Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].C(Br)C.II.[CH:7]1[C:12](Cl)=[CH:11][CH:10]=[C:9]([Cl:14])[CH:8]=1.[CH2:15](Cl)[CH:16]=[C:17]([CH3:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.II>[Cl:14][C:9]1[CH:8]=[CH:7][C:12]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: CC(C)=CCCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CC(C)=CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
Under a nitrogen atmosphere, 58.3 g of magnesium turnings, 800 ml of tetrahydrofuran and about 0.1 g of iodine were put in a flask. When 2 ml of ethyl bromide was added while stirring the above materials, coloration by iodine disappeared and the temperature of the contents of the flask rose. While tetrahydrofuran was refluxed, a solution of 294 g of p-dichlorobenzene in 2 liters of tetrahydrofuran was added dropwise over the course of about 4 hours. After the addition, the mixture was stirred for 2 hours, and cooled to room temperature. Then, a solution of 271.7 g of prenyl chloride in 800 ml of tetrahydrofuran was added dropwise at 15° C. to 20° C. over about 4 hours. After the addition, the reaction mixture was left to stand overnight at room temperature. Then, 2 liters of a 10% by weight aqueous solution of ammonium chloride was added, and the mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with 300 ml of diethyl ether. The diethyl ether layer was combined with the organic layer previously separated, and washed with water, dried, concentrated and distilled to give 222.3 g (yield 61.6%) of p-chloroprenylbenzene having a boiling point of 64° C. to 65.5° C./0.38 mmHg. The nuclear magnetic resonance spectrum of the product was as follows. (The chemical shifts are expressed in δ (ppm) when hexamethylsiloxane (HMS) is used as a standard.)
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([C:18]1[C:27]([CH3:28])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[Cl:29])[O:10][C:11]([CH3:17])([CH3:16])[C:12](F)([F:14])[F:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].ClC1C2C(=CC=CC=2)C=C(C)C=1C(OC(C)(C)C(F)F)CO>>[C:1]([O:7][CH2:8][CH:9]([C:18]1[C:27]([CH3:28])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[Cl:29])[O:10][C:11]([CH3:17])([CH3:16])[CH:12]([F:14])[F:13])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc2ccccc2c(Cl)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Agent: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)F
Product: Cc1cc2ccccc2c(Cl)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)F

Procedure:
Compound 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1-difluoro-2-methylpropan-2-yloxy)ethyl pivalate was prepared following the procedure used to prepare 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate of Example 31, except that 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1-difluoro-2-methylpropan-2-yloxy)ethanol was used instead of 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.57 (s, 1H), 7.56-7.50 (m, 2H), 6.01 (dd, J=8.4, 4.8 Hz, 1H), 5.53 (t, J=56.4 Hz, 1H), 4.47 (dd, J=11.6, 8.4 Hz, 1H), 4.19 (dd, J=11.6, 5.6 Hz, 1H), 2.72 (s, 3H), 1.27 (s, 6H), 1.16 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].F[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:19]([O:21][CH3:22])=[O:20].Cl>COCCOCCOC>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][C:24]1[CH:23]=[C:18]([CH:17]=[CH:16][C:25]=1[N+:26]([O-:28])=[O:27])[C:19]([O:21][CH3:22])=[O:20]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)aniline (2.15 g, 11.00 mmol) in diethylene glycol dimethyl ether (20 mL) was added sodium hydride (60% in oil, 440 mg, 11.00 mmol), and the resulting mixture was stirred at 80° C. for 30 min. To this reaction mixture was added methyl 3-fluoro-4-nitrobenzoate (1.99 g, 10.00 mmol), and the resulting mixture was stirred at 80° C. for 1 hr. After cooling, 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/1) and recrystallized from hexane/ethyl acetate to give crude methyl 3-[[2-chloro-5-(trifluoromethyl)phenyl]amino]-4-nitrobenzoate (1.92 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][CH:6]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)[C:5]([OH:46])=[O:4])=[CH:15][CH:14]=3)=[CH:21][CH:20]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C(CC(=O)c1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(Cc1cccc(C(F)(F)F)c1)C(=O)O)c1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C

Procedure:
2 N Sodium hydroxide solution (1 mL) was added dropwise to a stirred solution of methyl-4-(4′-dibenzofuran-4-ylbiphen-4-yl)-4-oxo-2-(3-trifluoromethy-benzyl)butyrate (220 mg) in tetrahydrofuran (5 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (5 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5-10% methanol in methylene chloride) afforded the title compound has a white solid (190 mg). Rf: 0.60 (10% methanol in dichloromethane); 1H-NMR (CDCl3, 300 MHz): δ 8.06 (4H, m, Ar—H), 7.96 (2H, m, Ar—H), 7.77 (4H, t, J=9 Hz, Ar—H), 7.62 (2H, t, J=9 Hz, Ar—H), 7.47 (6H, m, Ar—H), 7.37 (1H, t, J=8 Hz, Ar—H), 3.46 (2H, m), 3.26 (1H, dd, J=16, 7 Hz), 3.12 (1H, m), 3.02 (1H, dd, J=16, 8 Hz); ESI-LCMS e/z calcd for C36H25F3O4:578.583, found 579 (M+H)+, 601 (M+Na)+.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1)([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 mg of 5% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 2.0 mL of ethyl acetate containing 7.0 mg of 2-(4-nitrobenzamido)-4-phenethylbenzoic acid and stirred under hydrogen atmosphere at room temperature for 2 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 4.0 mg of 2-(4-aminobenzamido)-4-phenethylbenzoic acid as pale yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Cl.[NH2:21][OH:22].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[OH:22][N:21]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=NO)cc1
Reaction time: 2 h
Yield: 107.1 %

