Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.COC.[C:19]1([CH:26]=[CH:25][C:23](O)=CC=1)O>O.C1(C)C=CC=CC=1.C(O)CCC>[CH2:23]([O:10][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([O:9][CH2:19][CH2:26][CH2:25][CH3:23])=[O:8])[CH2:25][CH2:26][CH3:19]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)NC(O)C(=O)O
Agent: COC
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)NC(OCCCC)C(=O)OCCCC

Procedure:
One hundred parts of acrylamidoglycolic acid (AGA); 517 parts butanol, 1 part concentrated sulfuric acid and 0.1 part monomethyl ether of hydroquinone were mixed in a flask equipped with a Dean Stark water trap and a stirrer. The mixture was heated until homogeneous. After 5-10 minutes 100 ml of toluene was added and the mixture was brought to reflux and held 5 hours until the theoretical amount of water was collected by azeotrope.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].[C:9](Cl)(=[O:11])[CH3:10].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:9]([O:8][CH2:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])(=[O:11])[CH3:10]
Reactant: Cc1nnsc1CO
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1snnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
In 10 ml of tetrahydrofuran were dissolved 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5--ylmethanol, 0.50 g (5.7 numol) of acetyl chloride and 0.80 g (7.6 mmol) of triethylamine. The solution thus obtained was stirred at room temperature for 18 hours. Then, a saturated aqueous solution of sodium chloride was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.70 g of the objective compound was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:15]([F:16])=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:11]1[C:10]2[C:14](=[C:15]([F:16])[C:7]([Cl:6])=[CH:8][CH:9]=2)[NH:13][CH:12]=1)=[O:24]
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(F)c(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add phosphorus oxychloride (0.94 g, 6.16 mmol) to DMF (12 mL, cooled in an ice bath) with vigorous stirring. After about 10 minutes, add 6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in anhydrous DMF (4 mL), stir at 0° C. for 1 hour, warm to room temperature and stir overnight at room temperature (˜16 hrs). Treat with 14.0 mL of 2N NaOH (4 eq.) with vigorous stirring. Heat the reaction to 80° C. for half an hour then cool. Pour the reaction into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry overnight in a vacuum oven at room temperature, to give the title compound: 1H NMR (300 MHz, CD3COCD3/CDCl3) 7.09 (t, 1H, J=7.7 Hz), 7.83–7.86 (m, 2H), 9.89 (s, 1H). By the method of Example 316 the following compounds were prepared: a) 3-Formyl-5,7-difluoro-1H-indole: 1H NMR (300 MHz, CD3COCD3) 6.98–7.06 (m, 1H), 7.71–7.75 (m, 1H), 8.35 (s, 1H), 10.04 (s, 1H);
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30]C(OC)=CC=2)=[CH:21][CH:20]=1.C([OH:37])(C)C>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:31]([OH:37])[CH2:30][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)=[CH:23][CH:24]=1
Reactant: CC(C)O
Reactant: COc1ccc(Oc2ccc(OC)cc2)cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Product: COc1ccc(OCC(O)CN2CCC(c3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20 mmol) and 2,3-epoxypropyl]-4-methoxyphenyl ether (3.7 g, 20.5 mmol) in isopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixture was cooled and the crystals were collected to yield 6.81 g (85%), m.p.=134°-135° C.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:62]=[N:61][NH:60][CH:59]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Yield: 83 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-pyrazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 20 g C18 cartridge {gradient 10 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (73 mg, 83%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 3H), 8.14-8.08 (m, 3H), 7.95 (dd, J=7.9 and 1.8 Hz, 1H), 7.53-7.32 (m, 8H), 7.25 (d, J=8.3 Hz, 2H), 3.83 (bs, 1H), 2.57-2.43 (m, 4H), 2.19-2.06 (m, 1H), 1.82-1.69 (m, 1H). LCMS (Method E): RT=3.03 min, [M+H]+=434.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:6]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: COc1cccc(C=O)c1OCCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=NCCc2ccccc2)c1OCCCN1CCOCC1
Yield: 85.9 %

