Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[Cu][C:22]#[N:23]>Cl.O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: Nc1ccc(C2CCCc3cncn32)cc1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 0 °C

Procedure:
A solution of 2.13 g of 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water is cooled in an ice-bath and a solution of 0.78 g of sodium nitrite in 2 ml of water is added slowly. The solution is added via dropping funnel to an ice cooled solution of 3.0 g copper(I) cyanide in 10 ml of water, keeping the temperature between 30°-40°. The reaction mixture is heated on a steam bath for 1 h, cooled and brought to pH 9. The organic extracts are dried over sodium sulfate and evaporated and the residue is chromatographed on silica gel with ethyl acetate to yield the title compound.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl-].[Na+]>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14](=[N:1][OH:3])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)c1cc(I)ccc1F
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1cc(I)ccc1F
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
Employing the method utilized by Fray (Fray, J. M., Cooper, K., Parry, M. J., Richardson, K., Steele, J. J. Med. Chem. 1995, 38, 3514-3523), a solution of sodium nitrite (0.52 g) in water (3 mL) is added dropwise to a solution of ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate (Preparation 15, 2.4 g) in glacial acetic acid (3 mL) at 5° C. with stirring. After 1.5 h, the mixture is poured into saturated aqueous sodium chloride and extracted with dichloromethane. The organic extracts are washed with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated in vacuo to give a sticky oil which is flash chromatographed on silica gel (230-400 mesh, 10 g) eluting with 20% ethyl acetate and hexane to give, after concentration of product fractions, 1.31 g of the title compound as a yellow liquid (˜3/1 ratio of oxime isomers). Physical characteristics: MS (ESI+) m/z 366 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[O:15][CH:16]1[CH2:19][N:18](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17]1>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[O:15][CH:16]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:17]1
Reactant: Brc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 0.5 h
Yield: 175.4 %

Procedure:
A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylene chloride was treated with 29 g (0.23 mole) of potassium carbonate, stirred for 30 min, then 75.4 g (0.19 mole) of 3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylene chloride was added dropwise. After stirring for 5 hr, the inorganic salts were removed by filtration and the filtrate was washed with water to destroy excess phosgene. Concentration (after drying) in vacuo yielded 96.85 g of oily residue. Trituration of the residue with isopropyl ether yielded 42 g of crude tan-gray product. A sample for analysis was recrystallized from isopropyl ether, m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([C:3]1([OH:19])[C:15]2[CH:14]=[C:13]3[N:9]([CH2:10][CH2:11][C:12]3=O)[C:8](=[O:17])[C:7]=2[CH2:6][O:5][C:4]1=[O:18])[CH3:2].[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][CH:30]=2)[C:25]1=O)(=[O:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:20]([NH:23][CH:24]1[C:25]2=[C:11]3[CH2:10][N:9]4[C:13](=[CH:14][C:15]5[C@:3]([CH2:1][CH3:2])([OH:19])[C:4](=[O:18])[O:5][CH2:6][C:7]=5[C:8]4=[O:17])[C:12]3=[N:34][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:26]=32)[CH2:32][CH2:33]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC1CCc2cccc(N)c2C1=O
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2C(NC(C)=O)CC3
Reaction time: 24 h

