 0.015 m) was taken in chloroform (200 ml) and meta-chloroperbenzoic acid (7.8 gm, 0.045 m) was added with stirring at room temperature for about 16 hours. The reaction mixture was transferred, with the use of ether (200 ml) as a rinse, to a separatory funnel. The organic solution was washed sequentially with sodium sulfite (2×100 ml), sodium bicarbonate (200 ml), water (100 ml) and brine (200 ml). The solvent was removed after drying over anhydrous sodium sulfate. Recrystallization using ethyl acetate and hexane (1:4) afforded 4.3 gm of 3-(3',5'-dichlorobenzoylamino)-2-oxo-3-methylbutyl ethyl sulfone. A portion of this sulfone (1.00 gm, 0.0027 mole)was taken in methylene chloride (50 ml) and bromine (0.13 ml, 0.003 mole) was added in one portion. Another 2-3 drops of bromine were added and the mixture was heated to reflux for about 1 hour. The solvent was removed and the resulting oil was recrystallized from hexane to obtain 800 mg of the desired product.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[NH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].[I-].[K+]>CO>[C:15]1([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]2[CH2:5][CH:4]=[CH:3][CH2:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClC/C=C\CCl
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: C1=CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 6.5 h
Yield: 49.4 %

Procedure:
cis-1,4-Dichloro-2-butene (15.4 g) was dissolved in methanol (100.0 mL). Aminodiphenylmethane (18.3 g), sodium acetate (16.4 g), and potassium iodide (1.0 g) were added to the solution, and the mixture was stirred at 65° C. for 6.5 hours. The reaction mixture was extracted with methylene chloride and 1 mol/L aqueous sodium hydroxide, and the organic layer was dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the residue, and the mixture was heated. The insoluble material was removed through filtration, and the filtrate was concentrated. The formed crystals were collected through filtration. The crystals were further washed with a small amount of isopropyl ether, to thereby give the target compound (11.62 g, yield 41%) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:33].C(OCC)(=O)C>>[ClH:33].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(-c3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(trans-2-{4-[(biphenyl-3-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (154 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (130 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([SH:40])[CH3:39].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([CH2:14][S:40][CH2:38][CH3:39])([OH:13])[C:15]([F:16])([F:17])[F:18]
Reactant: CCS
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 19.1 %

Procedure:
To 66 mg (0.14 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 and 93 mg (0.29 mmol) Cs2CO3 in 0.6 ml DMF are added 16 μl (0.22 mmol) of ethyl mercaptan in DMF. The mixture is stirred vigorously for 20 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (ethyl acetate) yields 14 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:5][CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CNc1ccc(CCCCOCCCCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1ccc(CCCCOCCCCCCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of Intermediate 56 (0.92 g, 3.3 mmol) in dichloromethane was treated successively with tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol), DMAP (50 mg), and triethylamine (1.4 mL, 10 mmol). After a few minutes, additional quantities of tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol) and triethylamine (1 mL) were added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as clear, colorless syrup (0.99 g, 76%). ES/MS calcd. for C23H44NO2Si+ 394.3. Found m/z=394.4 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]([CH3:31])=[N:18]2)=[O:13])C>CN(C=O)C>[CH3:9][O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]([CH:31]=[CH:3][N:4]([CH3:6])[CH3:5])=[N:18]2)=[O:13]
Reactant: CCOC(=O)c1ccn2nc(C)n(Cc3ccccc3)c(=O)c12
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2nc(C=CN(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 140 °C
Yield: 88.1 %

Procedure:
Dimethylformamide dimethylacetal (0.625 ml, 4.75 mmol) was added to a solution of 3-benzyl-2-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester (0.18 g, 0.58 mmol) in DMF (1.0 mL) with 4 Å molecular sieves and the reaction mixture was heated to 140° C. in a sealed tube for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (50 ml), the organic layer washed with LiCl (10%, 3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.18 g, 85%): 1H NMR (CDCl3) δ 7.46 (d, 1H, J=12.44 Hz), 7.25–7.33 (m, 5H), 7.19 (m, 1H), 6.99 (m, 1H), 5.30 (s, 2H), 4.58 (d, 1H, J=12.49 Hz), 3.90 (s, 3H), 2.85 (s, 6H); MS (ESI+) 353 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:23])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: C=Cc1cnc(NC(C)=O)cc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C=O)cn1
Reaction time: 4 h

