Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:2]([C:3](=[CH:23][C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Reactant: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccnc1)C(=O)NCC=Cc1ccccc1

Procedure:
516 mg (2.37 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.255 ml (2.70 mmol) of 3-pyridylaldehyde and 0.06 ml (0.61 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture. After washing with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-acetyl-3-(pyridine-3-yl)-N-(3-phenyl-2-propene-1-yl)acrylamide. 20 ml of 2-propanol and 365 mg (2.37 mmol) of 2-cyanoethyl 3-aminocrotonate were added to the product, and they were heated at 80° C. under stirring overnight. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (chloroform/methanol=50/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20](O)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([NH:30][CH3:29])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Product: CNC(=O)Cn1c(=O)c(C(=O)NC)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-[(methylamino)carbonyl]-2-oxo-1,5-naphthyridine-1 (2H)-yl]acetic acid and methylamine employing methods similar to those described in example 558. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.00 (1H, br s), 8.53 (1H, s), 8.03 (1H, br s), 7.79 (1H, s), 7.33-7.30 (2H, m), 7.15-7.05 (2H, m), 4.83 (2H, s), 4.11 (2H, s), 2.88 (3H, d, J=3.8 Hz), 2.52 (3H, d, J=4.4 Hz); HRMS calcd for C20H19FN4O4+H+: 399.1463. Found 399.1465.
Reaction SMILES: [C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2].[CH2:37]([I:39])[CH3:38]>>[I-:39].[C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=1[CH2:37][CH3:38])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OC
Reactant: CCI
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2CC)C(C)=O)cc1OC
Product: [I-]
Temperature: 105 °C
Yield: 75.3 %

Procedure:
A mixture of 1.01 g of product from Example 49 and 15.83 g of ethyl iodide is heated at 105° C. for 23 hours. The reaction is concentrated in vacuo and triturated with diethyl ether to give 1.0 g of the desired product as yellow crystals.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)(=O)[NH2:2].C1(C)C=CC=CC=1.O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[C:1]([C:4]1[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)(=[S:35])[NH2:2]
Reactant: NC(=O)c1c[nH]c2sccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1c[nH]c2sccc2c1=O

Procedure:
To a solution of 4,7-Dihydro-5-carbamoyl-4-oxothieno[2,3-b]pyridine derivative (xxvi) in an appropriate solvent, e.g. toluene, tetrahydrofuran, dioxane, an equivalent amount or a small excess amount of thioamide reagent, e.g. Lawessons reagent, is added under room temperature or ice-cooling. The mixture is stirred at a temperature of 0° C. to 80° C., and subjected to refluxing under heating if required, to give a 4,7-dihydro-5-thiocarbamoyl-4-oxothieno[2,3-b]pyridine derivative (xxvii).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[C:5]([NH:22][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:21])=[CH:12][CH:13]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cc(OC)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 68, Part A, 4-methoxy-N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (3.35 g, 10.1 mmol) was reacted with 4-methoxybenzoyl chloride to yield 1.45 g (99%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[CH:7]1([SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8]1>O.[Ir](Cl)(Cl)Cl.CC1C=CC(C)=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][CH2:4][Si:12]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCO[SiH](OCC)C1CCCC1
Reactant: C=CC(F)(F)F
Agent: Cl[Ir](Cl)Cl
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CCO[Si](CCC(F)(F)F)(OCC)C1CCCC1
Reaction time: 3 h
Yield: 77 %

Procedure:
In analogy to Example 3, a mixture of 3 g of p-xylene, 5.3 g (0.055 mol) of 3,3,3-trifluoro-1-propene and 9.4 g (0.5 mol) of cyclopentyldiethoxysilane was reacted in the presence of 0.1 mg of iridium(III) chloride hydrate, after a mixing time of 70 minutes, at 83° C. over 180 minutes. Analysis by gas chromatography gave a product yield of 77% of 3,3,3-trifluoropropylcyclopentyldiethoxysilane.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13][C:14](=[CH2:17])[CH2:15][NH2:16].C(O)(=O)C(O)=O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][C:29]([O:30]C2CNC2)=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][C:14](=[CH2:13])[CH2:15][NH:16][C:1]([N:8]1[CH2:9][CH:11]([O:30][C:29]2[CH:35]=[CH:36][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:27][CH:28]=2)[CH2:12]1)=[O:2]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C(C)CN
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A stirred solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 75 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022 mole) of 2-methyl-2-propenylamine (added via a syringe and needle through a septum placed in one neck of the reaction flask). After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 30 min with 5 ml of triethylamine and stirring was continued for 3 hr. The reaction mixture was washed with water (2×25 ml), dried over magnesium sulfate and concentrated in vacuo. The oily residue solidified on standing and was recrystallized from isopropyl ether to yield 3.7 g (58.9%) of fine white crystals, m.p. 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[OH-].[Na+].[Na].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Cl)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C=Cc1ccc(Cn2ccnc2)c(Cl)c1