Procedure:
361 mg of (S) 4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter abbreviated as “trione”) was added to the solution of 300 mg of the compound prepared in (4) above in 200 ml of toluene. The mixture was heated under reflux using a Deanstark apparatus for 10 minutes. To the mixture was added 1 mg of pyridinium-p-toluenesulfonate (hereinafter abbreviated as “PPTS”) and the mixture was refluxed while stirring for a further 24 hours. After cooling, the residue obtained by removing toluene by concentration was suspended into 300 ml of chloroform-methanol (10:1) solvent. Insoluble substances were removed and the residue was powdered with methanol to obtain 336 mg of the title compound. mp: above 240° C. (decomposed)
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH2:28][CH3:29]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([CH2:28][CH3:29])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CCC(=O)O
Product: CCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and propionic acid, the title compound was obtained in 47% purity by HPLC. MS(ESI+): m/z=391.1.
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[I-].[Na+].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Cl)[CH3:26]>C(O)C.O>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:11][CH:10]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH3:26]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)Nc1ccc(C2C(=O)c3ccccc3C2=O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A solution of sodium (0.412 g) in absolute ethanol ((200 mL) was treated with 2-(4-acetylaminophenyl)-indan-1,3-dione (5 g, Reference Example 14) then with sodium iodide (2.69 g) and chloroacetic acid ethyl ester (3.6 mL). The mixture was heated at 100° C. for 20 minutes then poured into water (500 mL) and then extracted with ethyl acetate (500 mL). The organic extract was dried over magnesium sulfate and then evaporated to give the title compound (5.25 g) as a pale coloured solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:2]1[N:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=2[OH:19])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Product: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(O)cc3O)n2)c(O)c1

Procedure:
Following the procedure of Example 14, the title compound is prepared by the reaction of 2,4-dichloro-6-phenyl-s-triazine and resorcinol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:24]([O:14][CH:13]([C:15]1[N:16]=[N:17][NH:18][N:19]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: OC(CCCCCCc1ccccc1)c1nn[nH]n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nn[nH]n1
Yield: 74.4 %

Procedure:
A solution of 7-phenyl-1-(2H-tetrazol-5-yl)-heptan-1-ol (36 mg, 0.14 mmol), TBSCl (63 mg, 0.42 mmol) and imidazole (28 mg, 0.42 mmol) in DMF (0.7 mL) was stirred at room temperature for 72 h before it was diluted with EtOAc, and washed with H2O and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude material that was purified by flash chromatography (SiO2, 1.5×15 cm, 10% acetone-hexanes) to afford 5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazole (39 mg, 75%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.26 (dd, 2H, J=6.3, 8.4 Hz), 7.16 (m, 3H), 5.25 (t, 1H, J=5.8 Hz), 2.57 (t, 2H, J=7.7 Hz), 1.85 (m, 2H), 1.58 (m, 2H), 1.31 (m, 6H), 0.90 (s, 9H), 0.13 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[CH3:42])=[O:30].O>CN(C=O)C>[F:20][CH:2]([F:1])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=2[CH3:42])=[O:30])=[N:6][N:7]=1
Reactant: Cc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Reactant: CCC(=O)Nc1ccc(S(N)(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(C(F)F)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
In a solution of 5-difluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol(53 mg, 0.18 mmol), K2CO3 (27.0 mg, 0.20 mmol) in DMF (1.5 mL) was added 2-methyl-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (47 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (4.0 mL) was added to the reaction and stirred until precipitation occurred and filtered off product (77.0 mg, 83% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.70-7.53 (m, 7H), 7.18 (t, J=51.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.26 (s, 2H), 2.82 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@H:28]2[N:29]([C:34]([O:36][CH2:37][CH:38]3[C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:44]4[C:39]3=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])[CH2:30][C@H:31]([S:32][CH3:33])[C@H:27]2[O:26][CH2:25]1>ClCCl>[CH3:33][S:32][C@H:31]1[CH2:30][N:29]([C:34]([O:36][CH2:37][CH:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:45]3[C:50]2=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:35])[C@@H:28]2[C:24](=[O:23])[CH2:25][O:26][C@H:27]12
Reactant: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@@H]2C(=O)CO[C@H]12
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Dess-Martin periodinane (130 mg, 0.65 mmol) was added to a stirred solution of alcohol (55) (278 mg, 0.33 mmol) in dichloromethane (10 mL) under an atmosphere of argon. The mixture was stirred for 1 hour then diluted with dichloromethane (25 mL). The organic phase was washed with a mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulphate solution (1:1, 20 mL), then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 60:40 to 65:35 gave ketone (56) (113 mg, 87%) as a white solid. TLC (Rf=0.24, Et2O:pentane 2:1); analytical HPLC two main peaks, Rt=15.71 and 15.91 min.; HPLC-MS 396.1 [M+H]+, 414.1 [M+H2O+Na]+, 813.2 [2M+H]+; [□]D18−137.3° (c=2.33, CHCl3). δH (500 MHz, CDCl3) mixture of rotamers approx. 1:1; 2.15 (1.5H, s, SCH3), 2.19 (1.5H, s, SCH3), 3.30-3.38 (1H, m, CHSMe), 3.68-3.80 (1.5H, m, FmocNCH2), 3.93-4.05 (1.5H, m, 0.5×FmocNCH2 and OCH2C═O), 4.10-4.35 (2.5H, m, OCH2C═O, Fmoc-CH, and 0.5×Fmoc-CH2), 4.40-4.54 (2.5H, m 1.5×Fmoc-CH2 and FmocNCH), 4.74-4.84 (1H, m, OCHCHSCH3), 7.28-7.77 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3); 14.662 (SCH3), 47.133 (Fmoc-CH), 48.449/48.954 (CHSCH3), 50.539/53.419 (FmocNCH2), 61.005/61.420 (FmocNCH), 67.710/68.437 (Fmoc-CH2), 70.733 (OCH2C═O), 85.174/86.042 (OCHCHSCH3), 119.916, 119.987, 124.917, 124.964, 125.240, 125.448, 127.069, 127.712 and 127.969 (Fmoc aromatic CH), 141.255/141.317, 143.627, 143.778 and 144.264 (Fmoc quaternary), 154.942/155.049 (Fmoc C═O), 207.818/207.973 (ketone C═O).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1([C:42](=[O:44])[CH3:43])CCNCC1>C(#N)C>[C:42]([N:3]1[CH2:7][CH2:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)=[O:9])[CH2:4][CH2:2]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCN(C(=O)/N=c2\sc(C)cn2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial were combined a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) and diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added 1-(piperazin-1-yl)ethanone (13 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to supply the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11](=O)[CH2:12][CH2:13][CH:14]=[CH2:15]>>[CH3:15][C:14](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[CH2:13][CH2:12][CH:11]=[CH2:10]
Reactant: NNc1cc[nH]c(=O)c1
Reactant: C=CCCC(C)=O
Product: C=CCCC(C)=NNc1cc[nH]c(=O)c1
Yield: 71.3 %

