Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([OH:15])=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6](C)[O:7]2.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][O:15][C:9]2[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[C:2]([OH:1])=[C:3]3[C:8]=2[O:7][CH:6]=[CH:5][C:4]3=[O:17])=[CH:23][CH:24]=1
Reactant: Cc1cc(=O)c2c(O)c3ccoc3c(O)c2o1
Reactant: Fc1ccc(CCCBr)cc1
Product: O=c1ccoc2c(OCCCc3ccc(F)cc3)c3occc3c(O)c12

Procedure:
4,9-Dihydroxy-7-methyl-5H-furo[3,2-g]chromen-5-one was reacted with 1-bromo-3-(4-fluorophenyl)propane according to General Procedure A to give 9-(3-[4-fluorophenyl]propoxy)-4-hydroxy-5H-furo[3,2-g]chromen-5-one, that was further reacted according to General Procedure G step 1-3, to provide the title compound in 22% yield (over 4 steps). 1H NMR (300 MHz, CDCl3): δ 2.04-2.14 (m, 2H), 2.53 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.83 (t, J=7.8, 2H), 4.34 (t, J=6.3, 2H), 6.73 (d, J=2.1, 1H), 6.94 (t J=8.7 Hz, 2H), 7.13-7.18 (m, 2H), 7.50 (d, J=2.1 Hz, 1H), 8.98 (s, 1H, OH). MS (ES) m/z: 342.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Cl)[N:3]=1.C[O-].[Na+].[SH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS
Reactant: Nc1ccnc(CCl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 1 h

Procedure:
A solution of 4-amino-2-chloromethylpyrimidine (11.6 g.) in methanol (20 ml.) was added over 15 minutes to a stirred mixture of sodium methoxide (4.32 g.), N-(2-mercaptoethyl)phthalimide (16.6 g.) and methanol (100 ml.), and the mixture stirred for 1 hour after the addition was complete and then evaporated to dryness. The residue was partitioned between 1 N hydrochloric acid and ethyl acetate, and the aqueous phase separated and neutralised by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts dried and evaporated to dryness, and the residue was recrystallised from acetonitrile to give 4-amino-2-[(2-phthalimidoethyl)thiomethyl)pyrimidine, m.p. 131°-133°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[N:23]=1)[CH2:16][CH3:17]
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: CCCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCN(Cc1ccc(COc2ccc(C3CC3C(=O)OC)cc2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), {4-[(propyl{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]phenyl}methanol (0.303 g, 0.745 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 m1) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.366 g, yield 77%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:12][O:11]2)=[CH:4][N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[N:23]1[CH2:30][C@H:29]2[NH:31][CH2:32][C@@H:24]1[CH2:25][CH:26]=[CH:27][CH2:28]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:12][N:31]2[CH2:32][C@H:24]3[N:23]([C:14]4[CH:15]=[CH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:13]=4)[CH2:30][C@@H:29]2[CH2:28][CH:27]=[CH:26][CH2:25]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(OC[C@@H]2CO2)cn1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3C/C=C\C[C@H]2CN3c2ccc3ccccc3c2)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3CC=CC[C@H]2CN3c2ccc3ccccc3c2)cn1
Temperature: 95 °C

Procedure:
(S)-2-Methyl-5-oxiranylmethoxy-pyridine (13 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was removed and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:13]=[CH:14][CH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1>C1COCC1.N12CCCC1=NCCC2.C1C=CC=CC=1>[CH2:17]([C:16]1[C:2]2[C:1](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4](=[O:11])[C:3]=2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: O=C1CCC(=O)C2CC=CC=C12
Reactant: C=CC1CC=CCC1
Agent: C1CN=C2CCCN2C1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=CCCc1cccc2c1C(=O)C1=C(CCCC1)C2=O
Reaction time: 65 h
Yield: 34 %