Procedure:
A solution of 1.3 g of 2-[4-(2-oxocyclohexan-1-ylmethyl)phenyl]propionic acid, 0.33 g of hydroxylamine hydrochloride and 1.6 g of sodium acetate trihydrate in 85% ethanol was heated with stirring at 70°-75° C. for 2 hours, and the mixture was poured into 100 ml of water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 1.4 g of the desired compound, which by recrystallization from a mixture of ethyl acetate and n-hexane afforded colorless prisms, m.p. 143°-150.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:36][C:27]1[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:26]=1[O:25][S:22]([C:19]1[CH:20]=[CH:21][C:13]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[C:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=3)[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A vial was charged with perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (EXAMPLE 46, STEP 1) (134.9 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104 mg, 0.335 mmol), Pd(AmPhos)2Cl2 (7.90 mg, 0.011 mmol), potassium phosphate (142 mg, 0.670 mmol), dioxane (1116 μL), and water (372 μL). The vial as sealed and heated in a microwave reactor for 1 h at 100° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chomatography on silica gel (12 g, 0 to 40% EtOAc/Heptane) to give tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (125.5 mg, 0.178 mmol) as a clear oil. m/z (ESI) 729.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-])=O)=[CH:13][C:14]=2[N+:16]([O-])=O)[C:9]([NH2:22])=[N:8]1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:19])=[CH:13][C:14]=2[NH2:16])[C:9]([NH2:22])=[N:8]1)[CH3:24]
Reactant: CCN(CC)CCCn1nc(N)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c21
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCn1nc(N)c2cc(N)cc(N)c21
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 24.1 %

Procedure:
A mixture consisting of 9.0 g of 1-(3-diethylaminopropyl)-3-amino-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After the reaction mixture was cooled, the mixture was filtered. The pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution and the filtrate was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 1.78 g of 1-(3-diethylaminopropyl)-3,5,7-triaminoindazole having the following analytical values in a yield of 23%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[C:24]([C:26]1[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=1)#[N:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:31]([C:28]2[NH:29][CH:30]=[C:26]([C:24]#[N:25])[CH:27]=2)=[O:32])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCCC3)c2)CN(C)C1=O
Yield: 14 %

Procedure:
A mixture of 5-(4-amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in Example 9, step (a), 21 mg, 0.067 mmol), 4-cyanopyrrolecarboxylic acid (Canadian J. Chem. 59: 2673 (1981)). (24.6 mg, 0.180 mmol), EDCI (19.4 mg, 0.101 mmol), HOBt (9.2 mg, 0.068 mmol), DIEA (35 μL, 0.20 mmol) in DCM (0.5 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was purified RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to obtain the title compound (4.2 mg, 14%): 1H-NMR (CD3OD; 400 MHz): δ 7.58 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=8.2 Hz), 7.15-7.24 (m, 3H), 5.93 (t, 1H, J=6.5 Hz), 3.38-3.61 (m, 5H), 2.96 (m, 6H), 2.48 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.45-1.23 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C25H29N5O2, 432.2 (M+H). found 432.2.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N+:31]([O-])=O)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].O.[Sn](Cl)Cl>C(O)C>[NH2:31][C:13]1[C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[CH:15][C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])C1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
tert-Butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (265 mg, 0.583 mmol) was dissolved in ethanol (20 mL) and tin (II) chloride hydrate (658 mg, 2.92 mmol) was added. The suspension was heated for 30 min at 70° C. Solvents were removed by evaporation and the residue was dissolved in ethyl acetate and aqueous saturated sodium hydrogen carbonate. The mixture was filtered and the residue was washed thoroughly with ethyl acetate. The two phases of the filtrate were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (Na2SO4) and solvent was removed by evaporation affording tert-butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (139 mg, 56%). The crude product was used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[CH:8][C:9]=1[I:10])=[N+]=[N-].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[N-]=[N+]=[N-]>O>[Cl:11][C:5]1[C:4]([N:1]=[P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([I:10])[CH:8]=[CH:7][N:6]=1
Reactant: [N-]=[N+]=Nc1c(I)ccnc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nccc(I)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
3-azido-2-chloro-4-iodopyridine (7 g, 25 mmol) and triphenylphosphine (8.5 g, 32 mmol) was stirred in 100 mL 1:1 mixture of THF and water until azide starting material disappears in TLC. After that most of the THF was removed under vacuum. Crude product was partitioned between brine and ethylacetate. Organic layer was isolated, dried over anhd. Na2SO4 and purified by silica gel column chromatography using 5-40% ethyl acetate and hexanes as eluent. 2-chloro-4-iodo-N-(triphenylphosphoranylidene)pyridin-3-amine (12 g, 23 mmol, 93% yield) was isolated as crystalline white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH:43][C:44]([C:46]1[C:54]2[NH:53][C:52]([NH2:55])=[N:51][C:50]=2[CH:49]=[CH:48][CH:47]=1)=[O:45]>CN(C=O)C.CCN(C(C)C)C(C)C.[Cl-].[Na+].O>[NH:40]1[CH:41]=[CH:42][N:38]=[C:39]1[NH:43][C:44]([C:46]1[C:54]2[N:53]=[C:52]([NH:55][C:11]([C:10]3[N:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]4=[N:3][C:2]=3[CH3:1])=[O:13])[NH:51][C:50]=2[CH:49]=[CH:48][CH:47]=1)=[O:45]
Reactant: CC1=C(C(=O)O)N2C=CC=CC2N1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c1C(=O)Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1
Yield: 17.8 %

