Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([N:17]2[CH2:16][CH:15]3[CH:19]([CH2:20][N:13]([C:9]4[N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:12]=[CH:11][N:10]=4)[CH2:14]3)[CH2:18]2)=[O:35])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-c1cccc(Cl)c1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 3′-chloro-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C29H25ClN4O, 480.99; m/z found 481.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:28]1([C:34]2[C:42]3[S:41][C:40]4[C:43]([C:47]5[CH:48]=[CH:49][C:50]6[NH:51][C:52]7[C:57]([C:58]=6[CH:59]=5)=[CH:56][CH:55]=[CH:54][CH:53]=7)=[CH:44][CH:45]=[CH:46][C:39]=4[C:38]=3[CH:37]=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[C:28]1([C:34]2[C:42]3[S:41][C:40]4[C:43]([C:47]5[CH:48]=[CH:49][C:50]6[N:51]([C:2]7[CH:3]=[CH:4][C:5]([C:8]8[C:21]9[C:16]([C:15]([C:22]%10[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=%10)=[C:14]%10[C:9]=8[CH:10]=[CH:11][CH:12]=[CH:13]%10)=[CH:17][CH:18]=[CH:19][CH:20]=9)=[CH:6][CH:7]=7)[C:52]7[C:57]([C:58]=6[CH:59]=5)=[CH:56][CH:55]=[CH:54][CH:53]=7)=[CH:44][CH:45]=[CH:46][C:39]=4[C:38]=3[CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(-c2cccc3c2sc2c(-c4ccc5[nH]c6ccccc6c5c4)cccc23)cc1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccccc5c5cc(-c6cccc7c6sc6c(-c8ccccc8)cccc67)ccc54)cc3)c3ccccc23)cc1
Yield: 77.4 %

Procedure:
In a 50-mL three-neck flask were put 1.3 g (3.3 mmol) of 9-(4-bromophenyl)-10-phenylanthracene, 1.0 g (2.4 mmol) of 3-(6-phenyldibenzothiophen-4-yl)-9H-carbazole, and 0.95 g (9.9 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 11 mg (0.18 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 6 hours under a nitrogen stream. After the stirring, the aqueous layer of this mixture was subjected to extraction with toluene, and the solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried over magnesium sulfate. This mixture was gravity-filtered, and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (developing solvent, toluene:hexane=1:9 and then toluene:hexane=3:7). The obtained solid was recrystallized from toluene/hexane to give 1.4 g of a pale yellow solid which was the object of the synthesis in a yield of 80%. The synthesis scheme of Step 2 is illustrated in (b-11).
Reaction SMILES: BrCCC(C)CC(C)(C)C.CC(CC(C)(C)C)CC=O.[CH3:21][C:22]([CH3:46])([CH2:24][CH:25]([CH3:45])[CH2:26][CH:27]([O:37]C(N1C=NC=N1)=O)[CH2:28][CH2:29][CH:30]([CH3:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:23]>[Cu]>[CH3:46][C:22]([CH3:23])([CH2:24][CH:25]([CH3:45])[CH2:26][CH:27]([OH:37])[CH2:28][CH2:29][CH:30]([CH3:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:21]
Reactant: CC(CCC(CC(C)CC(C)(C)C)OC(=O)n1cncn1)CC(C)(C)C
Agent: [Cu]
Agent: CC(CC=O)CC(C)(C)C
Agent: CC(CCBr)CC(C)(C)C
Product: CC(CCC(O)CC(C)CC(C)(C)C)CC(C)(C)C

Procedure:
2,2,4,9,11,11-Hexamethyl-6-dodecanol (b.p. 104°-110° at 0.18 mm of mercury pressure) was prepared by reacting 1-bromo-3,5,5-trimethylhexane with 3,5,5-trimethylhexanal and converted into 1-[2,2,4,9,11,11-hexamethyl-6-dodecyloxycarbonyl]-1,2,4-triazole of formula: ##STR17## following the procedures of Example 18. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#N.C(O)=[O:19]>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:19]
Reactant: O=CO
Reactant: N#Cc1ccccc1COc1cccc(Cl)c1
Agent: [Ni]
Product: O=Cc1ccccc1COc1cccc(Cl)c1
Temperature: 150 °C
Reaction time: 17 h

Procedure:
Raney nickel alloy (9.72 g) was added to a solution of part of the crude (2-(3-chlorophenoxymethyl)benzonitrile (9.72 g) in 75% formic acid (150 ml). The resulting mixture was heated at 150° C. for about 5 hours, further Raney nickel alloy (3 g) was added, and heating at 150° C. was continued for a further 17 hours. The mixture was filtered and the solid was washed with a little methanol. The combined filtrate and washings were diluted with water and extracted with ether. The extracts was washed successively with water, aqueous potassium carbonate and brine, then dried and concentrated to give 2-(3-chlorophenoxymethyl)benzaldehyde (5.80 g) as a yellow-brown oil, 1H NMR delta 5.51 (2H, s), 10.18 (1H, s) ppm. A mixture of this crude benzaldehyde, methyl(methylthiomethyl)sulphoxide (1.73 g) and Triton B [(40 weight % solution of benzyltrimethylammonium hydroxide in methanol) 1.21 ml] in THF (6 ml) was heated at 110° C. for 3 hours. Further Triton B (2 ml) was added and the mixture was heated for a further 4 hours at 110° C. Further Triton B (2 ml) and methyl (methylthiomethyl)sulphoxide (1.5 ml) were then added and the mixture was heated for a further 6 hours at 110° C. After cooling, the mixture was poured into water and extracted with ether. The extracts were washed with water and brine, dried, concentrated and chromatographed using ether as eluant to give a single stereoisomer of the sulphoxide (A) [1.10 g, 7% yield from 2-(bromomethyl)benzonitrile] as a viscous oil, 1H NMR delta 2.18 (3H, s), 2.74 (3H, s), 5.04 and 5.12 (each 1H, d J 12Hz), 7.85 (1H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[OH:11][CH2:12][C:13]([CH2:15]O)=O.[Cl-].[NH4+]>[OH-].[NH4+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:15]=[C:13]([CH2:12][OH:11])[N:10]=1
