Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=O)[C:4]1C=CC(C2N=C(C3C=CC(CC(C)C)=CC=3)ON=2)=C(C)[CH:5]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][N:40]=[C:39]([C:42]3N=CC(C=O)=N[CH:47]=3)[N:38]=2)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(C1C=CC(C2ON=C(C3N=[CH:67][C:68]([CH2:71][NH:72][C@@H:73]4[CH2:76][C@H:75]([C:77]([OH:79])=[O:78])[CH2:74]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C:37]2[O:41][N:40]=[C:39]([C:42]3[CH:47]=[CH:67][C:68]([CH2:71][NH:72][C@@H:73]4[CH2:74][C@H:75]([C:77]([OH:79])=[O:78])[CH2:76]4)=[CH:3][C:4]=3[CH3:5])[N:38]=2)=[CH:35][CH:36]=1)[CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(C=O)cn3)no2)cc1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CN[C@H]4C[C@@H](C(=O)O)C4)cn3)no2)cc1
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(CC(C)C)cc3)n2)c(C)c1
Product: Cc1cc(CN[C@H]2C[C@@H](C(=O)O)C2)ccc1-c1noc(-c2ccc(CC(C)C)cc2)n1

Procedure:
The title compound was prepared from 4-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-3-methyl-benzoic acid methyl ester by procedures analogous to those described in Preparations (6F-6G) and Examples (1A-1B) for the preparation of 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyrazine-2-carbaldehyde and 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cis-cyclobutanecarboxylic acid, respectively.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: CN1CCCNCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCCN(C)CC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 73 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with 1-methyl-1,4-diazepane as described in Steps 5 and 6, Example 1 to give the title compound as a solid (73% yield). LC/MS: RT 2.00 min; m/e 380 (M+H); 1H NMR (CDCl3, δ, ppm): 11.81 (1H), 7.51 (1H), 7.29 (1H), 6.78 (1H); 3.85 (2H), 3.46 (6H), 3.19 (2H), 2.78 (3H), 2.40 (5H), 1.09 (3H, t).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCOC(C)=O>CN1C(=O)CCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:8]=[C:9]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a slurry of 2-morpholino-4,6-dichloropyrimidine (prepared as in Method 22, 2.0 g, 8.54 mmol) in NMP (14 mL), triethylamine (1.43 mL, 10.25 mmol) was added. The heterogeneous mixture was stirred for 15 minutes, then treated with morpholine (0.75 mL, 8.54 mmol). Upon refluxing at 85° C. under argon for 2 hours, the solution was cooled, then added to EtOAc (160 mL). The organic solution was washed with 25 mL of NaHCO3(sat.) (2×), water (2×) and brine, dried over Na2SO4, filtered and concentrated. The crude material was dissolved in 200 mL EtOAc and filtered through a SiO2 pad, further eluting with EtOAc, yielding 2.2 g (93%) of 2,4-dimorpholino-6-chloropyrimidine as an off-white solid. LCMS (m/z): 285.0 (MH+), 1H NMR. (CDCl3): δ 5.86 (s, 1H), 3.71-3.76 (m, 12H), 3.52-3.56 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([O:12]CC)=[O:11].O1CCCC1.CO.[OH-].[Na+].O.Cl>>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Br)sc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (6.54 g, 0.0193 mol) was dissolved in a mixture of tetrahydrofuran (40.0 mL, 0.493 mol) and methanol (20.0 mL, 0.494 mol), then sodium hydroxide in water (1.0 M, 60.0 mL, 0.0600 mol) was added at 0° C. The resulting solution was warmed to rt and stirred for 20 min. The mixture was neuturalized with hydrochloric acid in water (4.0 M, 20 mL, 0.080 mol) and extracted with 80 mL DCM twice. The combined organic layers were washed with 30 mL water, evaporated in vacuo to yield a white solid product (5.96 g, yield 99.4%). LCMS: (FA) ES−, 307, 309, 311.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8](=O)[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][CH2:8][N:9]2[CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:3]=1[F:17]
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n(C2CC2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.8 %