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 1, except for using 4-hydrazino-1H-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 1 and 5-hexen-2-one (7.41 ml, 64.6 mmol), the titled compound was obtained as a white solid. (Yield: 71.3%)
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[C:19]([CH2:21][N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]4([C:42]5[C:33](=[CH:34][C:35]6[O:40][CH2:39][CH2:38][O:37][C:36]=6[CH:41]=5)[O:32][CH2:31]4)[C:23]3=[O:43])[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3([C:42]4[C:33](=[CH:34][C:35]5[O:40][CH2:39][CH2:38][O:37][C:36]=5[CH:41]=4)[O:32][CH2:31]3)[C:23]2=[O:43])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1N(Cc2cccc(N=C(c3ccccc3)c3ccccc3)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of 1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.18 g, 0.32 mmol) in tetrahydrofuran (10 mL) was added 2 M aqueous hydrochloric acid (0.5 mL). The reaction mixture was stirred at ambient temperature for 10 min, cooled to 0° C. and saturated aqueous sodium bicarbonate (10 mL) was added. The mixture was diluted with ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers was washed with brine (45 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 65% ethyl acetate in hexanes to afford 1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.10 g, 76%) as a colorless solid: mp 240-241° C.; 1H NMR (300 MHz, CDCl3) δ7.45-7.35 (m, 1H), 7.25-7.14 (m, 2H), 7.06-6.98 (m, 1H), 6.91-6.86 (m, 1H), 6.59-6.54 (m, 1H), 6.50 (s, 1H), 6.45-6.39 (m, 1H), 6.37 (s, 1H), 5.12-5.03 (m, 1H), 4.99-4.92 (m, 1H), 4.80-4.63 (m, 4H), 4.25-4.05 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 177.5, 157.9, 155.2, 153.0, 144.6, 142.1, 139.0, 138.2, 132.2, 128.8, 123.7, 123.4, 121.2, 111.7, 111.1, 109.6, 107.9, 99.3, 80.0, 64.5, 63.9, 58.1, 45.2; MS (ES+) m/z 401.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([CH3:23])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1cccc(CN)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-(3-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.11,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.21,(1H, t), 7.14-7.11,(2H, m), 7.05,(1H, d), 4.47,(2H, d), 2.56,(3H, s), 2.31, (3H, s), 2.29,(3H, s). LCMS; retention time 3.48 min, MH+ 398.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:18]3=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(3-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (247 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at 50° C. under hydrogen for 40 min and at room temperature under hydrogen for 4 h. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (167.0 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10]Br>>[CH:1]1([NH:7][CH2:2][CH2:1][NH:7][CH:10]2[CH2:9][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: BrCCBr
Product: C1CCC(NCCNC2CCCCC2)CC1
Yield: 78.3 %

