Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][C:9]3=[N:10][N:11]=2)=[CH:3][CH:2]=1.O=C1[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])CCCN1.C(NN)(=O)C1C=CN=CC=1>C(Cl)Cl.CCO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]3=[N:10][N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: c1cc(-c2nnc3n2CCC3)ccn1
Agent: NNC(=O)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound was prepared analogous to 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me3OBF4 (2.66 g, 18 mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). 1H NMR: 1.29 (t, 3 H), 2.03 (m, 1 H), 2.14-2.25 (m, 2 H), 2.32 (m, 1 H), 4.01-4.12 (m, 1 H), 4.16-4.27 (m, 4 H), 7.64 (d, 2 H), 8.74 (d, 2 H)
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(O)(=O)=O.CNCCCCC=CCC.C(N1C[C@@H](O)C[C@H]1C(O)=O)(OC(C)(C)C)=O.[CH2:38]([N:44]([CH3:60])[C:45]([C@@H:47]1[CH2:51][C@@H:50]([OH:52])[CH2:49][N:48]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:46])CCCC=C>>[CH2:38]([N:44]([CH3:60])[C:45]([C@@H:47]1[CH2:51][C@@H:50]([OH:52])[CH2:49][N:48]1[C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])=[O:46])[CH2:7][CH2:6][CH2:5][CH2:11][CH:10]=[CH:8][CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CCC=CCCCCNC
Product: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C

Procedure:
Compound 70b was synthesized from compound 32c and cis-N-Boc-4-hydroxy-L-proline as yellow oil in quantitative yield, following the procedure as described for compound 48.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:16][C@@:10]1([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:3]=[C:4]2[NH:11]1
Reactant: C1COCCN1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Temperature: 120 °C

Procedure:
A mixture of 2.2 g of (2S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 60 mL of morpholine is heated to 120° C. After one hour of heating and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is concentrated under reduced pressure. On the obtained residue, 30 mL of cold water and 150 mL of ethyl acetate are added. The organic phase is then separated, dried on magnesium sulfate, filtered and then concentrated under reduced pressure in order to obtain 2.6 g of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one including the following characteristics:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:31])([F:32])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=C(NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F)C1CC1
Reaction time: 8 h

Procedure:
1-[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)pyridin-3-yl]methanamine (0.18 g) was dissolved in methylene chloride (5 ml), and to the solution was added cyclopropane carbonyl chloride (0.036 ml) at room temperature. The reaction mixture was stirred overnight and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][C:13]([N:20]([CH3:22])[CH3:21])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][NH2:15].[OH-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:15][CH2:14][C:13]([CH3:12])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C)(CN)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCC(C)(CNC(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.1 g.,) in dry benzene (25 ml.) was added to a solution of 2-methyl-2-dimethylamino-hexylamine (1.58 g.,) in dry benzene (25 ml.) and the mixture heated under reflux for 1.5 hrs. The mixture was diluted with water, basified with 2N sodium hydroxide solution, and extracted with benzene (4 × 100 ml.). The combined benzene extracts were washed with water (4 × 50 ml.), dried (Na2SO4) and evaporated affording 3,4-dichloro-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (3.6 g., ca 100%) which slowly crystallised.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+].ClCCl>C(#N)C>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(F)cc3)CC1)O2
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (1.0 g, 3.32 mmol) in acetonitrile (12.0 mL) was added (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.614 g, 3.65 mmol) followed by lithium perchlorate (0.388 g, 3.65 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and dichloromethane (100 mL) added to it. The reaction was then washed with water (100 mL). The organic layer was separated, washed with water, dried with sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO2, 80% EtOAc in dichloromethane to 100% EtOAc) to give the desired product as a purple solid (0.73 g, 45%). M.p.=174-175° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.6, 7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.66 (dt, J=1.6, 7.6 Hz, 1H), 7.5 (dt, J=1.6, 7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.9-6.84 (m, 2H), 4.18-4.1 (m, 1H), 4.0-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.96 (s, 2H), 2.86-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.6-2.5 (m, 2H), 2.2-2.12 (m, 2H), 1.98-1.82 (m, 2H); LCMS: 470 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=30.54
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reaction time: 8 h
Yield: 198.6 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (25 ml) was added potassium carbonate (12.4 g, 0.09 mol). The reaction was allowed to stir for twenty minutes at which time benzyl bromide (8.9 ml, 0.075 mol) was added to the flask. The reaction was allowed to stir overnight. Solvent was removed. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield the title compound (9.9 g, 99% yield): ES-MS (m/z) 243 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1Cl)([O-:3])=[O:2].C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:31]([O:33][P:34]([CH2:39][NH2:40])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]>C(Cl)Cl>[CH2:31]([O:33][P:34]([CH2:39][NH:40][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Reactant: CCOP(=O)(CN)OCC
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(CNc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)OCC
Yield: 68 %

