Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[Br:16][CH2:14][C:7]1[C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1oc2ccc(F)cc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1oc2ccc(F)cc2c1CBr
Temperature: 50 °C
Reaction time: 60 h
Yield: 71.1 %

Procedure:
To a solution (150 mL) of methyl 5-fluoro-3-methyl-1-benzofuran-2-carboxylate (15.4 g) synthesized above in acetonitrile were added N-bromosuccinimide (19.8 g) and 2,2′-azobis(isobutyronitrile) (1.21 g), and the mixture was stirred under argon atmosphere at 50° C. for 2.5 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20-30% ethyl acetate/hexane) to give a white solid. The obtained solid was washed with hexane to give the title object compound (15.1 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([C:3](=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH3:2].[CH2:24]([Mg]Br)[CH3:25]>>[CH2:24]([C:7]1([OH:11])[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH3:25]
Reactant: CC[Mg]Br
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1=O
Product: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1(O)CC

Procedure:
2-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]cyclopentanone can be treated with ethylmagnesium bromide according to the procedure of Example 2, part (c) to give 1-ethyl-2-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]cyclopentanol [XV; Ar is 3,4-methylenedioxyphenyl, Y is C(C2H5)=CHCH2CH2, R' is C2H5, m is 1].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]1>CS(C)=O>[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]3)[CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCCC(CCl)C1
Reactant: Oc1cccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCCC(COc2cccc(Nc3ncc(Br)c(Nc4ccccc4)n3)c2)C1
Yield: 14.2 %

Procedure:
A mixuture of potassium carbonate (160 mg, 1.2 mmol), 4-anilino-5-bromo-2-(3-hydroxyanilino)pyrimidine (Method 10, 200 mg, 0.6 mmol) and 3-chloromethyl-1-methylpiperidine (obtained as described in Eur. J. Med. Chem. 1994, 29, 967–73; 0.11 ml, 0.62 mmol) in DMSO (2 ml) were heated at 100° C. for 18 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was loaded onto a Varian Mega Bond Elut column and the column was eluted with 0–10% 2.0 M methanolic ammonia solution to give the product as a brown solid (40 mg, 15%). NMR: 1.0 (m, 1H), 1.4 (m, 1H), 1.6 (m, 3H), 1.8 (m, 2H), 2.1 (s, 3H), 2.6–2.8 (m, 2H), 3.6 (m, 2H), 6.4 (d, 1H), 7.0–7.4 (m, 6H), 7.6 (m, 2H), 8.2 (s, 1H), 8.5 (s, 1H), 9.2 (s, 1H); MS (MH+): 468.5, 470.5.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=CC=[CH:17][C:16]=1OC.Br.[C:24]([OH:27])(=O)[CH3:25].[OH2:28]>>[OH:28][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:25][C:24]([OH:27])=[CH:17][CH:16]=2)=[CH:3][CH:8]=1
Reactant: O
Reactant: COc1ccccc1CCCCCCc1ccccc1OC
Reactant: CC(=O)O
Agent: Br
Product: Oc1ccc(CCCCCCc2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
64.0 g (0.21 mole) of 1,6-bis(methoxyphenyl)hexane, 107.4 g of 48% hydrobromic acid and 281.2 g of pure acetic acid are put into a flask and the thick suspension is slowly heated to gentle reflux. The clear solution so obtained is then refluxed overnight. After cooling to room temperature, the slightly brownish red solution is stirred into 3 liters of water. The precipitate is isolated by filtration, washed with water until neutral and dried in vacuo at 70°-80° C., affording 55.6 g (97.9% of theory) of 1,6-bis(4-hydroxyphenyl)hexane with a melting point of 143°-144° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(C)=O
Product: COc1ccc(NS(=O)(=O)c2cccs2)cc1N1CCN(C)CC1
Reaction time: 8 h

