Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:6])[CH3:2].C1C=CC(O[C:23](Cl)=[S:24])=CC=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][C:23](=[S:24])[NH:14][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-amino-4-hydroxy-phenyl)-propionic acid ethyl ester (370 mg) in DMF (2 mL) was added phenyl chlorothionoformate (380 mg in DMF), and DBU (540 mg, in DMF) at room temperature. The reaction mixture was stirred for 16 h at room temperature and water was added to this mixture. The resulting mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=4:1) to afford the product as white solid. (130 mg, 29.2%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH2:22]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:22][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C#N)[CH:5]=[CH:4][N:3]=1.CC[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:13](=[O:12])[CH3:14])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCOCC
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloropyridine-4-carbonitrile (250 g, 1.80 mol, 1.00 equiv) and ether (3750 mL) were combined in a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. A solution of MeMgI in ether (1200 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred for 6 h at room temperature and then poured into water/ice/6N hydrogen chloride (3000 mL) and stirred for 10 min. The organic phase was separated and the aqueous phase was extracted with ether (3×2000 mL). The combined organic layer was washed with brine (2×2000 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (1:20 ethyl acetate/petroleum ether) to afford 1-(2-chloropyridin-4-yl)ethan-1-one as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][CH3:56]>CN(C=O)C.CS(C)=O>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][N:55]([CH3:56])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[CH:19]=1
Reactant: CNCCN(C)C
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (21 mg, 0.06 mmol) in anhydrous DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and N,N,N′-trimethylethylenediamine (7.9 μL, 0.06 mmol). The reaction solution was stirred 16 hours at ambient temperature then diluted with DMSO (1 mL), filtered through a 0.45 um syringe filter, and purified by reverse phase chromatography in a mobile phase of H2O and acetonitrile (with 0.1% formic acid as the modifier). Clean fractions were combined and lyophilized, affording the title compound as a white powder (14.0 mg, 54% yield). 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.83 (br s, 1H), 7.81 (bs, 1H), 7.69 (s, 1H), 7.60 (m, 2H), 7.49 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.13 (d, 8.5 Hz, 1H), 7.07 (t, J=6.5 Hz, 1H), 3.90 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.33 (s, 3H), 3.17 (s, 3H), 2.91 (s, 3H), 2.80 (br s, 2H). MS: m/e 429.1 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.CCCCO.O.[Os](=O)(=O)(=O)=O.[Os](=O)=O>[O:14]=[C:11]1[N:10]2[CH:4]([CH2:1][CH:2]=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]2=[N:13][O:12]1
Reactant: C=CCC1CCCCc2noc(=O)n21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=[Os]=O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: C1COCCO1
Product: O=CCC1CCCCc2noc(=O)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Ex-8) To a solution of the product of Example 6 in dioxane (200 mL) and water (135 mL) was added sodium periodate (15.11 g, 0.071 mol) and osmium tetraoxide (12 drops of a 1 ppm solution of osmium dioxide in n-BuOH/H2O). The reaction was stirred at room temperature and monitor by thin layer chromatography for one day. Since the starting material had not completely reacted, additional osmium tetraoxide (12 drops of 1 ppm solution of osmium dioxide in n-BuOH/H2O) was added. A white precipitate was filtered off and the filtrate was removed under reduced pressure to the point where no dioxane remained. Additional water (75 mL) was then added to the aqueous layer and this aqueous mixture was washed with CH2Cl2 (3×75 mL). The organic layer was combined, dried over magnesium sulfate, and stripped of all solvent under reduced pressure to afford a yellow oil. Chromatographic (silica gel) purification of this material eluting with the 1:1, ethyl acetate:hexane afforded 4.0 g (67%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:12])[CH2:10][CH2:9]1.Cl>ClCCl>[C:14]([CH:13]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:12])[C:17]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([F:27])([F:29])([F:25])([F:26])[F:28])=[CH:22][CH:23]=1)=[O:16])#[N:15]