Procedure:
4 g of 2,4 dinitro-1-chloronaphthalene (15.84 mmol) is dissolved in 6.5 g of aminomethanephosphonic acid diethyl ester and 4 g of diphenylmethane and stirred for 72 hours at room temperature. The batch is diluted with methylene chloride, washed with 1N NaOH and washed twice with brine, dried and spun in. The crude product is chromatographed on silica gel with 3.5 liters of cyclohexane and ethyl acetate 1:1 as mobile solvent. 68% of product is obtained in several fractions as viscous oil. NMR (DMSO, delta in ppm): 1.15(6H,tr), 4(4H dq)4.25 (2H m), 7.8, 7.98, 8.9, 9.05 each 1H, 8.6 (2H,d)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[BH4-].[Li+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (277 mg) in tetrahydrofuran (5 mL) was added lithium borohydride (55 mg) at 0° C. After stirring at 0° C. for 1.5 h, lithium borohydride (22 mg) was added to the mixture. The whole was stirred at 0° C. for 2 h, at room temperature for 2.5 h, and then at 50° C. overnight. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give the title compound (37% mg, 15%) as a white amorphous solid. MS 505 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[C:8]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH:7]=1)=[CH2:5])C.[Br:31]N1C(=O)CCC1=O>O1CCCC1.O>[N:26]1([C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][Br:31])[CH:11]=[CH:10][C:9]=2[C:12](=[O:13])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: C=C(OCC)c1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(-n2cncn2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(C(=O)CBr)cc2-n2cncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the same manner as in the synthesis of Compound 515, 1,2,4-triazole was added to Compound 21 of Reaction 6. Then, tributyl(1-ethoxyvinyl)tin was added to the mixture, and the resulting mixture was reacted to obtain (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone was dissolved in a mixed solution of tetrahydrofuran and water (1/1), and N-bromosuccinimide (NBS) was added thereto. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous Na2 SO3 solution, water, and brine. The extracted organic layer was dried over anhydrous MgSO4, and the solid substance was filtered off. The filtrate was vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=3/1→1/2) to obtain 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone. Thus obtained 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone (65 mg, 0.14 mmol) was dissolved in 3 ml of 95% ethanol, and thiourea (16 mg) was added thereto. The mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, CH2Cl2/MeOH=30/1→10/1) to obtain Compound 516 (29.3 mg, 48%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[C@@H:32]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][C@H:35]2[C@@H:33]1[CH2:34]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CO>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[C@H:36]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][C@H:33]2[C@@H:35]1[CH2:34]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of triphenylphosphine (6.4 g, 24.292 mmol), phthalimide (6.2 g, 42.511 mmol) and benzyl (1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hexan-3-ylcarbamate (3.0 g, 12.146 mmol) in toluene (250 mL) was stirred at −78° C. for 30 minutes under nitrogen protection, followed by the addition of diisopropyl azodicarboxylate (8.6 mL, 42.511 mmol) dropwise. The resulting mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The reaction mixture was treated with 10 mL of methanol, and the solvents were removed under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to afford the title compound (3.0 g, 65%) as a light yellow oil. MS (ES+) C22H20N2O4 requires: 376, found: 399 [M+23]+.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([N:15]([CH2:24][CH2:25][CH2:26][CH3:27])[C:16]1[CH:21]=[CH:20]C=[C:18]([O:22][CH3:23])[CH:17]=1)[CH2:12][CH2:13][CH3:14]>CN(C)C=O>[C:5]([C:4](=[C:3]([C:1]1[CH:20]=[CH:21][C:16]([N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:18]=1[O:22][CH3:23])[C:9]#[N:10])[C:7]#[N:8])#[N:6]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCCCN(CCCC)c1cccc(OC)c1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(C#N)=C(C#N)C#N)c(OC)c1
Yield: 76.9 %

