Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH:13]=[CH:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:23]1([C:29]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:37][C:31]=3[O:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(Cl)Cl>[C:42]1([C:29]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38]([N:11]4[CH2:10][CH:9]=[C:8]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:13][CH2:12]4)(=[O:39])=[O:40])=[CH:37][C:31]=3[O:30]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C1=CC(c2ccccc2)CCN1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
4-Phenyl-1,2,3,4-tetrahydropyridine hydrochloride (15.92 mg, 0.10 mmol) was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solution was shaken for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol) was added and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30 minutes, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ packing; 20%→95% CH3CN/H2O) to yield the sulfonamide (23.6 mg, 48%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]([O:13]CC)=O)[CH:4]=1)[CH3:2].[OH-].[NH4+:17].CO>>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]([NH2:17])=[O:13])[CH:4]=1)[CH3:2]
Reactant: CCCn1nc(C(=O)OCC)cc1CC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCn1nc(C(N)=O)cc1CC
Temperature: 125 °C

Procedure:
Ethyl 5-ethyl-1-propyl-1H-pyrazole-3-carboxylate (13.0 g, 62 mmol) in a 4:1 mixture of concentrated ammonium hydroxide/methanol (50 mL) was heated at 125° C. for 18 hours in a pressure vessel. After cooling to ambient temperature, the contents of the vessel were poured into a flask and a precipitate formed immediately. The precipitate was isolated by filtration to yield 5.02 g of analytically pure 5-ethyl-1-propyl-1H-pyrazole-3-carboxamide as off-white crystals, mp 105-106° C. MS (APCI) m/z 182.1 (M+H)+; Anal. calcd for C9H15N3O: C, 59.64; H, 8.34; N, 23.19. Found: C, 59.59; H, 8.54; N, 23.39. An additional 0.50 g of product was obtained in the second crop from the filtrate.
Reaction SMILES: CC(C)(C)C(N[C:6]1[CH:15]=CC=C(OCC#C)[C:7]=1[C:8](OC)=O)=O.[C:22]([O:26][C:27]([N:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[C:31]=1[C:32]([O:34][CH3:35])=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].BrCC#CC>>[C:22]([O:26][C:27]([N:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:15][C:6]#[C:7][CH3:8])[C:31]=1[C:32]([O:34][CH3:35])=[O:33])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: C#CCOc1cccc(NC(=O)C(C)(C)C)c1C(=O)OC
Reactant: COC(=O)c1c(O)cccc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC#CCBr
Product: CC#CCOc1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 46, starting from methyl 2-[bis-(tert-butyoxycarbonyl)amino]-6-hydroxybenzoate (Intermediate 55) and 1-bromobut-2-yne
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].S([O-])([O-])(=O)=O.[Na+].[Na+].Br[CH2:26][CH2:27][C@@:28]([CH3:38])([S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH3:38][C@@:28]([S:34]([CH3:37])(=[O:35])=[O:36])([CH2:27][CH2:26][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: c1cnc(-c2cn[nH]c2)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@](C)(CCn1cc(-c2cnccn2)cn1)S(C)(=O)=O
Temperature: 50 °C
Yield: 129.9 %

Procedure:
To a solution of 2-(1H-pyrazol-4-yl)pyrazine (0.157 g, 1.07 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.873 g, 2.78 mmol, 2.5 eq), sodium sulfate (0.032 g, 0.214 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.4 g 1.39 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth. The filtrate was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]butanoate (0.320 g, 1.39 mmol, 65% yield). LC-MS M+H+353.2.
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:18]([NH:22][C:23](=[NH:26])[O:24][CH3:25])([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:18]([NH:22][C:23](=[N:26][S:8](=[O:10])(=[O:9])[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:24][CH3:25])([O:20][CH3:21])=[O:19]
Reactant: COC(=N)NC(=O)OC
Reactant: O=S(=O)(Cl)NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)NC(=NS(=O)(=O)NC1CCCCC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
59.6 parts of cyclohexylaminosulfonyl chloride and 26.9 parts of pyridine were introduced through two feed lines, into a stirred solution of 39.6 parts of N-carbomethoxy-O-methylisourea in 300 parts of ethyl acetate, at from 15° to 20° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid and was then dried and concentrated under reduced pressure. This gave 79 parts of N-carbomethoxy-N'-cyclohexylsulfamyl-O-methylisourea, of nD25 =1.4970. After trituration with a small amount of ether, the compound crystallized, and these crystals melted at 84°-86° C. 15 parts of this product were dissolved in a mixture of 9 parts of 50% strength by weight sodium hydroxide solution and 20 parts of water and the reaction solution was stirred for 4 minutes at from 55° to 60° C. It was then cooled, extracted once with ether, and stirred into a mixture of 9.5 parts of concentrated hydrochloric acid and 10 parts of water. Filtering off the product, washing with water and drying gave 9 parts of 6-cyclohexyl-3-methoxy-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide, of melting point 173°-177° C. This constitutes active compound No. 3.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH2:34]([NH2:37])[CH:35]=[CH2:36]>>[CH2:34]([NH:37][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:35]=[CH2:36]
Reactant: C=CCN
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: C=CCNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with allylamine; ESI-MS [M+H]+: 482.2
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([S:9](F)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:9]([C:6]1[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: CNc1ccccc1
Product: COc1ccc(S(=O)(=O)N(C)c2ccccc2)nn1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 6-methoxy-pyridazine-3-sulfonyl fluoride (1.62 mmol, 312 mg) and N-methyl aniline (24.3 mmol, 0.26 mL) was prepared and heated at 100° C. for 12 hours. The mixture was then cooled. The resulting solid residue was purified by silica gel chromatography to isolate the title compound (53%, 240 mg); M+, 279.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[CH:12]([NH2:15])([CH3:14])[CH3:13]>CO.[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:15][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)NCc1ccccc1N
Reaction time: 3 h