Procedure:
To a suspension of 390 mg (1.532 mmol) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-quinoxaline-2,3-dione in 20 mL tetrahydrofuran was added 3.37 mL (3.369 mmol) 1M borane tetrahydrofuran complex. The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The mixture was stirred for 30 min. at room temperature and the layers were separated. The aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 211 mg (61%) of the desired compound as a white solid. MS (ESI): m/z=225.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.Cl[C:21]([O:23]C)=[S:22].[CH2:25](N(CC)CC)C>C(O)C>[CH3:25][S:23][C:21](=[O:22])[NH:15][C:8]1[CH:9]=[C:10]2[C:14](=[C:6]([C:5]3[S:1][C:2]4[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=4[CH:4]=3)[CH:7]=1)[NH:13][N:12]=[CH:11]2
Reactant: COC(=S)Cl
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CSC(=O)Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 530 mg, 2.0 mmol) and methyl chlorothioformate (0.25 mL, 2.8 mmol) in ethanol (10 mL) was added triethylamine (0.56 mL, 4.0 mmol). The reaction mixture was stirred at ambient temperature for about 16 hours and the resulting solid was collected by filtration, washed with water (3×50 mL), and dried to yield (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-thiocarbamic acid S-methyl ester (448 mg, 66%); LC/MS (Table 1, Method e) Rt 2.14 min; m/z: [M−H]− 338.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)c2cccnc2)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
In the manner described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester (6.2 g) was saponified a refluxing mixture of methanol (30 mL) and 1N NaOH (30 mL). After 1 hour, the cooled reaction was neutralized with the addition of 1N HCI (30 mL) and the resulting crystalline solid was filtered off and washed well with water to give 5.8 g of (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid, mp 235°-238° C. A sample was recrystallized from methanol to furnish the analytical specimen, mp 238°-240° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([O:20][C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:18][C:17]([NH:31][C:32]([N:34](C=O)[NH2:35])=[S:33])=[C:16]([F:38])[CH:15]=1.C[C:40](C)=[O:41]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:19]([O:20][C:21]2[C:26]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:18][C:17]([N:31]=[C:32]2[S:33][C:2](=[O:4])[N:35]([CH:40]=[O:41])[NH:34]2)=[C:16]([F:38])[CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN(C=O)C(=S)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Product: O=Cn1[nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)sc1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triphosgene (0.7 g) in toluene (20 ml) was dropwise added to a solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylaminothiocarbonyl]-N1 -formyl-hydrazine (2.8 g) in acetone (70 ml) stirred at 0° C. Stirring was continued at room temperature for 1 hour and the solvents removed under reduced pressure. Column chromatography (methylene chloride:ethyl acetate, 3:1) yielded the product (3.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14]S[C:11]=2[C:10](I)=N1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].N#N.O1CC[CH2:27][CH2:26]1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:11](=[CH:10][CH:17]=[CH:14][CH:13]=2)[CH:27]=[CH:26]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sccc21
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2ccccc21
Temperature: 57.5 °C
Yield: 69 %

Procedure:
A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indole-2-boronic acid 1-carboxylic acid tert-butyl ester [3.82 g, 9.42 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No. WO 02/32861], 3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [4.0 g, 11.42 mmol, Example 5B above], tetrakis(triphenylphosphine)palladium(0) (544 mg, 0.470 mmol), potassium carbonate (2M aqueous, 12 mL) in tetrahydrofuran (60 mL) is purged with N2 for 10 minutes then heated to 55-60° C. for 7.5 hours. The reaction is diluted with ethyl acetate (50 mL) and washed with water (20 mL). Water layer is back extracted with ethyl acetate (50 mL). The combined ethyl acetate phases are dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge (5-30% ethyl acetate gradient in heptane) to give 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxlic acid tert-butyl ester [3.8 g, 69%, Intermediate (9)]; 1H NMR [(CD3)2SO)]: δ 8.08 (2H, m), 7.64 (1H, s), 7.38 (2H, m), 7.14 (1H, s), 4.81 (2H, s, —OCH), 1.65 (9H, s), 1.32 (9H, s), 0.92 (9H, s, Si(CH3)3), 0.10 (6H, s, Si(CH2)); LC/MS: 584 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(Cl)cc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(Cl)cc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 54.5 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 5-chloro-2-methyl-phenol (26 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(5-chloro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 55%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.54-7.64 (m, 3H), 7.18 (d, J=7.8 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.91 (dd, J=8.0, 2.0 Hz, 1H), 5.22 (s, 2H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(F)cc2)nn1
Yield: 89.6 %

