Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][S:19]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])(=[O:21])=[O:20].N1C=CC=CC=1.C1C=CC=CC=1>N1CCCCC1.O>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:22]([S:23]([CH3:26])(=[O:25])=[O:24])[S:19]([CH3:18])(=[O:21])=[O:20])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)CS(C)(=O)=O
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=C(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of 23.3 g (0.10 mol) of 4-dibutylaminobenzaldehyde, 17 g (0.10 mol) of di(methylsulfonyl)methane, 15 mL of pyridine, 7 drops of piperidine, and 400 mL of benzene was heated at reflux for 18 hr, with continuous azeotropic separation of the water evolved. Approximately half of the benzene was removed by distillation, and 200 mL of heptane was added. Upon cooling to room temperature, a white precipitate formed. The crude product was purified by silica gel chromatography followed by micrystallization from ethanol, from toluene, and from methanol, producing 18 g (46%) of (2). A sample of (2) that was sublimed in vacuo melted at 114.5°-115° C.
Reaction SMILES: N1C=CN=C1.[I:6][C:7]1[C:8](=[O:23])[NH:9][C:10](=[O:22])[N:11]([CH:21]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].Cl>CN(C=O)C>[Si:28]([O:19][CH2:18][C@H:17]1[O:20][C@@H:12]([N:11]2[CH:21]=[C:7]([I:6])[C:8](=[O:23])[NH:9][C:10]2=[O:22])[C@H:13]([OH:14])[C@@H:15]1[OH:16])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
Imidazole (216 mg) was added to a mixture of triol 3a (490 mg) and tert-butyldimethylchlorosilane (239 mg) in 1 mL of DMF cooled by an ice bath. The mixture was allowed to warm to room temperature. After 16 hours, the mixture was poured into 0.1 M HCl (25 mL) and extracted with ethyl acetate (3×50 mL), the aqueous phases were washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. Purification by flash chromatography (7% MeOH/CH2Cl2) gave 460 mg of the product as a colorless solid: 1H NMR (DMSO-d6) δ 0.08-0.12 (m, 6), 0.90 (s, 9), 3.72 (dd, 1), 3.80 (dd, 1), 3.90 (bs, 2), 4.02-3.98 (m, 1), 5.76 (d, 1), 7.93 (s, 1), 11.74 (bs, 1).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:27]=3)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)C>O1CCOCC1>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)=[CH:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Yield: 46.8 %

Procedure:
120 mg (0.2 mmol) of N-tert-butyl-4-[3-{3-[(diphenylmethylidene)amino]phenyl}-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridin-2-amine were dissolved in 20 ml of 1,4-dioxane and 5 ml of HCl 4M in dioxane were added. After 4 hours the solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to give, after trituration with diethylether, 40 mg (46% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[N+:19]([CH3:21])[CH3:20])=[CH:16][CH:15]=1.FC(F)(F)C1C=CC(C=O)=CC=1.CNC>>[CH3:20][N:19]([CH3:21])[CH:18]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:23][CH:22]=1
Reactant: C[N+](C)=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CNC
Agent: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(C(F)(F)F)cc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (4-trifluoromethyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-trifluoromethyl-benzaldehyde and dimethylamine.
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)c2c([nH]c1=O)CCCC2
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of ethyl 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (26.0 g, 110 mmol) and phosphorus oxychloride (51.3 mL) was stirred at 130° C. for 1.5 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and ice was added to the residue. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogen carbonate solution, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was collected by filtration, and washed with ethyl acetate-hexane to give the title compound (4.65 g, 17%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=2)=[CH:57][CH:56]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=2)=[CH:59][CH:60]=1
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.021 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.019 g of product in 55% yield: LCMS (ESI) m/z 456 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[N:11]1[N:12]=[CH:13][NH:14][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: c1nnc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Cl)ccc1-n1cncn1
Temperature: 45 °C

Procedure:
To a reaction vessel was added 5-chloro-2-fluorobenzaldehyde (1.29 g, 7.89 mmol), 4H-1,2,4-triazole (0.574 g, 7.89 mmol), Cs2CO3 (2.83 g, 8.68 mmol) and DMSO (15.78 ml). The mixture was capped and heated at 45° C. for 4 hrs before cooling down to rt and stirred at rt over weekend. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography to yield 71A as white solid product (674 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.17 (s, 1H), 8.33 (s, 1H), 7.99-7.91 (m, 2H), 7.84 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)[CH3:21]
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1
Solvent: Cc1ccccc1
Product: CCN(CC)CCC1(c2ccccc2)C=CCC=C1
Temperature: 150 °C

