Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:29]=1)[CH:27]=[O:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:22]3[CH:29]=[C:26]([CH:27]=[O:28])[CH:25]=[N:24][CH:23]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: O=Cc1cncc(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A flask is charged with N-(tert-butoxycarbonyl)-6-chloro-1H-indol-2-ylboronic acid (8.3 g, 28.1 mmol), 5-bromonicotinaldehyde (4.35 g, 23.4 mmol), K3PO4 (9.94 g, 46.8 mmol), s-Phos (0.480 g, 1.170 mmol) and Pd2(dba)3 (0.429 g, 0.468 mmol), and the flask is flushed with N2. Toluene (250 mL) is added, and the mixture is heated to 85° C. for 1.5 h. The mixture is cooled to room temperature. Ethyl acetate (250 mL) is added and the mixture is filtered through a pad of silica gel, which is washed with EtOAc. Silica gel is added to the combined filtrate, which is concentrated in vacuo. The residue is placed under high vacuum at 63° C. overnight, and after elution with ethyl acetate, 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde is obtained. MS (ESI) m/z 257.0 and 258.9 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][S:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSCCCl
Solvent: ClCCl
Product: COC(=O)CS(=O)CCCl
Reaction time: 0.5 h

Procedure:
3-Chloro-peroxybenzoic acid (81%, 4.7 g, 0.022 mole) was added to the title compound of Example 10 (3.7 g, 0.022 mole) in cold (5° C.) methylene chloride (75 ml) stirred for 30 minutes and cooled in a refrigerator for 48 hours. After removing the solid by filtration, a saturated solution of sodium thiosulfate (30 ml) was added and the mixture stirred for 15 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2×50 ml), dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was crystallized from ethyl acetate and hexane to give a white solid which was identified as the title compound by its NMR and IR spectra.
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[C-:13]#[N:14].[Na+].O.[OH-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[C:13]([C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2])#[N:14]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 150 °C
Yield: 64 %

Procedure:
3,4-Methylenedioxynitrobenzene (1.67 g, 10.0 mmol) was dissolved in 20 mL of HMPA and sodium cyanide (0.49 g, 10.0 mmol) was added. The reaction was heated to 150° C. under nitrogen and three portions of sodium cyanide (0.245 g, 5.00 mmol, total) were added over 15 min. The reaction was maintained at 150° C. for 45 min, cooled, and poured into 50 mL of H2O followed by the addition of 50 mL of 5% NaOH. The aqueous layer was extracted with ether (2×25 mL) and the organic layer was discarded. The basic aqueous layer was carefully acidified to pH 4 by addition of 10% HCl and extracted with ether (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave 1.05 g (64%) of compound 477A as a yellow-brown solid. HPLC: 91.6% at 1.03 min (retention time) (Phenomenex column, 30×4.6 mm, 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220 nm. MS (ES): m/z 165.23 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:15]1[CH:16]=[C:12]([C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[N:13]=[CH:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1c[nH]cn1)c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cn(Cc2ccccc2)cn1)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% in mineral oil, 23 mg, 0.58 mmol) was added to a solution of (2-fluoropyridin-3-yl)(1H-imidazol-4-yl)methanone (100 mg, 0.52 mmol) in tetrahydrofuran (3 ml), cooled to 0° C. The reaction mixture was then stirred for 30 minutes. Benzyl bromide (0.062 ml, 0.52 mmol) was added and the mixture was warmed up to room temperature. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (100 mg, 68% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])[CH:5]=[C:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])[CH:7]=1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C.O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][NH:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])[CH:5]=[C:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])[CH:7]=1
Reactant: CCCCCCCCCCNC(=O)c1cc(N)cc(C(=O)NCCCCCCCCCC)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)c1cc(NCC(=O)OC)cc(C(=O)NCCCCCCCCCC)c1
Yield: 66.5 %

Procedure:
A mixture of 0.202 g (0.455 mmol) of 5-amino-N,N'-didecyl-1,3-benzenedicarboxamide, 0.17 ml (1.8 mmol) of methyl bromoacetate, 0.14 g (1 mmol) of potassium carbonate and 0.15 g (1 mmol) of sodium iodide in 10 ml of acetone and 2 ml of DMF was stirred at reflux for 20 hours. Water was added and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure to an oil which was crystallized from methanol-water to give 0.1608 g (67% yield, mp 108°-109°) of N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine methyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:31]([C:36]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])([C:40](Cl)=[O:41])[CH:37]([F:39])[F:38])[C:32]([O:34][CH3:35])=[O:33])C1C=CC=CC=1.ClC(C(C(F)F)C(C)C(OC)=O)=O>>[CH:17](=[N:16][C:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:40](=[O:41])[C:36]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])([CH:37]([F:39])[F:38])[CH:31]([CH3:24])[C:32]([O:34][CH3:35])=[O:33])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(Cc1ccccc1)C(C(=O)Cl)(C(=O)OCc1ccccc1)C(F)F
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)N=Cc1ccccc1
Agent: COC(=O)C(C)C(C(=O)Cl)C(F)F
Product: COC(=O)C(C)C(C(=O)OCc1ccccc1)(C(=O)C(Cc1ccccc1)(N=Cc1ccccc1)C(=O)OC(C)(C)C)C(F)F