Procedure:
A solution of thiophene-2-sulfonyl chloride (82 mg; 0.45 mmol) in acetone (2 ml) was added to a solution of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (100 mg; 0.45 mmol) in acetone (2 ml) and the mixture stood overnight at room temperature. The resultant crystalline solid was filtered off and washed with acetone, then diethyl ether, to afford the title compound as the hydrochloride salt. (153 mg; 84%). MS: m/z=368.
Reaction SMILES: C1C[O:4]CC1.[CH2:6]1[CH2:11][CH2:10][CH:9]([N:12]=[C:13]=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH2:7]1.C(N)CCCCCCCCCCC>N1C=CC=CC=1>[C:13]([NH:12][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:11][CH2:10]1)([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:4]
Reactant: C1CCOC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCN
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
If the desacylsaponins are soluble in anhydrous pyridine, alone or with anhydrous THF, the reaction can be carried out with DCC. 100 mg of (4) (60 μmoles) are dissolved in pyridine and/or THF, using no less than 1 ml but no more than 5 ml. 1 ml of a 0.3M dodecylamine solution (300 μmoles) in pyridine and/or THF is thereafter added to the reaction mixture, followed by 300 μmoles of dry DCC. The mixture is allowed to react with mixing overnight at 0° C. to 10° C. During the reaction, insoluble dicyclohexylurea is formed; this is removed by centrifugation. The supernatant containing the conjugated desacylsaponins (5) is diluted with 10 volumes of EtOAc to precipitate (5). The EtOAc containing the free alkyl amine, residual DCC, and the pyridine and/or THF is discarded. Precipitate is washed with EtOAc, dissolved in water and re-extracted with EtOAc before removing the EtOAc and lyophilizing.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)(=O)=O.[Cl:28][C:29]1[CH:30]=[CH:31][C:32](O)=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C@@H:8]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[C@H:7]([CH2:6][O:5][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=3)[O:11][C:10]2=[O:12])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Cl)cc2)[C@H]1c1cc(F)cc(F)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](COc2ccc(Cl)cn2)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
The ((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (49 mg, 0.117 mmol), 5-chloropyridin-2-ol (45 mg, 0.35 mmol), and K2CO3 (48 mg, 0.35 mmol) are dissolved in DMF (1.0 mL) and stirred at 35° C. for 2 h, as judged complete by LC-MS. The reaction is diluted with water and ethyl acetate. The organic is washed with brine, dried over MgSO4, filtered and concentrated. Separation of the N- and O-alkylated products by preparative HPLC (C-18, 10-80% ACN/water (0.05% TFA)) gave 2.5 mg of the desired product. 1H NMR (acetone-d6, 400 MHz) δ 8.15 (d, 1H, J=2.7 Hz), 7.76 (dd, 1H, J=8.8, 2.7 Hz), 7.54-7.57 (m 2H), 7.32-7.36 (m, 2H), 7.22-7.28 (m, 2H), 7.02 (tt, 1H, J=9.1, 2.3 Hz), 6.86 (d, 1H, J=8.8 Hz), 5.77 (d, 1H, J=5.6 Hz), 4.85 (ddd, 1H, J=5.2, 4.0, 4.0 Hz), 4.72-4.79 (m, 2H). HPLC-MS calculated C21H14Cl2F2N2O3 (M+H+): 451.0, found: 451.0.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]Br)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])[CH2:21][CH2:22]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Ic1ccnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc3nccc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-iodo-1H-pyrazolo[4,3-b]pyridine (76 mg, 0.310 mmol) in DMF (4 ml) was cooled in an ice bath. Sodium hydride (16.13 mg, 0.403 mmol) was added and the reaction was stirred for 5 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (104 mg, 0.372 mmol) was added and the reaction was warmed to room temperature and then to 65° C. for 20 minutes. The reaction was then cooled, quenched with water and saturated NH4Cl solution and extracted with EtOAc. The organic layer were separated, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 4-((7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)methyl)piperidine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][CH:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[CH:16]1([O:19][C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]3([C:30](O)=[O:31])[CH2:29][CH2:28]3)=[O:25])=[CH:22][CH:21]=2)[CH2:18][CH2:17]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:16]1([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]3([C:30](=[O:31])[NH:11][CH:10]4[CH2:9][CH2:8][C:7]5[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=5[N:5]5[CH:1]=[CH:2][N:3]=[C:4]45)[CH2:29][CH2:28]3)=[O:25])=[CH:33][CH:34]=2)[CH2:18][CH2:17]1
Reactant: NC1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(OC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CC1)c1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a mixture of 5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (400 mg, 2.01 mmol), 1-(4-cyclopropoxybenzamido)cyclopropanecarboxylic acid (577 mg, 2.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (462 mg, 2.41 mmol) and 1-hydroxybenzotriazole hydrate (369 mg, 2.41 mmol) in dichloromethane (8 mL), add triethylamine (1.26 mL, 9.03 mmol) and stir the mixture at ambient temperature for approximately 16 hours. Purify the crude mixture by flash chromatography (0% to 5% MeOH/dichloromethane) to give the title compound (791 mg, 89%) as a tan foam: MS (m/z): 443 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.C1COCC1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1
Reactant: COc1cc(Nc2nc3n(n2)CCCCC3=O)ccc1-n1cnc(Cl)c1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CCCCC3(O)c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a suspension of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7,8-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-9(6H)-one (28 mg, 0.075 mmol) in THF (0.5 mL) was added (4-fluorophenyl)magnesium bromide/THF (0.188 mL, 0.188 mmol) at −20° C. under nitrogen. After warming from −20° C. to rt, the mixture was stirred for 16 h. An additional portion of (4-fluorophenyl)magnesium bromide/THF (0.225 mL, 0.225 mmol) was added. The rxn was stirred an additional 3 h at rt, then 4 h at 60° C. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dichloromethane (2 mL). The solution was washed with water (1 mL) and then loaded onto silica gel. The crude product was purified using silica gel column chromatography (0-80% EtOAc/hexanes). The fractions containing product were combined and concentrated. The residue was repurified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound (3.4 mg, 7.25 μmol, 9.7% yield). LC-MS (M+H)+=469.1. 1H NMR (500 MHz, chloroform-d) δ ppm 1.43-1.52 (m, 1 H) 1.82-1.95 (m, 2 H) 1.99-2.10 (m, 1 H) 2.11-2.21 (m, 1 H) 2.59 (ddd, J=14.34, 6.41, 2.14 Hz, 1 H) 3.85 (s, 3 H) 3.86-3.93 (m, 1 H) 4.43 (ddd, J=11.60, 2.90, 2.59 Hz, 1 H) 6.77 (s, 1 H) 6.95 (dd, J=8.39, 2.29 Hz, 1 H) 7.02-7.09 (m, 3 H) 7.09-7.17 (m, 3 H) 7.39 (d, J=2.14 Hz, 1 H) 7.53 (d, J=1.22 Hz, 1 H).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][C:5]3[C:10]([CH:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C1C2C(=CC=CC=2)C=C1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:1][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: C1=Cc2ccccc2C1
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Reaction time: 0.25 h

