Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10]2[S:11][C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=3)=[CH:13][C:9]=2C=[CH:7][CH:6]=1.[NH4+:30].[Cl-].O>CCO.[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:6]=[CH:7][N:30]=[C:9]3[CH:13]=[C:12]([C:14]4[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=4)[S:11][C:10]=23)=[C:2]([F:1])[CH:26]=1
Reactant: [NH4+]
Reactant: CC(=O)N1CC=C(c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 90.4 %

Procedure:
To a mixture of the nitro compound 390 (358.2 mg, 0.87 mmol) and NH4Cl (39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. Fe powder (411.3 mg, 7.36 mmol) was added in one portion and the mixture was heated to reflux under vigorous stirring for 40 min. It was then filtered through Celite®, the Celite® was washed with EtOH and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, dried (anhydrous Na2SO4) and concentrated under reduced pressure affording 391 (256.5 mg, 77% yield) as a white solid. LCMS:(M+H) 384.2.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1F.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1[N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [K]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1c(F)c(F)nc(F)c1Cl
Temperature: 40 °C
Reaction time: 24 h
Yield: 102.6 %

Procedure:
To a mixed solution of 40 ml dichloromethane and 20 ml N,N-methylformamide were added 18.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g potassium phthalimide, and the mixture was stirred at 40° C. for one day. After adding 40 ml of chloroform, the mixture was washed twice with 500 ml of distilled water and once with 500 ml of 0.5% aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersed in diisopropylether, and collected by filtration to obtain 32.0 g of the title compound as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:22][CH2:21][C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[C:8]3[C:7](=[CH:12][CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]3)[CH2:14][CH2:15]1)=[O:23]
Reactant: CCC(=O)NC1CCN(c2ccc(NC(=O)CCBr)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)NC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 0 °C

Procedure:
2.7 Grams of N-(β-bromopropionyl)-p-[4-(N-methylacetylamino)-1-piperidyl]aniline and 28 g of pulverized aluminum chloride were suspended in 50 ml of carbon disulfide, then the mixture was refluxed by heating for 4 hours. The reaction mixture was poured into ice-water, then the precipitates formed were collected and washed with water, and with diethyl ether, then this substance was converted into a hydrobromide and recrystallized from methanol-diethyl ether to yield 0.8 g of 6-[4-(N-methylacetylamino)-1-piperidyl]-3,4-dihydrocarbostyril. Light yellow needle-like crystals. Melting point: 195° C.-197° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3].[C:65]([Si:69]([CH3:83])([CH3:82])[O:70][C:71](=[O:81])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78](O)=[O:79])([CH3:68])([CH3:67])[CH3:66].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.O.C(Cl)Cl>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:78](=[O:79])[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][C:71]([O:70][Si:69]([C:65]([CH3:67])([CH3:66])[CH3:68])([CH3:82])[CH3:83])=[O:81])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([O:56][Si:57]([C:60]([CH3:61])([CH3:62])[CH3:63])([CH3:58])[CH3:59])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)CCCCCCC(=O)O
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
A mixture of 17-allyl-14-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (138 mg, 0.15 mmol), O-mono(tert-butyl-dimethyl-silanyl)octanedioic acid (86.7 mg, 0.218 mmol), dimethylaminopyridine (DMAP; 16.5 mg, 0.098 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC/HCl; 69.1 mg, 0.261 mmol) and methylene chloride (CH2Cl2; 1 ml) was stirred at room temperature for 1.5 hours. The reaction product was poured over an ethyl acetate-water mixed solution and extracted. The organic phase obtained was washed with water and saline, and dried over magnesium sulfate (MgSO4). After the MgSO4 was separated by filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified using a silica gel column (eluted with 20% AcOEt (in n-hexane)) to yield the desired 17-allyl-14-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-12-{2-[4-(7-(tert-butyl-dimethyl-silanyloxy-carbonyl)heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone (44 mg, 24.6%).
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:3].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25]([N:6]1[C:5](=[O:22])[C:4]([C:2]#[N:3])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)n1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O
Temperature: 110 °C

Procedure:
5.0 grams (0.016 mole) of the sodium salt of 4-cyano-5,6-diphenyl-3-(2H)-pyridazinone was reacted with 1.83 grams (0.017 mole) of dimethylcarbamyl chloride in 50 mls of dimethylformamide. This solution was heated 110° C. for 3 hours, cooled, and poured into excess water. The precipitant solid was filtered, washed with water and air dried. This solid was taken up in chloroform, dried over sodium sulfate and the solvent distilled at reduced pressure. The residual solid was recrystallized from ethyl alcohol to give 3.0 grams of a solid which melted at 231° C. The infrared spectrum showed the methyl group at 3.5μ, the nitrile band at 4.5μ, and two carbonyl bands at 5.8 and 6.0μ.
Reaction SMILES: [NH:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:17][N:18]=[C:19]=[S:20]>CN(C)C=O>[NH:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19]([NH:18][CH3:17])=[S:20])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)co1
Solvent: CN(C)C=O
Product: CNC(=S)Nc1cccc(-c2coc(NC(=N)N)n2)c1

Procedure:
Reaction of 2-guanidino-4-(3-aminophenyl)-oxazole with methylisothiocyanate in dimethylformamide gave 2-guanidino-4-[3-(3-methylthioureido)phenyl]oxazole having the following n.m.r. in d6DMSO: 2.8(d,4H); 3.25(s,H2O); 6.9(s,4H); 7.2-7.7(m,5H); 7.8(s,1H); 9.5(s,1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:6].[C-:14]#[N:15].[K+]>CO.C(OCC)(=O)C>[C:9]1([CH3:13])[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2([C:14]#[N:15])[CH2:4][CH2:3][CH2:2][O:6]2)[CH:8]=1
Reactant: [C-]#N
Reactant: Cc1cccc(C(=O)CCCCl)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C2(C#N)CCCO2)c1
Temperature: 35 °C