Procedure:
1-t-butyl 6-methyl 2-benzylideneamino-2-benzyl-4-benzyloxycarbonyl-4-difluoromethyl-5-methyl-3-oxohexanedioate is prepared in a similar manner except that t-butyl 3-phenyl-2-benzylideneaminopropionate is used in place of t-butyl 2-benzylideneaminopropionate and methyl 2-benzyl-3-benzyloxycarbonyl-3-chloroformyl-4,4-difluorobutanoate and methyl 3-benzyloxycarbonyl-3-chloroformyl-4,4-difluoro-2-methyl butanoate are used respectively in place of methyl 3-chloroformyl-4,4-difluoro-2-methylbutanoate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][NH2:6])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: NCc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1ccc(Sc2cccc(CN)c2)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzylamine (133 μL, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(4-methoxyphenyl)sulfanylbenzylamine (218 mg, 89% yield) as light yellow liquid. Column chromatographic solvent (CH2Cl2 (saturated with NH3)/MeOH=30/1). Rf=0.4 (CH2Cl2 (saturated with NH3)/MeOH=30/1), (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dt, 2 H, J=1.8 Hz, 8.7 Hz), 7.19 (t, 1 H, J=7.8 Hz), 7.06-7.13 (m, 2 H), 7.01 (dt, 1 H, J=1.5 Hz, 7.5 Hz), 6.89 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 3.82 (s, 3 H), 3.79 (s, 2 H), 1.40 (brs, 2 H). 13C NMR (CDCl3, 75 MHz) δ 159.9, 144.3, 139.0, 135.6, 129.3, 126.9, 126.7, 124.8, 124.3, 115.2, 55.7, 46.6. IR (neat, cm−1) 3373 (broad), 3072, 3060, 2939, 2836. MS (EI) m/z (relative intensity) 245 (100), 106 (60). HRMS (EI), Cald. for C14H15NOS 245.0869; Found 245.0862.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([CH3:36])[CH:30]=1)([CH3:25])=[O:27]
Reactant: Cc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: Cc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-methylaniline.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].ClCCC1SC(C2NC3C(C=2)=CC=CC=3N(C)S(C2SC=CC=2)(=O)=O)=NC1>O1CCCC1.O>[CH3:35][S:36]([O:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CCOS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (200 mg) and triethylamine (70 μL) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (60 mg) at room temperature, and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl methanesulfonate (126 mg, yield 54%, MS: 500 (MH+)) and N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (16 mg, yield 8%,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]([OH:22])[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:22])[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCC(O)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)C1CCC(=O)c2c(-c3ccc(Cl)cc3)noc2C1
Reaction time: 0.33 h