Procedure:
100 mg (0.56 mmol) of the 2-methyl-1,8a-dihydro-imidazo[1,2-a]pyridine-3-carboxylic acid and 234 mg (0.61 mmol) of HBTU in a mixture of 1.5 mL of DMF and 0.6 mL of DIEA was reacted with 137 mg (0.56 mmol) of the 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. After the reaction was complete, it was diluted with brine (20 mL), and the resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 40 mg (17%) of 2-[(2-methyl-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide as a solid. LCMS: 401 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[NH:17][CH:18]1[CH2:23][O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:17]([CH:18]1[CH2:23][O:22][C:20](=[O:21])[CH2:19]1)[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH3:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1N(C(=O)CCl)C1COC(=O)C1

Procedure:
A 2.4-g (0.020 mol) sample of chloroacetyl chloride was added to a refluxing solution of 5.0 g (0.021 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone in 100 ml toluene. The reaction mixture was heated under reflux for 30 minutes. Gas was evolved and a white precipitate formed during the 30-minute reflux period. The reaction mixture was cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 4.3 g of product, as a white solid, m.p. 121°-122° C. The infrared spectrum of the product showed two strong carbonyl absorption bands at 5.62 microns and 5.88 microns. The product is tabulated in Table C as Compound No. C-1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][NH:1][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:12]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CNC(=O)CCC(=O)O)nc3ccccc23)cc1

Procedure:
A solution of (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (76 mg, 0.25 mmol) and succinic anhydride (25 mg, 0.25 mmol) was stirred overnight in CH2Cl2 (1 mL). Solvent removal yielded the title compound. 1H NMR (CDCl3) δ 7.80-7.75 (m, 1H), 7.61 (ddd, 1H), 7.23-7.17 (m, 2H), 7.08-6.98 (m, 4H), 4.57 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.68-2.62 (m, 4H); HRMS (ES) m/z calcd for C21H23N4O4 395.1714, found 395.1737.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1.[OH-].[K+]>C(C(C)=O)C>[CH2:2]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[NH:13][C:12]=2[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Reactant: CCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCCCCCCOc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 149.8 %

Procedure:
2-Heptyloxy-6-dimethylsulphamoylphenothiazine (m.p. 160°-162°C.; 23.4 g.) is prepared by reacting 1-iodoheptane (8.4 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (76.8 g.) in the presence of powdered potassium hydroxide (41.4 g.) in methyl ethyl ketone (600 cc.).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CC(C)=O>[OH:4][C:5]1[CH:14]=[C:13]([CH2:15][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:12]([C:17]([F:18])([F:19])[F:20])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CBr)cc1OC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1O
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-(bromomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 47; 240 mg, 0.68 mmol) in acetone (5 ml) was added triethylamine (0.19 ml, 1.35 mmol) and piperidine (0.09 ml, 0.88 mmol). The solution was stirred for 18 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound. 228 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]C(CC)C.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:17]=[O:18]
Reactant: COc1ccccc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1cccc(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
27 ml (240.62 mmol) of 2-fluoroanisole is dissolved in 700 ml of tetrahydrofuran. At −70° C., 200 ml of sec-BuLi (1.3 M solution in cyclohexane) is added in drops. It is stirred for one hour at −70° C., and then 152 ml of N,N-dimethylformamide, dissolved in 50 ml of tetrahydrofuran, is added in drops at this temperature. After another hour of stirring at −70° C., 380 ml of hydrochloric acid (w=10%) is added in drops. In this case, the batch slowly comes to room temperature. After stirring overnight at room temperature, methyl tert-butyl ether is added, and the organic phase is separated after vigorous stirring. The aqueous phase is extracted two more times with methyl tert-butyl ether. The combined organic extracts are washed with brine and dried. After the desiccant is filtered off, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 25.66 g (69.2%) of the desired compound is isolated.