Reactant: O=C(c1cnoc1-c1ccc(S(F)(F)(F)(F)F)cc1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1

Procedure:
Triethylamine (0.73 g) was added to a stirred solution of 4-cyclopropylcarbonyl-5-(4-pentafluorosulphanylphenyl)isoxazole (Compound 2, 0.4 g) in dichloromethane. After 16 hours the solution was washed (2M hydrochloric acid), dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography eluting with ethyl acetate/hexane to give a residue which was suspended in dichloromethane and shaken with hydrochloric acid until dissolved. The organic phase was evaporated and triturated with hexane to give 2-cyano-3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)propan-1,3-dione as a white solid (Compound 3, m.p.108-110° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([NH2:29])[C:25]([CH3:30])=[N:24]1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(OCC)(=O)C.CN1CCCC1=O>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]2[C:15]([CH3:16])=[C:5]([N:4]3[CH2:19][CH2:20][N:29]([C:26]4[C:25]([CH3:30])=[N:24][N:23]([CH3:22])[C:27]=4[CH3:28])[CH2:2][CH2:3]3)[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]=2[O:12]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nn(C)c(C)c1N1CCN(c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To 1-methyl-2-pyrrolidone (5.0 mL) solution of N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (660 mg, 2.0 mmol) synthesized in Reference example 146, 1,3,5-trimethyl-1H-pyrazole-4-amine (300 mg, 2.4 mmol), sodium hydrogen carbonate (400 mg, 4.8 mmol) and sodium iodide (300 mg, 2.0 mmol) were added, and stirred at 120° C. for 16 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 9:1). The resulting solids were recrystallized from ethanol-water to obtain the title compound 320 mg (yield 42%). Melting point was 162 to 164° C. (ethanol-water).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11]>C(O)CC(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]2)=[N:3][CH:4]=1)#[N:7]
Reactant: CC(=O)NC1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CC(C)CCO
Product: CC(=O)NC1CCN(c2ccc(C#N)cn2)CC1
Temperature: 140 °C
Yield: 58.5 %

Procedure:
6-Chloronicotinonitrile (300 mg, 2.1 mmol) and 4-acetylaminopiperidine (610 mg, 4.33 mmol) were taken in isoamyl alcohol (15 mL) and the mixture was heated to 140° C. for 2 h. Reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CHCl3) to afford N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)acetamide (300 mg, yield 57%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=2.4 Hz, 1H), 7.83-7.80 (m, 2H), 6.95 (d, J=9.3 Hz, 1H), 4.32-4.28 (m, 2H), 3.89-3.80 (m, 1H), 3.14-3.07 (m, 2H), 1.80 (m, 2H), 1.78 (s, 3H), 1.33-1.24 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12]([NH:15][C:16]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:19]2[C:20](=[O:26])[C:21]([NH:24][CH3:25])=[CH:22][O:23][C:18]=2[CH:17]=1)(=[O:14])=[O:13].C(OC(C)C)(C)C>C(Cl)Cl>[CH3:11][S:12]([NH:15][C:16]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:19]2[C:20](=[O:26])[C:21]([N:24]([CH:1]=[O:3])[CH3:25])=[CH:22][O:23][C:18]=2[CH:17]=1)(=[O:13])=[O:14]
Reactant: CNc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O=CO
Solvent: ClCCl
Product: CN(C=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
340 mg of acetic anhydride and 310 mg of formic acid were mixed. The mixture was stirred for 1.5 hours at 40°-45° C. Thereto was added 10 ml of methylene chloride. There was further added 400 mg of 7-methylsulfonylamino-3-methylamino-6-phenoxy-4H-1-benzopyran-4-one. The resulting mixture was stirred for 1 hour at 25°-30° C. 10 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and then recrystallized from acetonitrile to obtain 330 mg (yield: 76.7%) of 7-methylsulfonylamino-3-(N-formyl-N-methylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN2CCCC2)c2ccnc3cc4c(cc23)OCO4)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCN3CCCC3)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 36 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide; (36% yield); reaction time 30 min; mp 255-257° C. (dec.); IR (CHCl3) 1653; 1H NMR (CDCl3) δ 1.79 (m, 4H), 2.64 (m, 4H), 3.20 (t, 2H, J=7.1), 4.07 (s, 3H), 4.14 (s, 3H), 4.69 (t, 2H, J=7.1), 6.18 (s, 2H), 7.46 (s, 1H), 7.68 (s, 1H), 7.89 (s, 1H), 7.95 (s, 1H), 9.37 (s, 1H); 13C NMR (CDCl3) δ 23.7, 49.6, 54.3, 56.3, 56.4, 56.4, 101.3, 102.0, 102.3, 107.0, 108.7, 111.7, 114.8, 119.3, 127.7, 140.9, 143.4, 147.3, 147.8, 150.0, 150.3, 154.2, 164.2; HRMS calcd for C25H25N3O5H: 448.1872; found 448.1872.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.Cl[C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.O.[H-].[Na+]>CN(C=O)C>[CH3:30][C@@:28]1([CH2:31][N:13]2[CH2:12][CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[O:29][C:19]2=[N:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][N:20]2[CH2:27]1