Procedure:
2.4 g (7.5 mmol) of a cis/trans mixture of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-hydroxy-4H-cyclohept[d]isoxazole-7-carboxylate were stirred in 150 ml of acetone and Jones' reagent was added dropwise until the orange color persisted for 20 minutes. The mixture was filtered and the residue was washed with acetone. The combined filtrate and washings were treated with isopropanol and the mixture was neutralized by stirring with solid sodium bicarbonate. The mixture was filtered. The filtrate was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulfate and evaporated. The residue was treated with hexane and the resulting solid was collected and dried to give 1.85 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-oxo-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 108°-109° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]([F:18])([F:17])[CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]([F:18])([F:17])[F:9])[CH2:12]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: FC(F)(F)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nsc(N2CCCC(C(F)(F)F)C2)n1
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In 3 ml of tetrahydrofuran were added 376 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 230 mg of 3-trifluoromethylpiperidine and 1.52 g of triethylamine at room temperature. The mixture was stirred for 1.5 hour under reflux condition, and left as it for 14 hours at room temperature. The reaction mixture was extracted with ethyl acetate after the addition of water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 398 mg of 3-methylthio-5-(3-trifluoromethylpiperidino)-1,2,4-thiadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[F:18][C:19]1([F:31])[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][CH:27]1[CH2:26][CH2:25][CH:24]([N:21]2[CH2:22][CH2:23][C:19]([F:31])([F:18])[CH2:20]2)[CH2:29][CH2:28]1
Reactant: NC1CCC(N2CCC(F)(F)C2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1NC1CCC(N2CCC(F)(F)C2)CC1)C1CC1
Yield: 45.6 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(3,3-difluoropyrrolidin-1-yl)cyclohexanamine (306 mg, 1.5 mmol) to afford the desired product (218 mg, 46%) as a yellow solid: ESI MS m/z 478 [C23H26BrF2N3O+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>O.CN(C=O)C>[OH:1][C:2]1[C:3]([C:12]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
8-Hydroxyquinoline-7-carboxylic acid (0.51 g) of Preparation 1 is added to 20 mL DMF. 4-Nitrobenzylamine hydrochloride (0.53 g) followed by diisopropylethylamine (0.49 mL) is then added. After 10 minutes, all solids go into solution. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g) and 1-hydroxybenzotriazole monohydrate (0.38 g) are added and the reaction stirred at room temperature overnight. The reaction is poured into 75 mL H2O. The resulting solid is filtered and dried to give the title product (0.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16]
Reactant: CC(C)(C)NO
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 7 using 2-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 82.9% overall yield as white crystals, m.p. 109.1 ° C. (Rf =0.53 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:28]([CH3:33])[CH3:27])[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(NC(=O)CN(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A solution of (S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide of Example 57 (46 mg, 0.12 mmol) in 1 ml of DCM was added to a suspension of N,N-dimethylglycine (25 mg, 0.24 mmol), DIPEA (0.041 ml; 0.24 mmol), anhydrous HOBt (32 mg, 0.24 mmol) and EDCI (46 mg, 0.24 mmol) in 1 ml of DCM. The reaction mixture was stirred at RT over three nights. N,N-dimethylglycine (25 mg), DIPEA (0.021 ml), anhydrous HOBt (16 mg) and EDCI (23 mg) were added to the reaction mixture, and stirring was continued overnight. N,N-dimethylglycine (25 mg), DIPEA (0.082 ml) and EDCI (46 mg) were added twice the following two days. Three days after last addition of reagents the reaction was quenched by adding DCM and washing with water. Organic phase was dried over Na2SO4, filtered and evaporated. Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: silica, eluent: 20-100% EtOAc in heptane) to obtain 3.2 mg (6%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.42 (s, 6H), 3.25 (s, 2H), 4.32 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.62 (d, 1H), 7.49 (d, 1H), 7.62 (d, 1H), 7.68 (d, 1H), 7.78 (s, 1H), 7.82 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([NH2:17])=[O:16])C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:15]1(=[O:16])[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[N:6]2[CH:5]=[CH:4][NH:17]1
Reactant: CCOC(Cn1c(C(N)=O)cc2c1CCCC2)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]ccn2c3c(cc12)CCCC3
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A mixture of 195d (2.7 g, 9.6 mmol) and acetic acid (10 mL) was heated at 110° C. for 2 h. The mixture was cooled to room temperature and neutralized with aqueous sodium carbonate solution and extracted with ethyl acetate (3×30 mL). The combined organic phase was concentrated under reduced pressure to afford 195e as a yellow solid (1.6 g, 88%). MS-ESI: [M+H]+ 189.3. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.02 (d, J=5.5 Hz, 1H), 6.63 (s, 1H), 6.52 (pt, J=5.5 Hz, 1H), 2.66 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 1.83-1.82 (m, 2H), 1.73-1.72 (m, 2H).
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.N1CC[O:18]CC1>C1(C)C=CC=CC=1>[O:18]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 8.29 g (0.06 mole) of bicyclo [3.3.1]9-nonylidene and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure and the remaining chromanone compound was recrystallized from acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.8 g of a chromene compound represented by the following formula: ##STR159##
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[C:10](=[O:24])[NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:30][O+](C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])[C:10]([O:24][CH3:30])=[N:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[O+](C)C
Reactant: CCOC(=O)N1CCNC(=O)C(N2C(=O)c3ccccc3C2=O)C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCN=C(OC)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 45.00 g (135.82 mmol) of (+/−)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid ethyl ester in 339 mL of anhydrous dichloromethane was added 22.09 g (149.40 mmol) of trimethyloxonium tetrafluoroborate. The resulting mixture was stirred at room temperature for 12 h. The mixture was hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried over sodium sulfate and the solvent was evaporated to afford 46.90 g (99%) of pure product as yellow oil. The compound was used as such in the next step.