Procedure:
To a 500 ml 3-necked round bottom flask equipped with overhead mechanical stirrer, thermometer and nitrogen bubbler was charged 2-nitrobenzaldehyde (200 g, 1.32 mol) in methanol (1300 ml), to which was added isopropylamine (78.0 g, 113 ml, 1.32 mol) in one portion with stirring under nitrogen. The reaction mixture was then stirred for 100 minutes (followed reaction by GC), then added to a 4 litre stainless steel Parr hydrogenator, containing a suspension of 5% palladium on charcoal (13.24 g, 6% cat. loading) in methanol (500 ml) and the suspension hydrogenated under hydrogen at 60 psi for 3 hours. The suspension was filtered through a pad of celite, the pad washed with methanol (500 ml) and the combined filtrate evaporated under reduced pressure to leave a yellow oil, 2-amino-N-(1-methylethyl)-benzylamine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:11][CH:12]([F:25])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:12]([F:11])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Oc1ccc2ccoc2c1
Reactant: Fc1ccc(C(F)(F)F)cc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cc(C(F)(F)F)ccc1Oc1ccc2ccoc2c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-benzofuran-6-ol (13.4 g, 100 mmol) and 2-(difluoromethoxy)-1-fluoro-4-trifluoromethylbenzene (29.9 g, 130 mmol) in DMF (300 mL) was added cesium carbonate (65.2 g, 200 mmol). The reaction mixture was stirred at 75° C. for 16 hours (or at 110° C. for 2 hours). After cooling to room temperature, it was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-20%) in hexanes. The final product was collected as a colorless oil. 1H NMR (CDCl3, δ ppm): 6.7 (t, 1H, J=74 Hz), 6.8 (s, 1H), 7.0 (m, 2H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)CC)(C)C.C[N:69]1[C:73](=[O:74])CCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:69][C:73]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:74]
Reactant: CN1CCCC1=O
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, PREPARATION 3, 0.5 g, 1.47 mmol) in dry N-methyl pyrrolidinone under a carbon monoxide atmosphere is added palladium (II) acetate (0.017 g, 0.074 mmol), 1,3-bis(diphenylphosphino)propane (0.045 g, 0.11 mmol), hexamethyldisilazane (1.0 mL, 4.7 mmol), and diisopropylethylamine (0.38 g, 2.94 mmol). The mixture is heated at 100 degrees C. for 24 hours. The mixture is cooled to 20-25 degrees C. and partitioned between water and ethyl acetate. The layers are separated and the aqueous phase is back-washed with ethyl acetate. The organic phases are combined and washed three times with saline, dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography (silica gel, 75 mL; methanol/methylene chloride, 2.5/97.5) gives the title compound, NMR (CDCl3) delta 0.77, 1.02, 1.57, 1.71, 3.17, 3.49, 3.98, 5.78, 6.34, 8.07, 8.20 and 8.48.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:13])[C:11]=2[CH:12]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: O=C1NCCc2ncc(C(F)(F)F)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2ncc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (as prepared in the previous step, 1.7 g, 7.87 mmol, 1.00 equiv) in dioxane (20 mL) and 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (2.68 g, 11.81 mmol, 1.50 equiv). The reaction mixture was stirred for 6 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was dissolved in 20 mL of sodium bicarbonate. The resulting solution was extracted with 3×100 mL of dichloromethane, and the combined organic layers dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:10-1:2). The title compound was obtained as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH:12]([C:42]([O:41][CH2:40][CH:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:39]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:43])[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:16]=[CH:17][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C

