Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:5][C:4]([NH:32]C(=O)OC(C)(C)C)([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]4[C:18]5=[N:28][N:29]=[C:30]([OH:31])[N:17]5[CH:16]=[CH:15][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:32][C:4]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]4[C:18]5=[N:28][N:29]=[C:30]([OH:31])[N:17]5[CH:16]=[CH:15][C:14]=4[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][C:2]([F:1])([F:40])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CC(F)(F)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl {3,3-difluoro-1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (5-20) (11 mg, 0.021 mmol) in CHCl3 (0.5 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-[4-(1-amino-3,3-difluorocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol (5-21) as a yellow oil. HRMS (M+H)+: observed=444.1636, calculated=444.1653.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.[CH3:15][NH2:16]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:16][CH3:15])=[O:14])=[CH:7][CH:6]=[CH:5]2
Reactant: CN
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: CNC(=O)c1cccc2cc(O)ccc12

Procedure:
Prepared from 6-hydroxy-1-naphthoic acid and methylamine using the method of preparation 57 to give the title compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:17][C:16]=3Cl)=[O:11])=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=[CH:17][CH:16]=3)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(Cl)ccc(C(F)(F)F)c2c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cccc(C(F)(F)F)c2c1O
Temperature: 190 °C
Yield: 3.4 %

Procedure:
N-((4-Chlorophenyl)methyl)-8-chloro-4-hydroxy-5-trifluromethyl-3-quinoline-carboxamide (2.00 g) from Example No. 59 is dissolved in glacial acetic acid (100 mL) along with NaOAc·3H2O (937 mg) and 5% palladium on carbon (666 mg). The mixture is placed under hydrogen pressure (25 psi) in a Parr hydrogenator for 3 h. The reaction mixture is filtered through a plug of celite, concentrated, suspended in water (30 mL), and filtered. The resulting solid (500 mg) and 4-chlorobenzylamine (2.13 mL) are then heated at 190° C. for 1 h. The crude product is purified by column chromatography (dichloromethane/methane, 50/1) to afford 62 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH:10]([C:12]1[N:13]=[CH:14][N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH2:10][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1
Reactant: CCc1cccc(Cl)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(Cl)c1Cc1c[nH]cn1
Reaction time: 16 h

Procedure:
Prepared in analogy to Example 57(e) from rac-(2-chloro-6-ethyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol, triethylsilane and trifluoroacetic acid in dichloromethane, except that the reaction was carried out in a pressure tube at 70° C. for 16 h. White crystalline solid. MS (ISP): 223.3 ([{37Cl}M+H]+), 221.2 ([{35Cl}M+H]+).
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.C(OC=C)(=O)CCCCC.C1C(CCCCC(N)=O)SSC1>C(OC(C)C)(C)C>[OH:1][C@@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)C1=CCOCC1O
Agent: C=COC(=O)CCCCC
Agent: NC(=O)CCCCC1CCSS1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C1=CCOC[C@@H]1O
Temperature: 35 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
To a solution (380 mL) of ethyl 3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (91.2 g) in diisopropyl ether were added vinyl hexanoate (150 mL) and Lipozyme IM (4.8 g). The reaction mixture was stirred at 35° C. for 24 hr and the insoluble material was filtered off. The obtained filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=6:1→1:1) to give the title compound (45.9 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2Cl.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(Br)cccc2c1NCc1ccc(OC)cc1
Temperature: 120 °C
Yield: 50.5 %

Procedure:
To a solution of ethyl 8-bromo-4-chloroquinoline-3-carboxylate (1.8 g, 5.72 mmol) in DMF (10 mL) were added p-methoxybenzyl amine (860 mg, 6.27 mmol) and DIPEA (2.22 g, 17.21 mmol) and the reaction mixture was heated at 120° C. for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.11 (br s, 1H), 8.89 (s, 1H), 8.46-8.43 (d, J=8.7 Hz, 1H), 8.12-8.09 (d, J=7.8 Hz, 1H), 7.38-7.33 (t, J=8.4 Hz, 1H), 7.27-7.24 (d, J=8.4 Hz, 2H), 6.91-6.89 (d, J=8.1 Hz, 2H), 8.17 (d, 2H), 4.26-4.24 (q, J=7.2, 14.1 Hz, 2H), 3.72 (s, 3H), 1.29-1.24 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7](Cl)=[O:8])=[O:4].O[NH:11][C:12](=[NH:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(#N)C.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[N:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[O:8][N:22]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CC(=N)NO)cc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)CCc1nc(Cc2ccc(OC)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
3-Methoxycarbonylpropionyl chloride (4.5 g) was added dropwise to a mixed solution of N-hydroxy-2-(4-methoxyphenyl)ethaneimidamide (3 g) in acetonitrile (20 ml) and pyridine (5 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, which was diluted with ethyl acetate. The reaction mixture was washed twice with 2N hydrochloric acid and water, then dried and concentrated. The obtained residue was dissolved in pyridine (20 ml) and stirred under heating at 100° C. for 18 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain methyl 3-[3-(4-methoxyphenyl)methyl-1,2,4-oxadiazol-5-yl]propionate (2.5 g).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])=[O:19])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1ccccc1O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 2-aminophenol (27 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-hydroxyphenyl)benzamide as an off-white solid. Yield: 23 mg (23%). 1H-NMR: 9.72 (br s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.24-7.02 (m, 4H), 6.91 (dd, J=8.0, 1.0 Hz, 1H), 6.81 (dt, J=8.0, 8.0, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]#[N:15].C(=O)([O-])[O-:17].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:15])=[O:17]
Reactant: N#Cc1c(Nc2cccnc2)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile (100 mg) in DMSO (5 mL), added potassium carbonate (0.50 eq., 50 mg), then added hydrogen peroxide solution (40 uL of 50% solution in H2O) dropwise over ice bath over the course of 10 minutes. After the final addition, kept on ice bath for 2 hrs, then heated to room temperature and stirred until complete by TLC. After 24 hrs, reaction was incomplete so additional (120 uL) hydrogen peroxide was added and reaction was heated to 50 degrees C. Reaction was complete by TLC after 3 days of stirring at 50 degrees C. and was poured into 20 mL of ice water but no precipitate was observed. Extracted with EtOAc three times, washed with brine and dried with MgSO4. Volatiles were removed via vacuo. 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide was obtained as a brown oil (100 mg, 92% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.8 %