Procedure:
1,2-Epoxy-2,3-dihydro-1-H indene, prepared from indene (34.2 g) according to the procedure of M. Imuta and H. Ziffer, J. Org. Chem., 44, 1351 (1979), was treated immediately with pyrrolidine (50 ml). The exothermic reaction mixture was set aside for 15 minutes and then evaporated to remove the excess pyrrolidine under reduced pressure. The residue was distilled under vacuum to yield trans-2,3-dihydro-2-hydroxy-1-(pyrrolidin-1-yl)-1H-indene (10.2 g), b.p. 148°-150°/0.25 torr.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][O:26][CH3:27].N1C=CC=CC=1>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:24])[O:26][CH3:27])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
16.25 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.05 mol) and 5.36 g of N,O-dimethyl hydroxylamine hydrochloride (0.055 mol, 1.1 eq) are dissolved in 100 mL of dichloromethane. The reaction mixture is cooled to 0° C. and 9.25 g of pyridine (0.11 mol, 2.2 eq) is added. The mixture is heated to room temperature and it is stirred for 1 hour. The solvent is evaporated in vacuum and 30 mL of brine and 30 mL of dichloromethane are added to the residue. After 15 min stirring the phases are separated and the organic phase is dried on sodium sulfate, the solvent is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 11.9 g of the title compound (VIc) (68%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:11].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:12]([N:21]1[CH:26]=[CH:25][CH:24]([CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH:23]=[CH:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Reactant: Cc1nc2ccccc2n1C
Product: Cn1c(CC2C=CN(C(=O)c3ccccc3)C=C2)nc2ccccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 6 parts of 1,2-dimethyl-1H-benzimidazole in 50 parts of dry pyridine were added dropwise 6.2 parts of benzoyl chloride at room temperature. Upon completion, stirring was continued for 2 hours at room temperature. The whole was evaporated. The residue was dissolved in 260 parts of dichloromethane. Water was added and the solution was treated with concentrate ammonium hydroxide. The dichloromethane layer was decanted, dried, filtered and evaporated. The residue was taken up twice in 45 parts of methylbenzene and the latter was evaporated each time, yielding 1-benzoyl-1,4-dihydro-4-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyridine as an oily residue (63).
Reaction SMILES: C[Mg]Br.[C:4]([C:6]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][N:7]=1)#N.Cl.[C:19](=O)(O)[O-].[Na+].[OH2:24]>CCOCC.C1COCC1>[C:4]([C:6]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][N:7]=1)(=[O:24])[CH3:19]
Reactant: O=C([O-])O
Reactant: O
Reactant: N#Cc1nccc(OCC(F)(F)F)n1
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1nccc(OCC(F)(F)F)n1
Temperature: -40 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Methyl magnesium bromide (115 ml of a 3.0M solution in ether) was added to 2-cyano-4-(2,2,2-trifluoroethoxy)-pyrimidine (70.0 g) in THF (300 ml) at -40° C. After the addition it was stirred for 11/2 hours at -40° C. then treated with water (50 ml), followed by enough 2M hydrochloric acid to make the reaction mixture just acid, this was stirred for 11/2 hours and then neutralised with sodium bicarbonate, and extracted with ether (3×300 ml). The combined ether extracts were dried and concentrated to give 2-acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine (66.8 g, 88% yield) as a brown oil; IR maxima (film): 1718 cm-1 ; 1H NMR (270 MHz): δ2.74(3H,s), 4.92(2H,q), 7.05(1H,d), 8.74(1H,d) ppm.
Reaction SMILES: [IH:1].[CH:2]([NH:15][C:16](=[NH:19])SC)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC([OH:35])C>CC(O)(C)C>[OH2:35].[IH:1].[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15][C:16]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[NH:19])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:3]1([CH:2]([NH:15][C:16]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[NH:19])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[IH:1]
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: CC(C)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: I
Solvent: CC(C)(C)O
Product: N=C(NC(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2)CC1
Product: O