Procedure:
3-Methoxy-2-[3-(4-morpholinyl)propoxy]benzaldehyde (42.5 g) and 18.5 g of phenethylamine are reacted in 150 ml of toluene following the procedure described in Example 1B, yielding 50.0 g of the title compound, boiling point 229°-234° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.[Br:34]C1C=C(F)C(C(OCC)=O)=NC=1>[Fe](Cl)(Cl)Cl.C(#N)C>[Br:34][C:6]1[C:5](=[O:21])[N:4]2[CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[NH:23][C:24](=[O:25])[C:3]2=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: CCOC(=O)c1ncc(Br)cc1F
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: O=C1NC(c2cccc(F)c2)n2c1c(Cl)cc(Br)c2=O
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g, 1.59 mmol), 3-fluorobenzaldehyde (2, 0.69 g, 5.57 mmol), acetonitrile (15 mL) and iron(III) chloride (1.81 g, 11.13 mmol) in a sealed tube was heated at 90° C. for 16 h. Once TLC showed consumption of the starting material, the mixture was cooled and filtered through a celite bed. The celite was washed with acetonitrile and the filtrate was concentrated under vacuum. The crude residue was subjected to flash column chromatography eluting with 35% ethyl acetate in hexane. The desired fractions were collected, concentrated and dried under high vacuum to afford 6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-c]pyridine-1,5-dione (3) as a yellow solid. Yield: 0.35 g, 61%; MS (ESI) m/z 357.20 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]([C:16]1[N:17](C(OC(C)(C)C)=O)[CH2:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][CH:14]([C:16]2[NH:17][CH2:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1(c2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)N)=N1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: COC(=O)C1(c2ccccc2)CNC(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline (Example K), the title compound was prepared as a white foam (90%). The reaction was monitored by tlc (Rf=0.39 in 3:2 hexanes/EtOAc) and the product was purified by flash column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:8]([CH:22]([CH3:24])[CH3:23])[NH:7][C:6]=1[CH:25]([CH3:27])[CH3:26])([O:3][CH3:4])=[O:2].[S].S.C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:1]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]([CH:22]([CH3:23])[CH3:24])=[C:9]([C:18]([O:20][CH3:21])=[O:19])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OC)C1c1ccc(F)cc1
Agent: S
Agent: [S]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 300 g dihydropyridine of Step 1 and 2 g freshly sublimed sulfur in 100 ml xylene was heated to 200°-210° C. for 30 minutes. When the development of hydrogen sulfide had subsided, the reaction mixture was cooled to room temperature, and ca. 100 g of Charcoal plus 1000 ml of ethyl acetate was added. This mixture was heated to reflux for 6 hours and then filtered through Celite filter aid. The filtrate was concentrated under vacuum and the residue was chromatographed on silica-gel, eluting with ethyl acetate/hexane to yield 78 g of the Step 2 title product.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](Cl)[N:20]=1>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:21]3[N:20]=[C:19]([NH2:18])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 300 mg (1.9 mmol), DMF 10 ml, potassium carbonate 520 mg (3.7 mmol) and 2-amino-6-chloro-3-nitropyridine 300 mg (1.9 mmol) was stirred at room temperature for 30 minutes, and 6-(5-isoquinolylsulfanyl)-3-nitro-2-pyridylamine 460 mg (86.7%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)[N:7]=1.[O-:17][C:18]#[N:19].[K+]>O>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[N:7]=[C:3]([CH2:2][NH:1][C:18]([NH2:19])=[O:17])[S:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: N#C[O-]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) and potassium cyanate (0.5 g) in water (50 ml) was stirred for 3.5 hours at room temperature. The resulting precipitate was collected by filtration. The precipitate was suspended in water (30 ml) and then a saturated aqueous potassium carbonate solution (20 ml) was added. The mixture was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-(2-ureidomethylthiazol-4-yl)thiazole (0.35 g).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][S:6][C@H:5]2[CH2:8][C@:9]([NH:16]C(=O)OC(C)(C)C)([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:11])[N:4]12)#[N:2].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C1(SC)C=CC=CC=1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:16][C@@:9]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:11])[N:4]2[C@@H:5]([S:6][CH2:7][C@H:3]2[C:1]#[N:2])[CH2:8]1
Reactant: CC(C)C[C@@]1(NC(=O)OC(C)(C)C)C[C@@H]2SC[C@@H](C#N)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(C)C[C@@]1(N)C[C@@H]2SC[C@@H](C#N)N2C1=O

Procedure:
53 mg of tert-butyl (3R,6R,7aS)-(3-cyano-6-isobutyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate were reacted with 3 ml of trifluoroacetic acid and 600 μl of thioanisole at 0° C. for 30 min. The solvents were then removed in vacuo, and the residue was stirred in diethyl ether, filtered off with suction and dried.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1)[CH3:4].[CH3:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:21]1[CH:20]=[C:19]([O:18][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[N:15]([C:28]([NH:27][CH3:26])=[O:29])[CH:14]=[CH:13]3)[CH:24]=[CH:23][N:22]=1
Reactant: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(N)c1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
50-72% Oily sodium hydride (265 mg) was added to a solution of 4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 24-7 (1.92 g, 6.13 mmol) in N,N-dimethylformamide (20 mL) under nitrogen atmosphere at 0° C. The reaction liquid was stirred at the same temperature for 10 minutes. Phenyl methylcarbamate described in Production Example 1-7 (1.20 g, 7.97 mmol) was added to the reaction liquid, and then the mixture was warmed to mom temperature and stirred for 1 hour. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (the solution: n-heptane:ethyl acetate=9:1-0:1) to obtain the title compound (1.97 g, 87%).
Reaction SMILES: C1(N2C(C3C=CC(O)=CC=3)=CC(/C=C/C(OC)=O)=N2)CCCCC1.C([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[N:42]=[C:41](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])[C:40]=2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:35][CH:34]=1)C1C=CC=CC=1>>[CH:44]1([N:43]2[C:39]([C:36]3[CH:37]=[CH:38][C:33]([OH:32])=[CH:34][CH:35]=3)=[C:40]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:41](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[N:42]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: COC(=O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1-c1ccccc1
Agent: COC(=O)/C=C/c1cc(-c2ccc(O)cc2)n(C2CCCCC2)n1
Product: COC(=O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(O)cc2)c1-c1ccccc1
Yield: 101.5 %