Procedure:
A 45 g sample of the tetrahydronaphthoquinone-butadiene dimer adduct of Example 1 was dissolved in 400 ml THF and 20 drops of 1,5-diazabicyclo[4.3.0]non-5-ene were added. The solution was stirred for 65 hours while exposed to air. The THF was then blown off with air and the residue was dissolved in benzene. The benzene solution was filtered to remove insoluble impurities and the solution was then chromatographed on Florisil. The product was eluted with a 4:1 mixture of benzene/ethyl acetate, and the yield of crude product was 15 g (34% yield). An analytical sample, after recrystallization first from ethanol, then from hexane, had a mp of 111° to 113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 106.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.13 mg (0.131 mMol) isopropyl isocyanate, 21.9 mg of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[C:2]1([NH:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCOC(=O)C(C)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Nc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 1-aminonaphthalene (1.43 g, 10 mmol) and triethylamine (1.5 mL, 10.8 mmol) in dimethylformamide (3.0 mL) at room temperature under nitrogen was added ethyl 2-bromopropionate (1.4 mL, 10.8 mmol). After stirring at 60° C. (bath temperature) 18 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a brown oil. Purification of the crude product by flash chromatography on silica gel eluting with Et2O-hexane (5:95) to give ethyl 2-(1-naphthylamino)propionate (1.726 g, 73%) as a white crystalline solid after trituration with cold hexane. TLC(Et2O-hexane; 2:3) Rf=0.43.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1.[Cl-].[NH4+].CO>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 13 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.2 g (1.1 mol) of benzophenone (8a; Ar=R=Ph) and 365 ml of dry THF at 35° to 40° C. over a period of 30 minutes. This mixture was stirred at that temperature for 2 hours and for further 13 hours to complete the reaction. The reaction mixture was poured into 1.4 kg of cooled 10% aqueous ammonium chloride solution with cooling with ice. This mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.2 g of a crude carbinol (theoretical yield based on the benzophenone, 98.6%). Into a 1-liter reaction flask were introduced 200.2 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94°-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.1 g of crude 1,1-diphenylethylene. This crude reaction product was distilled with a Claisen flask equipped with a vigreux to obtain 174.1 g of 1,1-diphenylethylene (9a; Ar=R=Ph). b.p., 103° C./1 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:20])[NH:15][C:16](=O)[CH2:17]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:17]=[C:16]([NH:15][C:14]([O:13][CH3:12])=[O:20])[N:1]=2)[CH:4]=1)(=[O:10])=[O:9]
Reactant: COC(=O)NC(=O)CCl
Reactant: CS(=O)(=O)c1ccc(N)nc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(S(C)(=O)=O)ccc2n1

Procedure:
A suspension of 2-amino-5-(methylsulfonyl)pyridine (58.7 mmol) and methyl(chloroacetyl)carbamate (70 mmol) in 88 ml of HMPT is treated in a manner similar to that described above with respect to Example 1D to yield the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=1.CC([O-])(C)C.[K+].O>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([CH3:15])[N:11]=[C:12]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1nccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)cc(Nc2nccs2)n1
Temperature: 0 °C
Yield: 51.5 %

Procedure:
To a cool (0° C.), stirring suspension of 2-aminothiazole (3.05 g, 0.0305 mol), 4,6-dichloro-2-methylpyrimidine (5.84 g, 0.0358 mol) in THF (50 mL) was added dropwise over 10 minutes via addition funnel a solution of t-BuOK (40 mL, 30% wt in THF, 0.1069 mol). The reaction was allowed to slowly warm to room temperature overnight. To the reaction was added water (40 mL) and the resulting clear solution was extracted with chloroform and then chloroform/methanol (4:1). The combined extracts were concentrated to near dryness to give a precipitate. The solid was collected by filtration to give the title material (3.559 g) as a solid. The filtrate was concentrated to dryness and the resulting solid was dissolved in boiling methanol and allowed to precipitate overnight aided with the addition of some water. The solid was collected by filtration, washed with water and air dried to give the title material (1.451 g) as a solid. The aqueous layer from the extraction was acidified with 10% HCl and a precipitate was formed. The solid was collected by filtration, washed with water to give the title material (1.559 g) as a solid. The solids were combined to give the title material (6.569 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.53 (3H, s), 6.90 (1H, s), 7.21 (1H, d, J=3.5 Hz), 7.46 (1H, d, J=3.5 Hz), 11.87 (1H, s). LC/MS (M+H)+: 227, 229. HPLC ret. time (Condition E): 1.427 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH2:1]([N:3]([CH2:6][C:7]#[C:8][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2)[CH2:4][CH3:5])[CH3:2]
Reactant: C#CCN(CC)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N,N-diethyl propargylamine (38 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-(3-(N,N-diethylamino)-1-propynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:28].FC(F)(F)C(O)=O>C(#N)C>[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:16]1[N:15]=[C:14]2[N:13]([CH2:24][CH3:25])[C:12](=[O:26])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:28]
Reactant: CCN(CC)CCCCN
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCCCNc1ncc2c(n1)N(CC)C(=O)N(c1cc(OC)cc(OC)c1)C2
Temperature: 90 °C
Yield: 56 %