Procedure:
A mixture of ethyl 3-[3-chloro-4-(imidazol-1-yl-methyl)phenyl]prop-2-enoate (0.5 g) and sodium hydroxide (0.25 g) in water (10 ml) was stirred and heated under reflux for 3 h. The resulting solution of the sodium salt of the acid was acidified to pH 6 with glacial acetic acid, and the mixture was evaporated to dryness. Ethanol (10 ml) was added to the residue, and the mixture was boiled and filtered. Concentration of the filtrate gave a residue which was recrystallised from ethanol/ether, to give 3-[3-chloro-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid, m.p. 227°-229°.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Reactant: CN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)NC)C1(C)C

Procedure:
The product from Example 96 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 99 to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.47 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.22 (s, 3H), 1.26-1.33 (m, 2H), 1.36-1.45 (m, 1H), 1.57 (s, 9H), 1.57-1.68 (m, 3H), 1.95-2.07 (m, 1H), 2.57 (d, J=4.7 Hz, 3H), 2.60-2.67 (m, 3H), 2.72-2.83 (m, 1H), 4.78 (q, J=4.5 Hz, 1H), 8.49 (s, 1H). MS (ESI+) m/z 408 (M+H)+. Anal. calcd. for C22H37N3O2S: C, 64.83; H, 9.15; N, 10.31. Found: C, 64.55; H, 9.02; N, 10.29.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:33]5[CH2:34][CH2:35][CH2:36][CH:32]5[CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CC1CCCN1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 2-methylpyrrolidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(2-methylpyrrolidin-1-yl)isonicotinamide (35 mg). NMR; δH [2H6]—DMSO 10.27,(1H, s), 8.62,(1H, t), 8.20,(1H, d), 7.93,(2H, d), 7.70,(1H, d), 7.66,(1H, s), 7.44,(2H, d), 7.30,(1H, d), LCMS: retention time 2.89 min, MH+469.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:52])[CH3:51]>C(#N)C>[C:50]([O:54][C:55](=[O:73])[C@@H:56]([NH:72][C:12](=[O:14])[C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of the product from Example AA ((R)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (1.0 g, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) in acetonitrile (15 mL) was treated with HBTU (1.54 g, 4.06 mmol). The resulting solution was treated with the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.33 g, 4.06 mmol), and the resulting solution was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 mL) and washed sequentially with 0.6 M aqueous NaHCO3 solution, saturated aqueous NaCl solution, and water. The organic phase was dried over MgSO4 and activated charcoal, filtered, and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate/hexane) to give the title compound as a white solid (1.9 g, 86%), mp=64-66° C.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)(=[O:3])[CH3:2].Cl.[N:11](OCCCCC)=[O:12]>CCOCC>[CH3:9][C:6]1[CH:5]=[C:4]([C:1]([CH:2]=[N:11][OH:12])=[O:3])[O:8][N:7]=1
Reactant: CCCCCON=O
Reactant: CC(=O)c1cc(C)no1
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)C=NO)on1
Yield: 32.5 %

Procedure:
In 30 ml of ether was dissolved 2.5 g of 5-acetyl-3-methylisoxazole. While gaseous hydrogen chloride was passed through the resultant solution with stirring, a solution of 4.5 g of amyl nitrite in 10 ml of ether was dropped thereinto. After a further one hour stirring at room temperature after completion of said dropwise addition, the resulting precipitate was isolated by filtration. Recrystallization from chloroform gave 1.0 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C. Yield, 27%.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[C:6]2[C:7]([N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:26]=[N+:27]=[N-].[Na+].O>CS(C)=O>[N:1]([C:4]1[CH:25]=[CH:24][CH:23]=[C:6]2[C:7]([N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:26]=[N-:27]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1cccc2ccc(O)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1cccc3ccc(O)cc13)C2=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
A mixture of 2.4 g (0.007 mol) of 1-(3-nitrophthalimidyl)-7-hydroxynaphthalene and 0.52 g (0.008 mol) of sodium azide in 14 ml of dimethylsulphoxide is stirred for 24 hours at 80° C. 100 ml of water are added to the solution. The crystals which have precipitated are filtered off with suction, washed with water and dried at 80° C./100 mm Hg. 1.7 g (73.6% of theory) of 1-(3-azidophthalimidyl)-7-hydroxynaphthalene are obtained; melting point 154° C. (with decomposition). IR spectrum (KBr): 1775 and 1720 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[O:19]=O>C(#N)C>[C:1]1(=[O:19])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:1]1([OH:19])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=O
Reactant: C1=CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: O=C1C=CCCC1
Product: OC1C=CCCC1
Yield: 4 %
Yield: 1 %