Procedure:
To a suspension of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (0.640 g, 2.29 mmol) (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (0.700 g, 2.30 mmol) (prepared in this example, step (d)) in DCM (12 mL) was added DIPEA (0.800 mL, 4.60 mmol) and PyBroP (1.29 g, 2.76 mmol) and the mixture allowed to stir at RT for 10 h. The mixture was diluted with DCM (50 mL) and washed with NaHCO3 (2×50 mL) and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 1:1 DCM/hexanes to give 1.04 g (86%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C25H33BrN4O2Si, 529.1 (M+H), found 529.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl>[Cl:17][C:15]([N:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(NCCC(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(N(CCC(=O)O)C(=O)Cl)cc1
Yield: 99.5 %

Procedure:
By working in a manner similar to that described in Example 6, but starting from 3-(4-methoxyanilino)propionic acid (2.88 g; 14.7 mmol), methylene chloride (20 cc) and phosgene (4.3 g; 43.5 mmol), almost pure N-chloroformyl-3-(4-methoxyanilino)propionic acid (3.77 g) is obtained in the form of a white powder which melts at 90° C. After recrystallisation in a hexane/ethyl acetate mixture (50:50 by volume), the product melts at 93° C. The structure of the product obtained is confirmed by the infrared spectrum, mass spectrum and proton nuclear magnetic resonance spectrum.
Reaction SMILES: Cl[P:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([CH3:6])([CH3:5])[CH3:4].Cl.C1(C)C=CC=CC=1>CN(C)C=O.[Zn]>[C:3]([PH:2][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)PC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
0.849 g (4.70 mmol) of chloro-di-t-butylphosphine was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at room temperature for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, and the toluene layer was determined by gas chromatography, giving di-t-butylphosphine in 25% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: BrCCCCCBr
Product: Cc1ccc(CCOCCCCCBr)cc1

Procedure:
(17.9 g) as a colourless oil, from 4-methylbenzeneethanol (10.0 g) and 1,5-dibromopentane (50.7 g) with stirring at room temperature for 72 h. T.l.c. (ER-CX 1:19) Rf 0.29.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH:18]=C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:22]C(C)=O>CC(C)=O.O.CCCCCC.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:18]=[O:22])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred mixture of (2-(benzyloxy)-3-nitro-6-vinylpyridine (0.5 g, 0.0019 mol) in acetone:water (1:1, 5 mL), was added OsO4 (16.39 mg, 0.000064 mol, Aldrich) and NaIO4 (1.67 g, 0.0078 mol, Aldrich). The reaction mixture was stirred for 4 h at room temperature. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (5 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and purified by column chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in petroleum ether as an eluent to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 10.00 (s, 1H), 8.38 (d, J=6 Hz, 1H), 7.69 (d, J=6 Hz, 1H), 7.54 (d, J=5.7 Hz, 2H), 7.41-7.37 (m, 3H), 5.69 (s, 2H).
Reaction SMILES: [N:1]1([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl>C(O)C>[NH2:13][C:12]1[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCO
Product: Nc1cccnc1N1CCNCC1