Procedure:
Phenol 8.8 was prepared from 8.6 according to the procedure described above for the preparation phenol 3.1. Thus, 8.6 (60 mg, 0.12 mmol) was debenzylated to yield 49 mg (100%) of 8.8. MS (ESI) 403.3 (MH+), 401.3 (MH−).
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])CCC#N)[CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O>C(Cl)(Cl)Cl>[CH2:6]([NH:12][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCN(CCC#N)CCCCC=C
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: C=CCCCCNCCCCC=C
Yield: 20.5 %

Procedure:
Next, ethanol (8.6 ml) and potassium hydroxide (0.85 g, 13 mmol) were added to 3-(di-5-hexenyl)aminopropionitrile (2.0 g, 8.6 mmol), and the mixture was refluxed for 7.5 hours. The reaction mixture was allowed to stand, and then water (150 ml) and chloroform (150 ml) were added to the reaction mixture. Layers were separated, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography to give 0.32 g (21%) of the titled compound as a pale yellow oily matter.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NC1CCCCC1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and cyclohexylamine as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([S:13]([CH2:16][Cl:17])(=[O:15])=[O:14])[C:10](=[O:12])[CH3:11].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[N:9]([S:13]([CH2:16][Cl:17])(=[O:14])=[O:15])[C:10](=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N(c1ccc(F)cc1Cl)S(=O)(=O)CCl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 2.5 °C
Yield: 92 %

Procedure:
30 g (0.1 mol) of N-(2-chloro-4-fluorophenyl)-N-[(chloromethyl)sulfonyl]acetamide was dissolved in a mixture of 150 mL of concentrated sulfuric acid and 50 mL of 30% oleum with stirring. The mixture was cooled to 0-5° C. and 9.2 mL of the nitrating agent, made from equal volumes of concentrated sulfuric acid and fuming nitric acid, was added slowly keeping the temperature below 5° C. Another 50 mL of oleum and 30 g of the starting material were then added, followed by the further dropwise addition of 9.2 mL of the nitrating agent, allowing the mixture to warm up to 10° C. The mixture was stirred for an additional 40 minutes at 10-15° C. and poured with vigorous stirring onto ice. The precipitated yellow solid was filtered off, washed with water and dried to yield 63.5 g (92%) of the title compound as a solid, which was recrystallized from ethyl acetate, melting at 183-187° C.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[C@@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][NH:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C@@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(C)=O)C2
Reaction time: 1 h

Procedure:
A solution of (S)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (169.0 mg) in DCM (3.18 mL) at 0° C. was treated with pyridine (0.077 mL, 0.954 mmol), followed by acetic anhydride (0.060 mL, 0.636 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A to give the title compound, as a TFA salt, as a yellow semisolid (84.9 mg, 43.4% over two steps). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 0.98 (m, 3H), 1.27 (m, 3H), 1.68 (m, 2H), 1.97 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (td, J=5.9, 1.5 Hz, 0.7H), 2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.11 (m, 2H), 3.45 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.50 (m, 1H), 4.61 (d, J=3.9 Hz, 0.7H), 4.64 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 460.00.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=1>C1COCC1.CCOCC.[Cl-].[Na+].O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:14])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of 220 mL (1.0 M, 220 mmol) of vinylmagnesium bromide in 100 mL THF, was added dropwise under nitrogen atmosphere at 0° C. a solution of 21 g (106.6 mmol) 2-(4-fluoro-phenyl)-N-methoxy-N-methylacetamide (step A) in ˜150 mL dry ether. The reaction mixture was stirred at 0° C. for 0.5 hr then poured slowly into an ice/2N aq HCl mixture. The resulting mixture was diluted with ether and brine, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with brine, dried over drying agent, filtered and the solvent evaporated under vacuum to give 14.2 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.19 (2H, m), 7.02 (2H, t, J=9.5 Hz), 6.42 (1H, dd, J1=14.2 Hz, J2=11 Hz). 6.34 (1H, d, J=14.2 Hz), 5.86 (1H, d, J=11 Hz), 3.87 (2H, s).