Procedure:
The general click procedure was used substituting the following quantities: 37 (27.3 mg, 0.08 mmol); 1-azido-4-fluorobenzene (10.4 mg, 0.08 mmol); CuSO4 (2.0 mg, 0.01 mmol); NaAsc (6.0 mg, 0.03 mmol); TBTA (5.0 mg, 0.01 mmol); in t-BuOH/EtOH/H2O (2:1:0.5); afforded the 39 as a white solid (35 mg, 92.2%). 1H NMR (CDCl3, 400 MHz): δ 8.73-8.72 (d, 1H, J=1.91 Hz); 7.90 (s, 1H); 7.74-7.67 (m, 3H); 7.58-7.55 (t, 1H); 7.24-7.18 (t, 2H); 7.07-7.06 (d, 1H, J=1.71 Hz); 4.84-4.79 (q, 1H); 4.54-4.50 (d, 2H, J=5.90 Hz); 4.29-4.21 (m, 2H); 3.68-3.67 (d, 1H, J=1.78 Hz); 3.53-3.52 (d, 1H, J=1.78 Hz); 3.37-3.18 (m, 2H); 1.30-1.26 (t, 3H). 13C NMR (CDCl3, 100 MHz): 169.82, 166.17, 166.03, 163.28, 160.81, 152.86, 152.00, 144.94, 132.78, 122.10, 122.01, 120.48, 116.45, 116.22, 115.59, 61.91, 53.43, 52.40, 52.24, 34.55, 32.42, 13.63.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][C:7]([CH3:14])=[N:6][C:5]=2[S:4][C:3]=1[C:15](=[O:17])[NH2:16].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[CH:8][C:9]=2[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])[S:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: Cc1cc(C(=O)O)c2c(N)c(C(N)=O)sc2n1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCOCC2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid (see Example 10) (0.5 g, 2.0 mmol), morpholine (0.87 g, 10 mmol) and PyBop (0.88 g, 2.0 mmol) in DMF (10 mL) was stirred at room temperature overnight. It was diluted with water and extracted with methylene chloride (50 mL). Concentration of the organic phase the title compound as an orange solid (0.45 g, 70.3%).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([CH3:15])([N+:12]([O-:14])=[O:13])[CH2:10][CH:11]=1.C(N)(N)=[O:17].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH3:5][C:6]1[N+:7]([O-:17])=[CH:8][C:9]([CH3:15])([N+:12]([O-:14])=[O:13])[CH2:10][CH:11]=1
Reactant: CC1=CCC(C)([N+](=O)[O-])C=N1
Reactant: NC(N)=O
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC1=CCC(C)([N+](=O)[O-])C=[N+]1[O-]
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a chloroform (10 mL) solution of 2,5-dimethyl-5-nitropyridine (1.2 g), under ice cooling in a nitrogen atmosphere, carbamide peroxide (1.9 g) and trifluoroacetic anhydride (2.3 mL) were added dropwise, and the resultant was stirred for 30 minutes under ice cooling and then stirred at room temperature for 13 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The obtained organic layer was washed with a 10% aqueous sodium thiosulfate solution and then dried over sodium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; chloroform/ethyl acetate-gradient elution=100/0→0/100) to obtain the title compound (1.0 g) as a yellow solid.
Reaction SMILES: [Cl:1][CH:2]([O:4][C:5](Cl)=[O:6])[CH3:3].[CH3:8][C:9]1([CH3:19])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([OH:18])[C:11]=2[O:10]1.N1C=CC=CC=1>ClCCl>[C:5](=[O:6])([O:18][C:17]1[C:11]2[O:10][C:9]([CH3:19])([CH3:8])[CH2:13][C:12]=2[CH:14]=[CH:15][CH:16]=1)[O:4][CH:2]([Cl:1])[CH3:3]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 20 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
21.5 g (0.15 mole) of 1-chloroethylchloroformate are added in a single portion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6 g; 0.15 mole) in dichloromethane (150 ml). The mixture is cooled to between 0° and 5° C., and 12 g (0.15 mole) of pyridine are added dropwise. The mixture is stirred for 3 hours at 20° C. The organic phase is then washed with 2×50 ml of iced water. It is dried over magnesium sulphate and the solvent is evaporated. A yellow oil is obtained which is distilled. 34.1 g of the expected carbonate is then recovered (84% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])[N:29]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(-c2ccc(F)cc2F)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.9 g of 2,4-difluorophenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 25 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 144-146 C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15]Br)=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][N:28]=[N+:29]=[N-:30])=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
In a 25 mL pear-shaped flask, 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (150.6 mg, 0.341 mmol) and sodium azide (66.6 mg, 1.02 mmol) were combined with DMF (2 mL) to give a light yellow solution. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (2×25 mL), dried over MgSO4, and concentrated in vacuo to give 3-azidomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (134.7 mg, 97.8%) as a yellow oil which contained DMF as an impurity. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.78-8.27 (m, 1H) 7.26-7.76 (m, 5H) 4.30 (s, 2H) 3.52 (s, 2H). MS calcd. for C18H12F3N5O3 [(M+H)+] 404.0, obsd. 404.0, [(M+H-N2)+] 376.0, obsd. 376.0.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)C(O)=O)[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C1(P([N:40]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.CN(C)C=O>O>[NH2:40][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][CH:23]=1)[O:16][C:11]1[N:10]=[C:9]2[S:8][C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])=[N:15][C:14]2=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A mixture of 3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)benzoic acid (3.90 g, 11.0 mmol), diphenylphosphoryl azide (3.55 mL, 16.5 mmol), triethylamine (2.28 mL, 16.5 mmol) and N,N-dimethylformamide (80 mL) was stirred at room temperature for 3 hr, and water (20 mL) was added and the mixture was stirred at 100° C. for 15 hr. The precipitation solid was collected by filtration. 6N Hydrochloric acid (100 mL), ethyl acetate (30 mL) and tetrahydrofuran (10 mL) were added to the solid, and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off, and the aqueous layer was separated from the filtrate, neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.13 g, 31%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.C(Cl)(=O)C>>[Cl-:7].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccccc1Cl
Solvent: CC(=O)Cl
Product: Clc1ccccc1C=[N+]1CCCCC1
Product: [Cl-]

Procedure:
The reaction of 8.5 g (0.100 mol) piperidine and 7.0 g (0.050 mol) 2-chlorobenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 3.9 g (0.050 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 7.1 g (corresponding to 58% of the yield calculated by theory) 1-(2-chloro-benzylidene)-piperidinium chloride.