Procedure:
To 25 milliliters of acetonitrile, were added 1.64 grams (20 millimoles) of cyclohexene, and azobisisobutyronitrile (5 mole percent). The resultant mixture was stirred in an oxygen atmosphere at a temperature of 90° C. for 4 hours. In analysis of the product in the reaction mixture with gas chromatography, cyclohexene was transformed into 2-cyclohexen-1-one (cyclohexene-based selectivity 12%, yield 4%) and 2-cyclohexen-1-ol (cyclohexene-based selectivity 3%, yield 1%) with a transformation rate of 34 percent.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.[O:25]([CH2:33][C:34]1[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=1)[Si](C(C)(C)C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:57]>>[ClH:57].[CH3:22][C:21]1[C:16]([CH2:15][N:14]([CH2:40][C:35]2[C:34]([CH2:33][OH:25])=[CH:39][CH:38]=[CH:37][N:36]=2)[C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C=O
Reactant: ClCCl
Reactant: Cc1cnc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CN(Cc2ncccc2CO)[C@H]2CC[C@H](N)CC2)c(C)c1
Product: Cl

Procedure:
Using General Procedure B: Reaction of {trans-4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester and 3-(tert-butyl-dimethylsiloxymethyl)-pyridine-2-carbaldehyde in CH2Cl2 (4 mL) with NaBH(OAc)3 gave the crude material. Deprotection with 6 N HCl gave the amine as a white foamy solid. Conversion to the HBr salt using General Procedure D gave COMPOUND 257 as a white solid. 1H NMR (D2O) δ 1.33-1.62 (m, 4H), 2.06-2.13 (m, 4H), 2.40 (s, 3H), 2.41 (s, 3H), 2.74 (t br, 1H, J=11.4 Hz), 3.14 (t br, 1H, J=11.4 Hz), 4.20 (s, 2H), 4.35 (s, 2H), 4.84 (s, 2H), 7.89 (dd, 1H, J=7.8, 5.1 Hz), 8.10 (s, 1H), 8.32 (s, 1H), 8.48 (d, 1H, J=7.8 Hz), 8.61 (d, 1H, J=5.1 Hz). 13C NMR (D2O) δ 17.05, 17.44, 25.86 (2), 29.48 (2), 49.67, 50.68, 51.02, 59.43, 60.73, 126.55, 136.72, 137.44, 138.30, 139.13, 140.83, 145.85, 148.11, 148.86, 151.63. ES-MS m/z 355 (M+H). Anal. Calcd. for C21H30N4O.2.9HBr.1.8H2O: C, 40.58; H, 5.92; N, 9.01; Br, 37.28. Found: C, 40.28; H, 6.04; N, 8.79; Br, 37.52.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
64 mg (0.17 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine, 40 μL (0.23 mmol) DIPEA and 65 mg (0.17 mmol) HATU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.C[N:30](C1C=CC=CN=1)C>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH2:30])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccccn1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 376.8 %

Procedure:
To a suspension of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation E, 50.0 mg, 0.153 mmol) in CCl4 (1.0 mL) was added thionyl chloride (182 mg, 1.53 mmol) and the mixture was heated at reflux for 4 hours (homogeneous after 5 minutes). The mixture was cooled to ambient temperature and was concentrated to give a brittle foam. The foam was dissolved in dry THF (2 mL) and dimethylaminopyridine (DMAP) (3.74 mg, 0.031 mmol) was added. Anhydrous ammonia was bubbled into the mixture with stirring for 5 minutes. The reaction vessel was sealed and the reaction was stirred at ambient temperature for 18 hours. The mixture was added to H2O (4 mL) and extracted with EtOAc. The combined extracts were washed with 1M Na2CO3, H2O and saturated NaCl. The solution was dried over MgSO4/activated carbon and filtered through a SiO2 plug (EtOAc then 10% MeOH/EtOAc for elution). The solution was concentrated to give the title compound as a white solid (38 mg, 76%). MS (apci) m/z=326.0 (M+H).
Reaction SMILES: CC(NC(C)C)C.[Li]CCCC.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][S:23][N:22]=2)=[CH:17][CH:16]=1)[CH3:14].[I:31]I>O1CCCC1>[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([I:31])[S:23][N:22]=2)=[CH:19][CH:20]=1)[CH3:14]
Reactant: II
Reactant: CCOC(=O)c1csnc1-c1ccc(CC)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (15 mL). This was followed by the addition of bis(propan-2-yl)amine (1.34 g, 13.24 mmol, 1.50 equiv). The mixture was cooled to −78° C. To this was added n-BuLi (2.5M) (5.28 mL). The mixture was stirred at −78° C. for 40 minutes. To the mixture was added a solution of ethyl 3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate (2.3 g, 8.80 mmol, 1.00 equiv) in tetrahydrofuran (5 mL). The mixture was stirred at −78° C. for 40 minutes. To the mixture was added a solution of I2 (3.35 g, 13.19 mmol, 1.50 equiv) in tetrahydrofuran (5 mL). The resulting solution was stirred for 40 min at −78° C. The reaction was then quenched by the addition of 80 mL of water. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum. This resulted in 2.1 g (62%) of ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate as red oil.