Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Triethylamine (2.09 mL, 15.0 mmol) was added to a cold (0° C.) solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (3.05 g, 10.0 mmol) in DCM (100 mL), followed by methanesulfonyl chloride (0.929 mL, 12.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched with water (50 mL). The layers were separated, and the organic layer was washed with saturated NaHCO3, dried, filtered and concentrated to give the crude product. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (25:1) to give (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (3.80 g, 99%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 5.50 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), 2.98 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].CO.[NH2:14][NH2:15]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][NH2:15])=[O:7])#[N:2]
Reactant: NN
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
3-cyanobenzoyl chloride (4.8 g, 29.0 mmol) was dissolved in DCM (20 ml) and MeOH (40 ml) was added in portions at 0° C. The mixture was stirred at 0° C. for 1 h and at rt for 2 h. The solvents were evaporated and the crude methyl ester was dissolved in EtOH (50 ml) and hydrazine (24% aq., 9 ml, 45 mmol) was added. The reaction mixture was refluxed for 48 h and the solvents were evaporated (coevaporation with water). The residue was purified with prep. HPLC to give the title compound (1.8 g, 39%). 1H NMR (DMSO-d6): 9.98 (br s, 1 H), 8.21 (m, 1 H), 8.13 (m, 1 H), 7.99 (m, 1 H), 7.69 (t, 1 H), 4.61 (br s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:25][C:26]1([CH2:33][CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH:29]2[CH2:28][CH2:27][C:26]([CH2:33][CH2:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=4)[N:38]=[CH:37][N:36]=3)([OH:25])[CH2:31][CH2:30]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCC(O)(CCc3ncnc4ccc(OC)cc34)CC2)cc1
Reaction time: 8 h

Procedure:
4-Methoxybenzylamine (0.026 ml, 0.24 mmol) and then sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-hydroxy-4-[2-(6-methoxyquinazolin-4-yl)-ethyl]cyclohexanone (0.06 g, 0.2 mmol) in dichloromethane (1 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 and then dichloromethane/MeOH 9/1 and 2% triethylamine).
Reaction SMILES: [C:1]1([C:6]2([CH2:12][C:13]([CH3:15])=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH:1]1([C:6]2([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)CC1(C2=CCCC2)CCCC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CC1(C2CCCC2)CCCC1=O
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of the compound of Embodiment 4 (2-cyclopent-1-enyl-2-(2-methylprop-2-enyl)cyclopentan-1-one, 5.0 g, 0.02 moles) in ethyl acetate/ethanol (9:1, 100 mL) was added to a Parr reaction bottle. To this vessel was added 5% Pd—C (0.5 g) in one portion. The reaction vessel was placed in a Parr hydrogenation apparatus and H2 gas (40 psi) was introduced. The apparatus was agitated for 2 hours, and it was determined by TLC and GC that the reaction was complete. The resulting organic slurry was filtered through celite and concentrated. The pale yellow oil was distilled under vacuum to give 2-cyclopentyl-2-(2-methylpropyl)-cyclopentan-1-one (4.24 g, 83.1% yield).
Reaction SMILES: Cl[C:2]1[N:29]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[C:39]([NH:40][C:2]3[N:29]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([N:16]6[CH2:21][CH2:20][CH:19]([N:22]7[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]7)[CH2:18][CH2:17]6)=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:35][CH2:36]1
Reactant: CN1CCN(C2CCN(c3ccc(-c4cccn5nc(Cl)nc45)cc3)CC2)CC1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(N6CCC(N7CCN(C)CC7)CC6)cc5)cccn4n3)c2)CC1

Procedure:
206 b) [3-(4-Methyl-piperazin-1-yl)-phenyl]-(8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 2-chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine (23.0 mg, 0.0560 mmol) and 3-(4-methylpiperazin-1-yl)aniline (12.0 mg, 0.0627 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (5.0 mg, 0.0091 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.014 g, 44%). MP=222-225° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.33 (d, J=6.6 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.48 (s, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.95-6.89 (m, 2H), 6.82 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.86 (d, J=13.2 Hz, 2H), 3.31-3.26 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.70-2.38 (m, 13H), 2.37 (s, 3H), 2.30 (s, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.75-1.63 (m, 2H). MS=566 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1)#[N:2].BrC1C=C(C)C=C(C)[C:20]=1[NH2:21].C(=O)([O-])[O-].[K+].[K+].[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CO>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>[CH3:40][C:34]1[CH:39]=[CH:38][C:37]2[C:4]3[C:3]([CH:1]([NH2:2])[N:21]([CH3:20])[C:36]=2[CH:35]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc2c(c1)N(C)C(N)c1ccccc1-2
Yield: 82 %