Procedure:
6.52 g (27.5 mmoles) of finely ground O-t-butyl-tyrosine (Chemical Dynamics Corp.) was placed in a 500 mL round bottom flask (oven dried) which was fitted with a condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 100 mL of dry dioxane and stirred vigorously. Diisopropylethylamine (9.04 mL, 80 mmoles) was added. Tms-Cl (6.98 mL, 55 mmoles) was added and let stir for 1 hour. Methylene chloride (200 mL) was added and the entire mixture was chilled in an ice bath. 9-Fluorenyl-methyloxycarbonyl chloride (6.47 g, 25 mmole) was added in one portion. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH with 10% citric acid and extracted with 600 mL methylene chloride. The organic layers were dried over sodium sulfate, concentrated to an oil and dried by azeotroping with 2×30 mL acetonitrile. The oil solidified by pumping under high vacuum. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23][C:29]2[C:30]([F:39])=[C:31]([F:38])[C:32]([F:37])=[C:33]([F:36])[C:34]=2[F:35])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.30 g, 4.136 mmol), Et3 N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added pentafluorophenyl trifluoroacetate at 0° C. The resulting mixture was stirred at room temp for 1 hr. The mixture was poured into water (60 mL) and precipitate was collected with suction. The crude solid was washed with 0.1 N HCl, H2O, n-hexane, and dried at 40° C. to afford 1.91 g (96%) pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetate as a pale brownish crystalline powder. IR (KBr) 1785, 1224, 1216 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 6.49 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.91 (dd, J=1.5, 8.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 3H), 7.24 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H); MS (FAB) m/z 481 (M++1); Anal. Calcd for C30H33N3O5S.1/4H2O: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H, 3.75; N, 5:68.
Reaction SMILES: [CH2:1]([CH:20]([CH2:23][OH:24])[CH2:21][OH:22])[C:2]#[C: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][CH2:18][CH3:19].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[CH2:42]([O:24][CH2:23][CH:20]([CH2:1][C:2]#[C: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][CH2:18][CH3:19])[CH2:21][OH:22])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCCCCCCCCCC#CCC(CO)CO
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC#CCC(CO)COCCCCCCCCCCCCCCCC
Temperature: 70 °C

Procedure:
A mixture of 5.0 g of 2-(2-nonadecynyl)-1,3-propanediol, 75 ml of N,N-dimethylformamide, 710 mg of 60% sodium hydride and 5.4 ml of hexadecyl bromide is heated at 70° C. for 2 hours and then evaporated. The residue is purified by flash chromatography with an ethyl acetate:petroleum ether gradient to give 5.8 g of the desired compound as white crystals, mp. 46°-47° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH2:11])=[NH:10])[CH2:4][CH2:3]1.[O:16]=[C:17]1NC(C2C=CC=CC=2OCC=C)=N[CH:19]=[C:18]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[O:16]=[C:17]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:5][CH:2]2[CH2:4][CH2:3]2)=[N:10][CH:19]=[C:18]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: N=C(N)c1ccccc1OCC1CC1
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Agent: Cl
Product: CCOC(=O)c1cnc(-c2ccccc2OCC2CC2)[nH]c1=O

Procedure:
The title compound was prepared from 2-cyclopropylmethoxybenzamidine hydrochloride in a manner similar to that described for the preparation of ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate in Example 8. The product had m.p. 104°-105°.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4-dichloro-benzenesulfonamide. LC: Tr 0.98 min, MS: 317.0 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45 (t, 1H), 6.11 (d, 1H), 6.72 (d, 1H), 6.92 (t, 1H), 7.59 (dd, 1H), 7.80 (d, 3H) ppm.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH3:7].[CH2:8]([O:15][C:16]1[C:17](Br)=[N:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)C.BrCCC.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.O>[CH2:8]([O:15][C:16]1[C:17]([CH2:5][CH2:6][CH3:7])=[N:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ncccc1OCc1ccccc1
Reactant: CCCBr
Agent: Cl[Ni]Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CCCc1ncccc1OCc1ccccc1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
Solid magnesium (0.7 g, 30 mmol) was stirred in 15 ml of dry diethyl ether under a nitrogen atmosphere. An iodine crystal and 1 drop of 1-bromopropane was added and the mixture was heated to reflux. The heating source was removed and the remaining 1-bromopropane (2.46 g, 20 mmol) was added in portions. The Grignard reagent was stirred for 1/2 hour at room temperature. 3-Benzyloxy-2-bromopyridine (3.66 g, 13.8 mmol) and a catalytic amount of [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) was dissolved in 200 ml of dry diethyl ether under a nitrogen atmosphere, and the Grignard reagent was added dropwise. The reaction mixture was stirred for 3 hours, and carefully poured into 200 ml of water. The aqueous layer was extracted with 2×100 ml of diethyl ether. The combined organic layers were dried overmagnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 50% of diethyl ether in petroleum ether as the eluent to afford 2.25 g (71%) of 3-benzyloxy-2-propylpyridine. 1H--NMR (CDCl3, 200 MHz) δ: 0.98 (t,3 H); 1.77 (sextet, 2 H); 1.86 (t, 2 H); 5.07 (s, 2 H); 7.02-7.16 (m, 2 H); 7.27-7.45 (m, 5 H); 8.12 (dd, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(N2CCN(C(C)c3ccc(N)cc3)CC2)cc1
Product: Cc1ccc(N2CCN(C(C)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-methylphenyl)-4-[1-(p-aminophenyl)ethyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[1-[4-(p-methylphenyl)-1-piperazinyl]ethyl]phenyl]amino]-7-chloroquinoline.