Reactant: FC(F)(F)Oc1ccc(C2=CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CC=C(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
4-(4-Trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridine (0.985 g, 4.05 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.839 g, 3.86 mmol) were added to DMF (15 ml), and the solution was stirred at 60° C. for 8 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic phases was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford as oil. The oil was dissolved in DMF (20 ml), and sodium hydride (94 mg, 2.35 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (0.192 g, yield 23%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[C:26]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[CH:24][N:23]=2)=[C:19]([F:38])[CH:18]=1.CCCCCC>C(#N)C.C(OCC)C>[F:38][C:19]1[CH:18]=[C:17]([NH:16][C:13]([NH:14][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:12])[CH:37]=[CH:36][C:20]=1[O:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:28][C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH:27]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
2-(4-Fluorophenyl)acetyl chloride (135 mg) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (152 mg) was added thereto at 60° C., followed by stirring at the same temperature for 1.5 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-amino-2-fluorophenoxy)-6-[(pyrrolidin-1-yl) carbonylamino]pyrimidine (99.6 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 15 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (5 ml)-hexane (5 ml). The solid was filtered off and dried under aeration to provide the titled compound (111.8 mg, 69.5%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:12][I:13]>>[I-:13].[CH2:1]([N+:5]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCCCC1
Reactant: CI
Product: CCCC[N+]1(C)CCCCCC1
Product: [I-]

Procedure:
Procedure 1b—Following this, a second N-substitution was carried out on the 1-butylazepane using methyl iodide as an N-alkylating agent to form 1-butyl-1-methylazepanium iodide. A slight excess of methyl iodide was added dropwise to 1-butylazepane in dichloromethane keeping the temperature below 20° C. by an ice-water bath. The reaction mixture was then allowed to warm to room temperature and stirred until complete conversion of amine (as determined using 1H NMR). Diethyl ether was then added to the reaction mixture and the white precipitate (1-butyl-1-methyl-azepanium iodide) filtered, washed with ether and dried in air. δH (300 MHz, CDCl3) 3.40 (4H, m), 3.30 (2H, m), 3.02 (3H, s), 1.90 (4H, m), 1.78 (6H, m), 1.40 (2H, m), 1.00 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].[CH:10](OCC)(OCC)OCC.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[CH:10][N:20]([C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=2)[C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOC(=O)C(N)C#N
Reactant: CCOC(OCC)OCC
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2cccc(C#N)c2)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of amino-cyano-acetic acid ethyl ester (10.6 g, 83.3 mmol) and triethyl orthoformate (12.35 g, 83.3 mmol) in acetonitrile (110 mL) is heated at reflux for 45 min. The reaction mixture is allowed to reach rt and 3-amino-benzonitrile (9.80 g, 83.3 mmol) is added and stirred at rt for 48 h. The crude product obtained is purified by column chromatography (1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:2]=1.[H][H]>CCO.C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2]1
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)c1cccnc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1CCCNC1

Procedure:
Diethyl pyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, to which platinum oxide was added, for stirring under 3.4 kgf/cm2 hydrogen for 120 hours, to obtain diethyl piperidin-3-ylphosphonate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cc1

Procedure:
1-fluoro-4-nitrobenzene (133 mg, 0.94 mmol), bis(2-methoxyethyl)amine (125 mg, 0.94 mmol) and potassium carbonate (143 mg, 1.04 mmol) were stirred in DMSO (2 mL) at 70° C. for 24 hours. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound. MS (ESI+) m/e 255.1 (M+H)+.