Procedure:
Added together 2-cyanophenylboronic acid pinacol ester (13.7 g, 60 mmol), 2-bromo-4,6-dimethylaniline (10.0 g, 50 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 g, 2.0 mmol) and potassium carbonate (18.6 g, 138.21 mol) to a 125 mL of a 95/5 mixture of toluene/methanol. The solvents were degassed and the reaction mixture heated to reflux for 48 hours. After cooling, the reaction mixture was vacuum filtered and the organics evaporated and crude product was purified using silica gel column chromatography treated with triethylamine and 1:9 ethyl acetate and methylene chloride mixture as the eluants. The pure product was collected and concentrated to give 3,5-dimethyl-6-phenanthridinamine (9.1 g, 82% Yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) is taken up in dichloromethane. The suspension is cooled to 0° C. on ice. Diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) is added to the suspension. To the resulting solution, cholesteryl chloroformate (6.675 g, 14.8 mmol) is added. The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid. The product is purified by flash chromatography (10.3 g, 92%).
Reaction SMILES: [CH2:1]([CH:13]([CH2:17][C:18](O)=O)[C:14](O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(C1SC=CC=1)CCCCCCCCCCC>C1C(Cl)=CC=C(Cl)C=1>[CH2:1]([C:13]1[CH:17]=[CH:18][S:22][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(CC(=O)O)C(=O)O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: CCCCCCCCCCCCc1cccs1
Solvent: Clc1ccc(Cl)cc1
Product: CCCCCCCCCCCCc1ccsc1

Procedure:
The reaction was carried out in substantially the same manner as in Example 7, by using 27.2 g (0.075 mol) of the dipotassium salt of dodecylsuccinic acid as the initial materials (the salt was prepared in the manner described in Example 5), 33.3 g (0.075 mol) of tetraphosphorus decasulfide, and 9.3 g (0.3 mol) of red phosphorus, as well as 100 ml of dichlorobenzene as a solvent. The yield of dodecylthiophene was 48% (b.p. 196° C./20 mbar).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[N+](C1C=NC=CC=1[NH:32][C@@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]1)([O-])=O>>[N+:20]([C:19]1[CH:18]=[CH:17][C:4]([CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:3][C:2]=1[NH:32][C@@H:33]1[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][CH2:38]1)([O-:22])=[O:21]
Reactant: CC(C)[Si](OCc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2[N+](=O)[O-])CC1
Product: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2[N+](=O)[O-])CC1

Procedure:
The title compound was prepared from (3-fluoro-4-nitrobenzyloxy)triisopropylsilane using the preparation for cis-methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate described above. The yield was 3.5 g (39.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]([CH3:29])=[C:25]([CH:28]=2)[CH2:26]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[N:4]([CH2:26][C:25]2[CH:28]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[CH3:29])[C:5](=[O:8])[NH:6][N:7]=1
Reactant: Cc1ccc(-c2ccccc2)cc1CBr
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cc(-c2ccccc2)ccc1C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a solution of 626 mg (5.44 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one (said compound is a known compound described in J. Chem. Soc. Perkin I, 2645 (1973) and this was produced according to the method described in this literature. In this literature, said compound is named as 3-methoxy-1,2,4-triazol-5(4H)-one) in 7 ml of dry acetonitrile was added 0.79 g (5.71 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at the same temperature for additional 5 hours, water was added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. To the resultant solid residue (1.51 g) was added tert-butyl methyl ether and the solid was washed and ice-cooled. The solid was collected by filtration and dried to obtain 0.72 g (2.44 mmol) of 5-methoxy-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([NH:22][CH3:23])=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[OH:31][CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([NH:40][NH2:41])=O)[CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]3[N:22]([CH3:23])[C:38]([CH:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)=[N:40][N:41]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: NNC(=O)C1CCC(O)CC1
Reactant: CNC(=O)C1(c2ccc(Cl)cc2)CC1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(C2CCC(O)CC2)nnc1C1(c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Methyl trifluoromethanesulfonate (53.9 μL, 0.491 mmol) was added to 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide (100.0 mg, 0.48 mmol). The resulting reaction mixture was stirred at 60° C. for 30 min. To the reaction mixture were then added toluene (2.0 mL), triethylamine (68.6 μL, 0.492 mmol) and 4-hydroxycyclohexanecarbo-hydrazide (38 mg, 0.24 mmol). The resulting mixture was stirred for 3 h at 60° C. and an additional 1 h. at 110° C. The mixture was then cooled to room temperature (about 25° C.). After cooling, the reaction mixture was concentrated to provide a residue. The residue was purified by Prep-HPLC to afford the desired products (cis- and trans-two isomers). Isomer I: LCMS: (M+H)+=332.2/334.2; isomer II: LCMS: (M+H)+=332.1/334.1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:32]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 3 ml of methylene chloride, cooled to 0° C., under argon, is added 346 μl of triethylamine followed by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 295 mg of the desired product as a white solid, m.p. 170°-180° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:31]=[CH:30][C:22]([CH:23]=[CH:24][C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+].O.C(O)C>C(O)(=O)C>[F:1][C:2]([F:32])([F:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:31]=[CH:30][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of ethyl 4-aminocinnamate, one equivalent of 15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the product as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C:13](=[O:26])[CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[N:27]1([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[N:20]1([CH2:19][CH2:18][CH2:17][N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[N:7][N:6]4[C:2]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[N:28]6)[CH:37]=5)=[CH:3][N:4]=[C:5]4[CH:10]=3)=[CH:12][C:13]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1cc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 120 °C