Procedure:
In 8 ml of N,N-dimethylformamide, 0.5 g (3.9 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 0.8 g (3.4 mmol) of dibutyl(3-methoxyphenyl)amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 35 minutes. After the ice bath was removed, the mixture was further stirred for 2 hours. After the reaction mixture was poured into 100 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with hexane to give 0.88 g of a black crystal having a mp of 86° C. (yield: 77.2%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>>[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:11]=3)[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)/C=C/c1ccncc1N=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COC(=O)CC1c2ccncc2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17A and 63 mg (0.36 mmol) of 3-methylphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 88 mg (48% of theory) of product.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:9][N:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]([NH:9][N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)NN1CC=CCC1
Temperature: 5 °C
Yield: 25.4 %

Procedure:
To a solution of tert-butyl isocyanate (0.991 g) in methylene chloride (8 ml) was added dropwise to a mixture of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in methylene chloride (40 ml) under ice bath cooling. The mixture was stirred for an hour at about 5° C. The reaction mixture was evaporated to dryness, and then the residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (40 ml), dried over magnesium sulfate and evaporated to dryness. The crude residue was washed with ether and dried to give N-[(tert-butylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (0.50 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([OH:29])=O.[CH2:36]([NH:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:37][CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C1COCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([N:41]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])=[O:29]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)CCNCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (4.4 g, 1.1 eq) in solution in chloroform (25 ml) and 1-hydroxybenzotriazole (HOBt) (3.05 g, 1.1 eq) in solution in THF (40 ml) are successively added to 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 eq) in solution in anhydrous THF (30 ml). The mixture is stirred for 1 hour at a temperature of approximately 20° C. then diisoamylamine (3.6 g, 1.1 eq) in solution in THF (30 ml) is added. After stirring for 16 hours at a temperature of approximately 20° C., the reaction mixture is concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1) produces the expected compound in the form of a yellow oil (4.3 g; 65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 52 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:27])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[N:29]1([C:38](=N)[NH2:39])C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[Cl:26][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:27])[C:20]=1[S:19][C:13]1[S:12][C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH2:39])=[NH:29])=[CH:7][CH:6]=2)=[O:10])=[CH:15][C:14]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Reactant: N=C(N)n1nnc2ccccc21
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N=C(N)Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Temperature: 60 °C
Yield: 9.2 %

Procedure:
To a solution of N-(4-aminophenyl)-5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamide (0.2 g, 0.45 mmol) and 1H-benzo[d][1,2,3]triazole-1-carboximidamide HCl salt (0.18 g, 0.91 mmol) in acetonitrile (4 mL) was added triethylamine (0.13 mL, 0.91 mmol). After the addition, the resulting reaction mixture was heated at 60° C. for 24 hours. After this time, the reaction mixture was concentrated and purified by reverse phase HPLC to afford the titled product as a solid (20 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.66 (1H, s), 9.68 (1H, m), 9.01 (2H, m), 8.74 (1H, s), 7.73 (2H, m), 7.39 (4H, m), 7.25 (3H, m), 7.12 (2H, dd). MS m/z: 483.06, 485.06 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([N:9]([CH3:11])[CH3:10])=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]([O:25][CH2:26][CH3:27])=[CH2:24])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH2:26]([O:25][C:23]([C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([N:9]([CH3:11])[CH3:10])=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14])=[CH2:24])[CH3:27]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(F)c2oc(N(C)C)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c(C#N)c2nc(N(C)C)oc2c1F
Yield: 65.8 %

Procedure:
6-Bromo-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-168) (0.80 g, 2.68 mmol) was dissolved in toluene (25 ml), then tributyl(1-ethoxyvinyl)tin (1.30 ml, 3.85 mmol), 2,6-di-tert-butylcresol (12 mg, 0.05 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.10 g, 0.14 mmol) were added followed by heating under reflux for 3 days. The insoluble matter was removed by filtration through Celite, followed by washing with ethyl acetate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:hexane=1:2 to 2:3 to 9:1 to dichloromethane:methanol=200:1) to obtain a brown solid (0.51 g, 66%).