Procedure:
2-(1-piperazinyl)-3-nitropyridine (24.50 g), ethanol (445 ml) and hydrochloric acid (1.2N, 44 ml) are combined and hydrogenated overnight at 40 psi, refilling when necessary. The mixture is filtered through celite, washed with ethanol, chloroform, ethanol and water. The organic solvents are removed with heat and reduced pressure. The remaining material is partitioned between methylene chloride (3×250 ml) and sodium bicarbonate. The organic layers are combined, dried over potassium carbonate, filtered and concentrated under reduced pressure to give an oil which slowly solidified upon standing to give 3-amino-2-(1-piperazinyl)pyridine.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH:9]=1)=[O:6]
Reactant: Cc1cn(-c2nccc3ccccc23)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2nccc3ccccc23)cc1C(=O)Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added at a temperature in the region of 20° C. under an argon atmosphere to 1.1 g (4.36 mmol) of 3-carboxy-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole dissolved in 20 mL of chloroform. After stirring at the reflux point of the solvent for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and is then brought back to dryness to give 1.18 g (4.36 mmol) of 3-chlorocarbonyl-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole in the form of a beige-coloured solid which is used directly in the following step.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P:10](=[O:11])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: CCOP(=O)(CCCCCOC(C)=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CCCCCO)OCC

Procedure:
92 g (0.345 mol) of 5-(diethylphosphono)pentyl acetate were heated at 50° C. for 10 hours with stirring with 74 g (0.7 mol) of finely powdered sodium carbonate in 500 ml of methanol. The solution was filtered, concentrated and distilled in a bulb tube.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34](O)=[O:35]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:34](=[O:35])[C:33]4[C:37]([CH3:41])=[CH:38][CH:39]=[N:40][C:32]=4[CH3:31])[CH2:22][CH2:21]3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1
Product: Cc1ccnc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1
Yield: 32.7 %

Procedure:
Using general procedure E, 3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 273) (139 mg, 0.32 mmol) and 2,4-dimethylnicotinic acid (53 mg, 0.35 mmol) afforded COMPOUND 274 as a white solid (59 mg, 32%). 1H NMR (CDCl3) δ 0.84-1.19 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.45-1.62 (m, 3H), 1.66-1.79 (m, 1H), 1.89-1.99 (m, 2H), 2.31 (s, 3H), 2.36 (t, 1H, J=11.7 Hz), 2.54 (s, 3H), 2.68-2.81 (m, 3H), 3.02 (s, 3H), 3.26-3.34 (m, 1H), 3.49 (s, 2H), 3.80-3.89 (m, 1H), 6.78-6.88 (m, 3H), 7.00 (d, 1H, J=4.8 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.91 (d, 2H, J=7.8 Hz), 8.05 (br s, 1H), 8.42 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.58, 19.20, 22.67, 25.88, 26.50, 31.68, 40.00, 44.24, 44.80, 45.65, 52.34, 60.55, 109.09, 117.67, 122.11, 122.92, 127.29, 127.63, 134.00, 141.22, 144.09, 146.41, 147.20, 149.23, 154.55, 168.70. ES-MS m/z 564 (M+H). Anal. Calcd. for C31H37N3O5S.1.0CH2Cl2.0.3H2O: C, 58.77; H, 6.10; N, 6.42. Found: C, 58.42; H, 5.79; N, 6.37.
Reaction SMILES: [C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:20]1(C=CC(O)=CC=1)O.S(=O)(=O)(O)O>CO>[C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([O:8][CH3:20])=[O:7])(=[O:3])[CH3:2]
Reactant: Oc1ccc(O)cc1
Reactant: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=C(C)C(=O)NC1=CC(C(=O)OC)C(O)(C(C)=O)C=C1

Procedure:
To a solution of 2-acetyl-5-methacrylamidosalicylic acid and 1% by weight of hydroquinone in methanol was added 0.5% by weight of concentrated sulfuric acid, and the solution was subject to reflux for several hours. After evaporating the solvent, the remaining residue was recrystallized by a mixture of water and methanol to give methyl 2-acetyl-5-methacrylamidosalicylate.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 85.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the crude 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.236 mmol) prepared in Example 88h, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (98 mg, 80%, 2 steps) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:22]2(O)[CH2:25][O:24][CH2:23]2)=[CH:9][C:10]=1[F:21].C(N(S(F)(F)[F:34])CC)C>C(Cl)Cl>[F:21][C:10]1[C:11]2[O:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:6]=2[CH:7]=[C:8]([C:22]2([F:34])[CH2:25][O:24][CH2:23]2)[CH:9]=1
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(O)COC3)cc(F)c1O2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(F)COC3)cc(F)c1O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a RBF was added (S)-3-(2-amino-5′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)oxetan-3-ol (0.28 g, 0.75 mmol, prepared as described in Method CCl4) and DCM (5 mL). The resulting mixture was then cooled to 0° C. and (diethylamino)sulfur trifluoride (0.20 mL, 1.50 mmol, Alfa Aesar) was added drop wise. The mixture was then stirred at 0° C. for 15 min and at room temperature for 15 min. Then, the mixture was quenched with saturated sodium bicarbonate (5 mL). The mixture was stirred at 0° C. for 5 min and at RT for 5 min. Then, the organic layer was collected and the aqueous layer was extracted with DCM (1×10 mL). The combined organic extracts were dried over MgSO4 and silica gel was added. The solvent was removed and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 20-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 375 (M+H).