Procedure:
4-(3-Bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1.0 eq, 0.096 mmol, 40 mg), [3-(1H-pyrazol-1-yl)phenyl]boronic acid (1.50 eq, 0.144 mmol, 28.5 mg) and Na2CO3 (2.0 eq, 0.192 mmol, 20.4 mg) are dissolved in DME/H2O (3/1 ml) and PdCl2(PPh3)2 (0.1 eq, 0.0096 mmol, 6.74 mg) is added. The reaction mixture is then heated in a microwave at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the product is purified by flash column chromatography eluting with CH2Cl2/MeOH (80:20) to give 1-(3-piperidin-1-yl-propyl)-4-[3-(3-pyrazol-1-yl-phenyl)imidazo[1,2-b]pyridazin-7-yl]-1H-pyridin-2-one as a yellow solid; [M+H]+=480
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH:34]([C:44](O)=[O:45])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[N:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([NH2:62])[CH:60]=3)[N:55]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=2)=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]1([CH:36]2[CH2:35][CH:34]([C:44](=[O:45])[NH:62][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[N:55]([C:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=[C:53]4[C:50]3[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=3)[CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 0.129 mmol) was added to a suspension of 1-(tert-butoxycarbonyI)-5-phenylpiperidine-3-carboxylic acid (36 mg, 0.117 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.117 mmol) in DMF (0 5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[C:12]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:20])=[CH:7][C:6]=3[CH:5]([C:21]([OH:23])=[O:22])[C:4]=2[CH:3]=1.[CH3:24]O>OS(O)(=O)=O>[OH:1][C:2]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[C:12]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:20])=[CH:7][C:6]=3[CH:5]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[CH:3]=1
Reactant: CO
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1cc(O)c3cc(C)ccc3c1-2
Agent: O=S(=O)(O)O
Product: COC(=O)C1c2cc(C)ccc2-c2c1cc(O)c1cc(C)ccc21
Temperature: 25 °C

Procedure:
The product of Step 2 (4.5 g) was dissolved in MeOH (200 mL) and 3 drops of H2SO4 were added. The mixture was heated to reflux for 3 hrs and cooled to room temperature. After evaporation of the solvent, the resulting residue was dissolved in DCM (150 mL) and washed with brine (50 mL). The organic layer was collected and the solvent evaporated to afford the product methyl 5-hydroxy-3,9-dimethyl-7H-benzo[c]fluorene-7-carboxylate (4.5 g). MS analysis supported the molecular weight of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[Cl:15][C:16]1[S:20][C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][NH2:27])[CH:22]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH2:26][C:23]2[CH:22]=[C:21]([C:19]3[S:20][C:16]([Cl:15])=[CH:17][CH:18]=3)[O:25][N:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: NCc1cc(-c2ccc(Cl)s2)on1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 634.4 mg (3.19 mmol) 4-Fluoro-3-nitro-benzoic acid methyl ester in 12 mL DMF were added 800.0 mg (3.19 mmol) C-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-yl]-methylamine and 0.88 mL (6.37 mmol) triethylamine. The reaction mixture was stirred at room temperature for 16 h. 12 mL water was added. The precipitate was filtered off and washed with water. The yellow crystalline material was dried under reduced pressure at 40° C.