Procedure:
N,N′-Dicyclohexyl-1,2-diaminoethane (18.1 g, yield=83%) was prepared as in Synthesis Example 1-1, using cyclohexylamine (83.3 g, 0.840 mol) and 1,2-dibromoethane (19.3 g, 0.103 mol).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CCCCO>[Br:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[C:4]2[C:10]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccc(C(F)(F)F)c4)c23)C1
Yield: 69 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide (250 mg, 0.622 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (374 mg, 1.87 mmol) in n-BuOH (3 mL) was processed as described in Example 62, Step B, to provide (R)-tert-butyl 1-(5-bromo-3-(3-(trifluoromethyl)benzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (250 mg, 69% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([C:25]#[N:26])=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[S:16][CH:17]=[C:13]([C:11]2[CH:12]=[N:8][NH:9][C:10]=2[C:25]#[N:26])[N:14]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)c(C#N)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1[nH]ncc1-c1csc(Nc2ccccn2)n1
Yield: 48.4 %

Procedure:
According to Scheme 13 Step 2: A solution of 1-(4-methoxybenzyl)-4-(2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-3-carbonitrile (31 μmol, 12 mg) in TFA (1 mL) was microwaved for 3 minutes at 130° C. After evaporation of the solvent, the crude residue was dissolved in AcOEt. The organic phase was washed with a saturated aqueous solution of Na2CO3, was dried over MgSO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 95:5) as eluent to yield 4-(2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-5-carbonitrile (15 μmol, 4 mg, 48%) as a white solid.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](OC(=O)C)(=[O:8])[CH3:7].[NH2:13][CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]>O1CCOCC1.O>[NH:13]([CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16])[C:6]([CH3:7])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC(/C=C/CP(=O)(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
At 0°, 170 mg of sodium hydrogen carbonate and, within a period of 5minutes, 50 microliters of acetic anhydride are added to a solution of 100 mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/water (1:1). The whole is stirred for 30 minutes at 0°, approximately 2 ml of Dowex 50 H+ are added and filtration is carried out. The filtrate is concentrated by evaporation and purified by ion exchange chromatography (Dowex 50 H+). Lyophilisation of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 155°.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=O)[CH2:7][NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[CH2:7][NH:8][C:9](=[O:10])[NH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCC(=O)c1ccc(O)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: O=C1NCC(c2ccc(O)cc2)=NN1
Yield: 54 %

Procedure:
A mixture of 20 g of ethyl N-(p-hydroxyphenacyl)carbamate (prepared as described in Preparation 6), 56 g of 80% hydrazine hydrate and 100 ml of butanol was heated under reflux for 30 hours, whilst stirring. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was washed with ethanol to give 9.25 g of the title compound as crystals, melting at 266°-269° C. (with decomposition).