Procedure:
A mixture of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (0.5 g, 1.33 mmol), 4-diethylaminobutylamine (0.38 g, 2.66 mmol,) and trifluoroacetic acid (0.31 g, 2.66 mmol) in acetonitrile (6 mL) was heated in a sealed tube at 90° C. for 18 hours. The solvent was removed under reduced pressure and the residue taken up in 1N HCl. The solution was made basic with 50% NaOH and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by radial chromatography eluting with a solvent mixture of ethyl acetate/methanol/ethyl (89:10:1 v/v/v) to give 0.34 g (56%) of the titled compound: mp 83-85° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 458.2
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:12]1[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:5]([C:12]1[C:17](=[O:18])[C:16]([N+:1]([O-:4])=[O:2])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCc1c(C)[nH]c(C)c([N+](=O)[O-])c1=O
Temperature: 80 °C

Procedure:
Premixed nitric acid (d 1.5, 0.15 g) and sulfuric acid (0.05 g) was added dropwise at 5-10° C. to 3 (94 mg) in sulfuric acid (d 1.64, 0.5 g). The mixture was heated at 80° C. for 1 hr then cooled and added to ice. Saturated aqueous sodium carbonate was added until effervescence ceased. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. Elution with hexane/ethyl acetate gave 3-heptyl-2,6-dimethyl-5-nitropyridin-4(1H)-one (13) as a yellow oil: yield 76 mg (67%); silica gel TLC Rf 0.45 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.77-0.81 (m, 3H), 1.19-1.27 (m, 10H), 2.29 (s, 3H), 2.35 (s, 3H) and 2.44-2.47 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52](O)=[O:53])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:52]([CH:48]3[CH2:49][CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:47]3)=[O:53])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (1.0 g) in dichloromethane (100 mL) was added N,N-di-iso-propylethylamine (0.56 mL) at room temperature. After 10 minutes N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (617 mg) was added followed by 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (671 mg) and 1-hydroxybenzotriazole (435 mg). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the title compound as a white foam (1.4 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1C=CC=CC=1CBr.[H-].[Na+]>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH2:26][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1-c1nc2ccccc2[nH]1
Reactant: Fc1cccc(F)c1-c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cn1c(-c2c(F)cccc2F)nc2ccccc21
Yield: 4 %

Procedure:
2-(2,6-difluorophenyl)benzimidazole (Example 12) (2.00 g, 8.70 mmol) and 2,6-difluoro-α-bromo-toluene (25) (2.85 g, 160 M %), were dissolved in THF (20 mL). To this mixture, NaH (0.75 g, 215 M %) was added. After mixing for 2 hours, the reaction was quenched with MeOH and concentrated. The residue was redissolved in ethylacetate, and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was recrystallized from ethylacetate/hexane (1:1) yielding white powders of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (2.62 g, 0.35 mmol, 85% yield. M.p. 145° C. 1H-NMR (300 MHz, CD2Cl2): δ 7.77 (m, 1H, H4), 7.54 (m, 1H, H4′), 7.49m, 1H, H7), 7.29 (m, 2H, H5,6), 7.24 (m, 1H, H4″), 7.08 (m, 2H, H3′, 5′), 5.82 (m, 2H, H3″, 5″), 5.30 (s, 2H, CH2PhF2).
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([OH:46])=O.NN>O.CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([NH:7][NH2:8])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)c(F)cc32)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 245.2 %

Procedure:
HOBt (Aldrich, St. Louis, Mo., 303 mg, 2.24 mmol), EDC HCl (430 mg, 2.242 mmol) and 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carboxylic acid (858 mg, 1.87 mmol) were weighed into a 250 mL round bottomed flask and treated with DMF (7 mL). The resulting solution was stirred at RT for 30 min. The reaction mixture was then treated with anhydrous hydrazine (0.29 mL, 9.34 mmol) and stirred at RT for 30 min. The reaction mixture was diluted with water resulting in precipitate formation. The solid was collected by filtration, washed with water, and dried under high vacuum for 3 h at 50° C., affording crude 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.17 g) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 473.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (1H, br. s.), 8.17 (1H, s), 8.01 (2H, d, J=8.4 Hz), 7.97 (5H, s), 7.82 (1H, d, J=10.8 Hz), 7.50 (1H, d, J=6.5 Hz), 7.45 (3H, d, J=8.2 Hz), 4.56 (2H, br. s.), 4.11 (3H, br. s.), 2.36 (4H, s).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[C:13]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1Br
Yield: 83 %

Procedure:
3-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 113°-115° C., yield 83%.