Reactant: O=C(CO)CO
Reactant: N=C(N)c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Product: OCc1c[nH]c(-c2ccccc2Cl)n1
Temperature: 25 °C

Procedure:
According to literature reference (Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wu, L.; Mach, R. H. Bioorg. Med. Chem. 2001, 9, 3113–3122), to a mixture of 2-chlorobenzenecarboximidamide (5.4 g, 34.8 mmol), 1,3-dihydroxyacetone dimmer (6.2 g, 34.8 mmol) and ammonium chloride (7.5 g, 139 mmol) is added concentrated ammonium hydroxide (40 mL). The reaction mixture is then heated to reflux for 30 minutes after which time it is cooled to room temperature and poured into a ice/water mixture. This aqueous suspension is extracted with CH2Cl2 and the combined organic extracts are dried over sodium sulfate and concentrated to provide a crude solid. The crude product is recrystallized from ethyl acetate to afford 3.9 g of [2-(2-chlorophenyl)-1H-imidazol-4-yl]methanol.
Reaction SMILES: C(O[C:4](=[O:26])[CH2:5][N:6]([C:23](=[O:25])[CH3:24])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl.[CH2:30]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:31]1[CH:39]=[CH:38][C:37]2[O:36][CH2:35][O:34][C:33]=2[CH:32]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(O)C.CN(C=O)C.O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:9]=[CH:8][C:7]([N:6]([CH2:5][C:4]([N:43]3[CH2:44][CH2:45][N:40]([CH2:30][C:31]4[CH:39]=[CH:38][C:37]5[O:36][CH2:35][O:34][C:33]=5[CH:32]=4)[CH2:41][CH2:42]3)=[O:26])[C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCOC(=O)CN(C(C)=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl{acetyl[4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate (2.30 g, 6.40 mmol) in ethanol (50 mL) was added 5 M aqueous sodium hydroxide (1.92 mL, 9.60 mmol), and the resulting solution was stirred at room temperature for 30 minutes. To this reaction solution were added 5 M hydrochloric acid (2 mL) and water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.68 g of an oil. To a solution of this oil in DMF (10 mL) were added 1-piperonylpiperazine (1.29 g, 5.86 mmol), triethylamine (1.85 mL, 13.3 mmol) and diethyl cyanophosphonate (1.07 mL, 6.36 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 2.21 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH:22]CC(O)=O)=[N:3]1.[OH-].[Na+]>CCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:22])=[N:3]1
Reactant: Cn1nc(NCC(=O)O)c2c(Oc3ccc4ccccc4c3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(N)c2c(Oc3ccc4ccccc4c3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[1-Methyl-4-(naphthalen-2-yloxy)-1H-indazol-3-ylamino]-acetic acid (A25) To a 50 mL round-bottomed, one-necked flask containing K-3 (90 mg, 0.25 mmol) was added 1:1 EtOH/H2O (2 mL). To this stirring suspension was added 15% aqueous NaOH (0.133 mL, 0.5 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated on the vacuum line and the resulting solid was suspended in H2O (2 mL) and 1N HCl was added until a pH of 1-2 (litmus paper) was reached. The mixture was stirred at room temperature for 30 min and then filtered. The resulting solid was dried to afford 65 mg (75%) of A25 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 3.77 (s, 3H), 3.93 (s, 2H), 5.63 (br s, 1H), 6.18 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0, 8.0 Hz, 1H), 7.41 (dd, J=8.8, 1.2 Hz, 1H), 7.51 (m, 2H), 7.63 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 12.45 (br s, 1H), LC/MS (86%) (ESI+) Calcd. for 347.4; Found: 348.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([O:19]C)=[O:18])=[C:6]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])[CH:7]=1>Cl>[C:9]([CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:17]([OH:19])=[O:18])([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(F)cc1C(C(=O)OC)C(=O)OC
Agent: Cl
Product: O=C(O)Cc1cc(F)ccc1C(=O)O
Temperature: 110 °C

Procedure:
A suspension of dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate (1.80 g) in concentrated hydrochloric acid (25 ml) was heated at 110° C. for 48 h. The reaction was cooled and the subtitle compound collected as a white solid by filtration (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:39][C:37]2[CH:36]=[CH:35][C:33]3[N:34]=[C:30]([NH:29][C:20]4[C:19]5[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=5)[N:23]=[CH:22][N:21]=4)[S:31][C:32]=3[CH:38]=2)=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)cc5C(F)(F)F)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-2-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-2-(trifluoromethyl)phenyl isocyanate (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The solid was filtered off and washed thoroughly with dichloromethane to obtain a yellow solid (27 mg, 48 μmol, 42%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]−; Rt=3.79 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)OCc2ccccc2)N1CCc1ccccc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Sodium hydride (562 mg, 14.1 mmol, 60% mineral oil dispersion) is added to a solution of 1-(benzyloxycarbonyl)pyrazolidin-3-one (2.81 g, 12.8 mmol, prepared similarly to that described in J. Org. Chem. 1990, 55, 6037) and DMF (37 mL) at 0° C. The solution is stirred for 30 minutes and then (2-bromoethyl)benzene (1.90 mL, 13.9 mmol) is added. The solution is stirred at 0° C. for 1 hour and 16 hours at room temperature. Aqueous workup (EtOAc, brine, MgSO4) and purification by flash chromatography (2:1→1:1 hexane:EtOAc) gives 1.58 g (38%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH:6]2[CH:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH:6]2[CH:8]([CH3:14])[C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1
Reactant: CC1=CC(C)C2CC(C)(CO)OC2=C1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1=C2OC(C)(CO)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 0 °C

Procedure:
2.3 g of 2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran was dissolved in 30 ml of anhydrous acetic acid and 1.9 ml of nitric acid was added dropwise while stirring at 0° C. After stirring at 0° C. for one hour, the solution was poured into ice-water, followed by stirring at room temperature for one hour. The reaction solution was extracted with ether, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform) to obtain 1.34 g of the objective product.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:21](=[CH:22][C:11]3=4)[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[O:13]1[CH2:14][C:10]2([C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:8][C:9]2=[O:29])[C:11]2[CH:22]=[C:21]3[C:16](=[CH:15][C:12]1=2)[CH2:17][CH2:18][CH2:19][CH2:20]3
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCC3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one was obtained (80%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.33-7.19 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.68 (s, 1H), 6.49 (s, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 2.76-2.72 (m, 2H), 2.58-2.56 (m, 2H), 1.71 (t, J=3.2 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ180.5, 158.7, 140.4, 139.0, 132.9, 130.2, 128.8, 126.0, 124.1, 123.6, 123.3, 110.3, 110.2, 79.6, 58.6, 30.0, 29.0, 23.2, 23.0; MS (ES+) m/z 292.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:47]12[CH2:53][C@H:52]1[CH2:51][C@@H:50]([CH2:54][NH:55][C:56]1[CH:61]=[N:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][N:57]=1)[NH:49][CH2:48]2.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:49]2[C@H:50]([CH2:54][NH:55][C:56]3[CH:61]=[N:60][C:59]([C:62]([F:65])([F:63])[F:64])=[CH:58][N:57]=3)[CH2:51][C@H:52]3[C@H:47]([CH2:53]3)[CH2:48]2)=[O:10])[C:5]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cnc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)cn1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cccn2)c(C(=O)N2C[C@H]3C[C@H]3C[C@H]2CNc2cnc(C(F)(F)F)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-methyl-3-(1H-pyrazol-1-yl)-2-pyridinecarboxylic acid D38 (24.63 mg) was dissolved in 1 ml of DMF, then TBTU (46.0 mg, 0.143 mmol) and DIPEA (0.025 ml, 0.143 mmol) were added. The suspension was stirred for 30 minutes at room temperature. N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyrazinamine D31 (30 mg) dissolved in 1 ml of DMF was added and the reaction was stirred overnight at room temperature. NaHCO3 saturated solution were added, and the aqueous layer was extracted with of DCM. The organic layers were collected together, dried through a phase separator and concentrated under vacuum to give a crude which was purified by SCX chromatography (column size 5 g). A second purification was performed by silica —NH chromatography (Biotage SP—column size 11 g, using Cy:EtOAc=5:5 to EtOAc). It was recovered the title compound E5 (22 mg). UPLC: (Acid Final_QC): rt=0.81 and 0.85 minutes (rotamers present), peaks observed: 458 (M+1). C22H22F3N7O requires 457. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1 H), 7.85-7.77 (m, 3 H), 7.52 (s, 1 H), 7.38-7.32 (m, 1 H), 7.05-6.89 (m, 1 H) 6.35-6.30 (m, 1 H) 4.58-4.37 (m, 1 H), 3.77-3.66 (m, 1 H), 3.65-3.37 (m, 2 H), 2.65 (s, 3 H), 2.50-2.36 (m, 2 H), 1.42-0.83 (m, 3 H), 0.82-0.71 (m, 1 H), 0.15-0.06 (m, 1 H).
Reaction SMILES: OC[C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1.C1(=O)NC(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:13][O:12][C:5]1[N:4]=[CH:3][CH:10]=[C:9]([CH3:11])[C:6]=1[C:7]#[N:8]
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nccc(C)c1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (1.50 g, 8.42 mmol), phthalimide (1.3 g, 8.84 mmol) and triphenylphosphine (2.3 g, 8.77 mmol) in Tetrahydrofuran (THF) (50 mL) at 0° C. in an ice bath was added dropwise DIAD (1.8 mL, 9.26 mmol). Within minutes a white suspension formed. Additional THF (˜50 mL) was added to allow stirring. The reaction was allowed to warm to RT and stirred for 3 h. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. The remaining solid was triturated with a small volume of EtOAc, filtered, washed with a small volume of EtOAc, then dried under vacuum to give the product 6-(1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile (2.12 g, 6.90 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00-7.92 (m, 2H), 7.92-7.87 (m, 2H), 7.15 (s, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H). MS(ES)+ m/e 308.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21]CC)=[O:20])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:33](Cl)(Cl)=[O:34].O>C1(C)C=CC=CC=1.C(OCC)C>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([OH:21])=[O:20])[C:33]2=[O:34])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1ccccc1NCCNc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1ccccc1N1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-trifluoromethylphenyl)-N′-(2-ethyloxycarbonylphenyl)-1,2-diaminoethane (1.1 g, 3.1 mmol) and triethylamine (1.1. mL, 7.5 mmol) in toluene was added phosgene in toluene (1.84 mL, 3.5 mmol). After stirring at room temperature for 30 min. Water and diethyl ether were added. The organic phase was dried and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel using dichloromethane as eluent. The isolated ester (0.96 g) was hydrolysed in 4N aqueous sodium hydroxide to give the desired compound in a yield of 0.6 g. M.p. 197-198° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.C(Cl)(Cl)Cl.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:24]
Reactant: NN
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
12.3 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine are stirred in 40 cc of hydrazine hydrate at a bath temperature of 90° for 3 hours. The mixture is cooled with ice, 100 cc of chloroform are added, and the excess hydrazine is separated. Upon concentrating the chloroform phase, the crude title compound is obtained as an oil. This is converted to bis[3-hydrazino-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine]trisfurmarate by boiling with 4 g of fumaric acid in 50 cc of absolute ethanol. M.P. 132°-134° (decomp., from absolute ethanol).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([CH3:23])[CH2:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH2:16])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[Cl:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[NH:27][CH:26]=1>>[Cl:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([NH:16][C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][N:13]([CH2:12][CH:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]3)[CH3:23])=[O:35])=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: CC(C)N1CCC(CN(C)C[C@H](N)c2ccccc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: CC(C)N1CCC(CN(C)C[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, crude (R)-N2-(1-isopropyl-piperidin-4-ylmethyl)-N2-methyl-1-phenylethane-1,2-diamine dihydrochloride (500 mg, 1.4 mmol) and 3-chloroindole-6-carboxylic acid (325 mg, 1.7 mmol) afforded, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 115 mg (18%) of the title compound.