Procedure:
87 g. of methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester are dissolved in 600 ml. of toluene. 95 ml. (about 3 equivalents) of diethylamine are added and then the mixture is heated at 150° C. in a pressure vessel for 16 hours. The workingup is carried out as described in the second part of Example 7. There is obtained crude N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is dissolved in ether and converted with hydrogen chloride into the hydrochloride. After recrystallization from methylene chloride/ether, there is obtained the hydrochloride having the melting point of 134°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClC(OCC)=O.C(N1CCOCC1)C.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH:33][C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Product: N#Cc1ccc(CCNC(=O)c2ccc(O)cc2)cc1

Procedure:
The starting material was prepared by reaction of 4-hydroxybenzoic acid with ethyl chloroformate/4-ethylmorpholine and subsequent addition of p-cyanophenethylamine to give p-(p-cyanophenethylcarbamoyl)phenol and then etherification with methyl bromoacetate/KOH in acetone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[O:25]=[C:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:27]CC(Cl)=O>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH2:16][CH2:27][C:26](=[O:25])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCC(=O)CCC(=O)Cl
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
To a solution of 43.79 g acetic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester in 200 ml of tetrahydrofuran, a solution of 27.16 g potassium tert-butoxide in 200 ml of tetrahydrofuran was added at −78° C. After stirring at this temperature for 90 minutes, a solution of 53.00 g 4-oxo-undecanoyl chloride in 200 ml of tetrahydrofuran was added. After stirring at −78° C. for 2.5 hours, the solution was quenched with saturated sodium bicarbonate solution and diluted with ether. The organic phase was washed with saturated sodium bicarbonate solution and brine, dried and evaporated to dryness. The residue was purified by thin-film distillation and chromatography to yield 25.73 g of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=O.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2oc(C(=O)C3CCCCC3)c(Br)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a mixture of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanone (1.52 g) synthesized above, methyl 4-aminobenzoate (682 mg), triethylamine (5.03 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (593 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (1.29 mL) and sodium cyanoborohydride (567 mg), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give the title object compound (1.46 g, 69%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenoxy]-acetonitrile (0.288 g, 0.672 mmol) was reacted with NaN3 (0.218 g, 3.360 mmol) and NH4Cl (0.180 g, 3.360 mmol) in DMF (5 ml) to give the product (0.245 g, 0.520 mmol, 77%) as a white solid, dec. 224.5-226° C. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 5.39 (s, 2H), 5.50 (s, 2H), 6.85 (d, J=7.3 Hz, 2H), 7.12 (t, J=8.4 Hz, 3H), 7.18 (t, J=7.0 Hz, 2H), 7.35-7.44 (m, 4H), 7.48 (t, J=7.2 Hz, 2H), 7.60-7.62 (m, 4H), 16.80 (broad s, 1H); IR (solid) 3020, 2910, 1605, 1520, 1480, 1460, 1340 and 1240 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.33; H, 5.28; N, 14.91.
Reaction SMILES: [C:1]1([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[C:4]3=[C:5]([CH2:10][CH2:11][N:3]3[CH:2]=1)[CH:6]=[CH:7][CH:8]=2.[Mg].C(OCC)(=O)C>CO>[C:1]1([C@H:12]2[C@H:16]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[C:15](=[O:26])[NH:14][C:13]2=[O:27])[C:9]2[C:4]3=[C:5]([CH2:10][CH2:11][N:3]3[CH:2]=1)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC3)=C1c1c[nH]c2ccccc12
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CC3)[C@@H]1c1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 3-(4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (115 mg, 0.33 mmol) in anhydrous methanol (10 ml) was added magnesium turnings (200 mg). The mixture was heated to reflux for 1.5 hours. The mixture was cooled to room temperature poured into ethyl acetate (100 ml) washed with 1M hydrochloric acid (100 ml) and dried over anhydrous magnesium sulfate. Evaporation to dryness gave a residue that was purified by flash column chromatography (SiO2, 50% EtOAc in hexanes) to yield (±)-trans-3-(4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione as a pink solid (108 mg). M.p.=144-148° C., 400 MHz 1H NMR (DMSO-d6) δ: 11.53 (s, 1H), 11.05 (s, 1H), 7.41-7.35 (m, 4H), 7.14-7.07 (m, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.89-6.85 (m, 2H), 4.51-4.45 (m, 4H), 3.69 (t, J=7.2 Hz, 2H); LCMS: 356 [M+H].
Reaction SMILES: [Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[CH3:24]O.B(F)(F)F>CO>[Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([O:12][CH3:24])=[O:11]
Reactant: CO
Reactant: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)O
Agent: FB(F)F
Product: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)OC