Procedure:
To a solution of Example 91B (1.56 g, 8 mmol) in MeOH (15 mL) was carefully added KCN (0.8 g, 12.3 mmol) and the mixture was warmed at 35° C. for 48 hours. The mixture was diluted with 50 mL ethyl acetate, washed with conccentrated aqueous NaHCO3 (20 mL) and brine (10 mL). The aqueous solution was oxidized with excessive NaC100. The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound as an oil which was used directly for the next step (1.35 g, 90%). LC-MS: m/z (M+H): 161.
Reaction SMILES: [CH:1]([OH:14])([C:8]1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1(C(C)C)C=CC=CC=1.[C:26]([O:34]C)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(C1C=CC=CC=1)(=O)C.S(=O)(=O)(O)O>>[C:1]([CH2:8][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Benzhydrol (189.77 g; 1.03 mol), potassium hydroxide (84.3%; 66.56 g; 1.0 mol) and cumene (375 mL) were placed into a four-necked, round bottom, one liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 148-150° C). When no more water was collected (27 mL, yield=95%, about 2 hours) the mixture was cooled down to and kept at 90° C. The fractionation column and trap were replaced with a reflux condenser, while maintaining the nitrogen stream. Methyl benzoate (181.5 g; 1.33 mol) was added at once, and slow addition (12 minutes) of acetophenone (80.10 g; 0.667 mol) by means of a syringe pump was begun. After 60 minutes from the beginning of the addition of the ketone, the mixture was allowed to cool to room temperature, whereupon it was acidified with 10% sulfuric acid. The cumene layer was washed with a saturated solution of sodium bicarbonate in water and then with water. The organic layer was then concentrated under vacuum in a rotary evaporator. The residue was crystallized from 90% isopropanol, affording DBM (112.13 g, 75% yield) having a purity of 98% (GC).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1cc(N)c(F)cc1Cl
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A suspension of electrolytic iron powder (3.5 g) in a 5% aqueous acetic acid solution was heated to 90° C., and a solution of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene (5.7 g) in acetic acid (40 ml) was dropwise added thereto at the same temperature. The resultant mixture was stirred for at 90°-105° C. for 1 hour and allowed to cool to room temperature. Water (200 ml) was added thereto. Insoluble materials were filtered off, and the filtrate was neutralized, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with petroleum ether and carbon tetrachloride to give 3.6 g of 4-chloro-2-fluoro-5-(2-propynyloxy)aniline. M.P. 61.0°-61.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])[CH:19]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (509 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (753 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 96.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (809 mg, yield: 69%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccncn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylpyrimidine-4-carboxamide
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[CH:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)([CH3:6])[CH3:1]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: CC(C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-methylpropanamide (80 mg, 0.9 mmol) and triethyloxonium tetrafluoroborate (170 mg, 0.89 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (22 mg, 0.077 mmol) and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (2.9 mg, 11%). LCMS calculated for C19H23N4S (M+H)+: m/z=339.2. Found: 339.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCCC1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:41][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then, cyclopentylamine (44.8 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and the formed solid was filtered, washed by water and dried to afford the title compound (174 mg) as a yellow solid. LC-MS (ES) m/z=423 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 87 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.33 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[Na+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]([F:17])[F:16]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(F)F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
2-Bromo-4-nitrophenol (10.9 g) was dissolved in dioxane (60 ml), a solution of sodium hydroxide (18.4 g) in water (50 ml) was added thereto, and the resulting mixture was heated up to 60° C. while stirring vigorously. Chlorodifluoromethane gas was introduced therein, whereby the generation of heat was initiated. The reaction was continued for about 40 minutes. The reaction mixture was cooled to room temperature, poured onto ice-water and extracted with ether. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-4-difluoromethoxynitrobenzene (8.7 g) as a pale yellow oil. nD20.5 1.5500.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.[CH2:16]([N:18]([CH2:27][CH3:28])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)[CH3:17]>O.C(O)C>[CH2:27]([N:18]([CH2:16][CH3:17])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:28]
Reactant: CCN(CC)c1ccccc1CCl
Reactant: Cc1nc2ccccc2nc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccccc1CSc1nc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 0.73 g of sodium hydroxide in a mixture of 2 ml of water and 50 ml of ethanol were added successively 1.5 g of 2-mercapto-3-methylquinoxaline and 1.99 g of 2-diethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 3 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residual oil was purified by silica gel column chromatography (hexane/acetone) to give 1.74 g of 2-(2-diethylaminobenzylthio)-3-methylquinoxaline as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[CH:26]1([NH:29][C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([CH2:10][N:8]([C:5]3[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=3)[CH3:9])[CH2:16][CH2:15]2)=[O:19])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.50 g (1.52 mmol) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 4.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF followed by 0.14 mL (1.68 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, the residue was redissolved in CH2Cl2 and added dropwise to a solution of 2.14 mL (30.47 mmol, 20 eq) of cyclopropylamine in 3 mL of CH2Cl2 at 0° C. The reaction was warmed to RT and left for 3 h, then partitioned between Et2O (×3)/aqueous 10% NaHCO3, washed once with aqueous 10% NaHCO3, dried over Na2SO4 and evaporated to yield 0.55g (99%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropylamide, MS: 367 (MH+, 1Br).