Reaction SMILES: O1CCCC1.C(O)C.[N+](C1C=CC(C([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])=O)=CC=1)([O-])=O.[OH-].[Na+]>C(=O)(O)[O-].[Na+]>[N+:26]([O-:28])([O:25][CH2:24][CH:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:21][CH2:20][CH2:19][OH:18])=[O:27]
Reactant: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a tetrahydrofuran/ethanol 1:1 (12 mL) solution of 5,6-bis(nitrooxy)hexyl 4-nitrobenzoate (2.5 g, 6.70 mmol) at 0° C. was added 2.5 N sodium hydroxide (6.5 mL) dropwise. The solution was stirred at room temperature for 3 hours. The solution was diluted with a solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo, affording the title compound. 1H NMR (300 MHz, CDCl3) δ: 5.45-5.38 (m, 1H), 4.94 (dd, 1H), 4.73-4.67 (m, 1H), 4.43 (t, 1H), 3.40-3.36 (m, 2H), 1.75-1.68 (m, 2H), 1.43-1.36 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].C(Cl)CCl.C1C=CC2N(O)N=[N:44]C=2C=1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([NH2:44])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:26][CH:27]=2)[C:3]=1[C:32]#[N:33]
Reactant: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
33 mg (0.072 mmol) of rac-3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-pyridin-2yl}sulfanyl)ethyl]benzenecarboxylic acid Example 16 were initially charged in 1.6 ml of DMF. After addition of 20.6 mg (0.107 mmol) of EDC and 14.5 mg (0.107 mmol) of HOBT, the mixture was stirred at RT for 10 min. 19.2 mg (0.358 mmol) of ammonium chloride and 64.8 mg (0.502 mmol) of N,N-diisopropylethylamine were then added, and the reaction solution was stirred at RT overnight. The reaction solution was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[C:4]([CH3:7])[C:5]#[N:6].C(N)(=[S:18])C>O1CCOCC1>[NH2:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[C:4]([CH3:7])[C:5]([NH2:6])=[S:18]
Reactant: CC(N)=S
Reactant: COc1ccc(C(N)=C(C)C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(N)=C(C)C(N)=S)cc1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Add HCl (4 N in dioxane, 659 mL, 2.640 mmol) to a solution of 3-amino-3-(4-methoxyphenyl)-2-methylacrylonitrile (24.8 g, 132 mmol), thioacetamide (19.8 g, 264 mmol) and dioxane (132 mL) under dry nitrogen. Stir for 2 h. Evaporate, dilute the solid with dioxane (20 mL) and add dry TEA (40 mL). Add satd K2CO3 and extract with EtOAc. Evaporate the organic solution and crystallize from CHCl3/hexane (95/5); then recrystallize from MeOH/H2O to remove the excess thioacetamide to afford 3-amino-3-(4-methoxyphenyl)-2-methyl-thioacrylamide. Yield: 90.8%.