Procedure:
The dibromo acid product obtained in Example V, 2-(7,8-dibromohexadecyl)-acrylic acid, is dissolved in 50 ml of methanol and 5 ml of boron trifluoride methanol solution is added. The solution is heated under reflux for 6 hrs. The solution is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over Na2SO4. The ether solvent is removed under reduced pressure to give 4.80 g of crude oily product, methyl 2-(7,8-dibromohexadecyl)-acrylate.
Reaction SMILES: CN([C:4](=[O:13])[CH2:5][C:6]1[N:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)N.Cl.[O:15]1CCOCC1>>[CH3:12][N:7]1[C:6]([CH2:5][C:4]([OH:13])=[O:15])=[CH:10][C:9]([CH3:11])=[N:8]1
Reactant: Cc1cc(CC(=O)N(C)N)n(C)n1
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(CC(=O)O)n(C)n1

Procedure:
To a solution of (2,5-dimethyl-2H-pyrazol-3-yl)-acetic acid N-methyl-hydrazide (9.1 g, 41 mmol) in dioxane (50 mL) aqueous sodium hydroxide solution was added (5 N, 50 mL) and the and the resulting mixture was heated under reflux for 4 h. After addition of hydrochloric acid (5 N, 50 mL), all volatiles were evaporated. The residue was extracted with refluxing ethanol (150 mL) and the solvent was evaporated. Residual volatiles were azeotropically removed by coevaporation with toluene to afford (2,5-dimethyl-2H-pyrazol-3-yl)-acetic acid as a viscous oil. It was dissolved in ethanol (100 ml), p-toluene sulfonic acid (2.0 g, catalytic) was added and the resulting mixture was heated under reflux for 16 h. After evaporation of the solvent, the residue was extracted with ethyl acetate and water. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, heptanes:ethyl acetate=100:0 to 40:60) to afford the title compound as a colorless oil (7.6 g, 100%). 1H-NMR (400 MHz, CDCl3): δ=1.22 (t, J=7 Hz, 3H), 2.22 (s, 3H), 3.61 (s, 2H), 3.75 (s, 2H), 4.18 (q, J=7 Hz, 2H), 5.95 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[CH:10]/[CH3:11])/[CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: CCC(O)(CC)c1ccc(OC)cc1
Agent: BrB(Br)Br
Product: C/C=C(\CC)c1ccc(O)cc1
Yield: 86.3 %

Procedure:
Using a procedure analogous to Example 36C, 3-(4-methoxyphenyl)-3-pentanol (0.4 g, 2 mmol) and 1M boron tribromide (4 ml, 4 mmol) give the title compound (0.28 g, 86%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[C:30]([N:27]1[CH2:28][CH2:29][CH:24]([C:21]2[CH:22]=[N:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)N1CCC(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
4-(1′-(tert-Butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.166 g, 0.37 mmol) is placed in 0.65 ml of dichloromethane at 0° C. and then 4N HCl in dioxane (1.4 ml, 5.59 mmol) is added. The reaction medium is stirred at ambient temperature for 18 h. After concentrating to dryness, the reaction medium is hydrolysed with 20 ml of H2O and then K2CO3 is added until a pH of 10 is reached. The aqueous phase is extracted with ethyl acetate. The organic phase is then washed with a saturated aqueous sodium chloride solution, then dried over MgSO4 and concentrated to dryness. 0.12 g of 1-(1′-(tert-butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:37].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:37])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N(C)c1cc(Br)cnc1N1CCOCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (described herein) (18.0 mg, 0.035 mmol) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (2.11 mg, 0.053 mmol), followed by iodomethane (7.5 mg, 0.053 mmol). Stirring continued for 1.5 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-60% EtOAc/hexanes) to give N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-N,3-dimethyl-2-(pyridin-2-yl)quinolin-4-amine as a yellow foam. Mass Spectrum (ESI) m/e=526.2, (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[N:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.[Cu]I>[N:22]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]3[N:11]([CH3:21])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(Br)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(-n2ccnc2)n1
Yield: 58 %

Procedure:
2-Bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (102 mg, 0.3 mmol), imidazole (41 mg, 0.6 mmol), CuI (6 mg, 0.03 mmol), and K2CO3 (124 mg, 0.9 mmol) were mixed in dimethylformamide (2 mL). The resulting solution was heated for 5 h in a microwave reactor held at a constant temperature of 160° C. The crude product was purified using reverse phase column chromatography to give 2-(1H-imidazol-1-yl)-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-vinyl)pyridine (57 mg). MS (ESI): m/z 328 [M+H]+.