Procedure:
To a stirred solution of N-(4-chloro-5-vinylpyridin-2-yl)acetamide (6 g, 30.5 mmol) and 2,6-lutidine (7.11 mL, 61.0 mmol) in a mixture of 1,4-dioxane (110 mL) and water (25 mL) at 0° C. was added osmium tetroxide (2.5% in 2-methyl-2-propanol, 9.58 mL, 30.5 mmol) followed by the addition of sodium periodate (19.58 g, 92 mmol) and the reaction was stirred for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, concentrated under reduced pressure and residue so obtained was purified by comb flash column 120 g silica column using hexane/EtOAc as eluant. The desired product was isolated at 30% EtOAc in hexane. The required fractions were concentrated under reduced pressure to yield N-(4-chloro-5-formylpyridin-2-yl)acetamide as a off-white solid (5.8 g, 28.1 mmol, 92% yield). LC/MS (ESI) m/e 197.0 [(M)−, calcd for C8H6ClN2O2 197.04] LC/MS retention time (method A): tR=1.21 min; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.18 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16](=O)[CH:15]=[CH:14][NH:13][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[S:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2csc3[nH]ccc(=O)c23)c1
Product: COc1cccc(-c2csc3nccc(Cl)c23)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A mixture of 3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4(7H)-one (Description 42) (465 mg, 1.807 mmol) and phosphorus oxychloride (5 mL, 53.6 mmol) was heated at 110° C. for 1 h. After cooling to RT, the mixture was poured onto ice, stirred for 30 min and then extracted with DCM (10 mL×3). The organic layers were combined, washed with saturated NaHCO3 solution (100 mL), brine (100 mL), filtered through phase separator and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (424 mg). LCMS (A) m/z: 278 [M+1]+, Rt 1.33 min (acidic).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]3)[CH2:24][CH2:25]2)=[CH:18][CH:19]=1)[CH3:12]
Reactant: CCNc1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCCl)OC1=O
Product: CCNc1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 1-(4-ethylaminophenyl)piperazine.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCCN1CCCC1
Product: COc1cc(NCCN2CCCC2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 58 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-aminoethyl)pyrrolidine instead of thiomorpholine to the title compound (145 mg, 58%) which was obtained as an off-white solid. MS: m/e=464.2 [M+H]+.
Reaction SMILES: CCCCCC.[H-].[K+].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([N:27]=[C:28]=[S:29])[CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([NH:27][C:28]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]([CH3:19])=[C:10]2[CH3:9])=[S:29])[CH:26]=1
Reactant: Cc1[nH]c2ccccc2c1C
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cl)cc1NC(=S)n1c(C)c(C)c2ccccc21
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A stirred slurry of hexane washed potassium hydride (1.38 g, 34.5 mmol) in 10 mL of dry THF was treated dropwise with a solution of 2,3-dimethylindole (5.0 g, 34.5 mmol) in 30 mL THF. The mixture was stirred until a clear solution was obtained. A solution of 5-chloro-2-methylphenylisothiocyanate (6.3 g, 34.5 mmol) in 5 mL THF was slowly added and stirring was continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid was triturated with Et2O-hexane overnight to provide 7.5 g of the title compound as a light yellow solid, m.p. 115° C. (67% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)=[N:11][S:12][N:13]=2)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=1>CCOC(C)=O.CN(C=O)C>[F:56][C:57]([F:65])([F:66])[C:58]1[CH:59]=[C:60]([NH:64][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:10]3[C:9]([O:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:13][S:12][N:11]=3)[CH2:19][CH2:18]2)=[O:22])[CH:61]=[CH:62][CH:63]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C1CCN(c2nsnc2OCc2ccncc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (280 mg, 0.87 mmol), HATU (328 mg, 0.86 mmol), DMF (1.5 mL) and DIEA (0.5 mL, 3.87 mmol) were combined and vortexed until a homogeneous mixture was obtained. 3-Trifluoromethyl-phenylamine (0.109 mL, 0.87 mmol) was added and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 100 mg (25%) of 1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CD3OD) 8.54 (d, 2H), 8.02 (s, 1H), 7.74 (d, 1H), 7.51-7.46 (m, 3H), 7.36 (d, 1H), 5.57 (s, 2H), 4.32 (m, 2H), 3.00 (m, 2H), 2.64 (m, 1H), 1.96-1.90 (m, 4H) ppm. LC-MS (MH+)=464.
Reaction SMILES: Cl.[F:2][C:3]([C:26]1[CH:27]=[C:28]2[CH2:51][C@@:33]3([C:41]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[N:35](COCC[Si](C)(C)C)[C:34]3=[O:50])[CH2:32][C:29]2=[N:30][CH:31]=1)([F:25])[CH2:4][NH:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]([CH3:18])[N:8]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:7]1=[O:24].[OH-].[NH4+]>CO>[F:2][C:3]([C:26]1[CH:27]=[C:28]2[CH2:51][C@@:33]3([C:41]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:50])[CH2:32][C:29]2=[N:30][CH:31]=1)([F:25])[CH2:4][NH:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@@H:9]([CH3:18])[N:8]([CH2:19][C:20]([F:23])([F:21])[F:22])[C:7]1=[O:24]
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NCC(F)(F)c2cnc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NCC(F)(F)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
HCl gas was bubbled into a solution of (6S)-3-(1,1-difluoro-2-(((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)ethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.012 g, 0.017 mmol) in MeOH (3 mL) cooled to 0° C. until saturated. The resulting mixture was stirred at 0° C. for 1 h and then concentrated to dryness in vacuo. To a solution of this crude mixture in MeOH (5 mL) was added ammonium hydroxide (0.047 mL, 0.335 mmol), and the reaction was stirred at ambient temperature for 30 min. The reaction was concentrated to dryness in vacuo. The crude product was purified by reverse-phase HPLC, eluting with 10% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 80% acetonitrile in water, to give the title compound. MS: m/z=586.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 8.04 (d, 1H, J=7.0 Hz), 8.00 (s, 1H), 7.90 (bs, 1H), 7.61 (d, 1H, J=7.0 Hz), 7.40-7.29 (m, 3H), 7.26-7.10 (m, 3H), 4.87-4.81 (m, 1H), 4.07 (dd, 1H, J=11.4, 6.8 Hz), 3.98 (s, 2H), 3.90-3.75 (m, 3H), 3.73 (d, 1H, J=17.6 Hz), 3.57-3.48 (m, 2H), 3.38 (d, 1H, J=17.1 Hz), 3.35-3.27 (m, 1H), 2.63 (dt, 1H, J=12.5 Hz), 2.49-2.47 (m, 1H), 0.98 (d, 3H, J=6.5 Hz).