Procedure:
A mixture of 6.38 g (0.017 mole) of N-benzhydryl-S-methylpseudothiourea monohydroiodide and 5.81 g (0.034 mole) of N-phenylpiperazine in t-BuOH is heated under reflux overnight. About 50 ml of moist 2-propanol is added and the mixture is then allowed to crystallize. The crude guanidine melts at 119°-128° C. Recrystallization from 1:2 MeOH/t-BuOH and then from 2-propanol gives pure N-diphenylmethyl-4-phenyl-1-piperazinecarboximidamide monohydroiodide hemihydrate; mp (113-117) 208°-210° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.Cl[C:19](OC1C=CC=CC=1)=[O:20].CN1CCCC1.Cl.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH2:43][CH2:44][NH:45][CH:46]2[CH2:48][CH2:47]2)=[CH:38][CH:37]=1>CN(C=O)C.N1C=CC=CC=1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:49]2[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=2)[CH2:43][CH2:44][N:45]([CH:46]2[CH2:47][CH2:48]2)[C:19]([NH:1][C:2]2[S:3][C:4]([Cl:17])=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)[N:6]=2)=[O:20])=[CH:38][CH:37]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1ccc(C(CCNC2CC2)c2ccc(F)cc2)cc1
Reactant: Nc1nc(-c2ccc(S(N)(=O)=O)cc2)c(Cl)s1
Agent: CN1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCC(c3ccc(F)cc3)c3ccc(F)cc3)C3CC3)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-amino-5-chlorothiazol-4-yl)benzenesulfonamide (318 mg, 1097 μmol) and pyridine (266 μl, 3292 lμmol) in DMF (10 mL) was chilled to 0° C. To this solution was added slowly phenyl chloroformate (131 μl, 1043 μmol) via syringe. The mixture was slowly warmed to RT, and stirred for 2 hr. At this point, 1-methylpyrrolidine (342 μl, 3292 μmol) and N-(3,3-bis(4-fluorophenyl)propyl)cyclopropanamine hydrochloride (338 mg, 1043 μmol) were added consecutively to the reaction mixture. The mixture was heated to 80° C. and was stirred overnight. Volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 100 mL of a 1:1 mixture of water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted further with ethyl acetate (2×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. Purification by chromatography on silica (eluted with EtOAc/Hexanes) gave 4-(2-(((3,3-bis(4-fluorophenyl)propyl)(cyclopropyl)carbamoyl)amino)-5-chloro-1,3-thiazol-4-yl)benzenesulfonamide 182. Mass spectrum, calculated for C28H25ClF2N4O3S2 602. 1; found 603.1 (M++1).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N.C(O)C>CC(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:7][N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccnc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1

Procedure:
Reaction of 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone with 1.06 molar equivalents of 2-(5-methyl-4-imidazolylmethylthio)ethylamine in refluxing ethanol for 24 hours gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone, m.p. 128-130° (from 2-propanol).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].CC#N.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14].Cl>O.CCN(CC)CC>[CH3:1][S:2][C:3](=[N:8][S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])[NH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)N=C(N[N+](=O)[O-])SC
Yield: 60.5 %

Procedure:
A mixture of S-methyl-N-nitroisothiourea (5.0 g), CH3CN (50 ml) and Et3N (11.2 g) was cooled with iced water. To the cooled mixture was added 10.6 g of n-propanesulfonyl chloride dropwise below 15° C. under stirring. After stirring at the same temperature for 1 hour, the mixture was poured into a mixed solution of conc. hydrochloric acid (20 ml) and water (180 ml) and the resulting mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo to afford 9.9 g of crude crystals. Recrystallization of the product from CCl4 (5 ml) gave 5.4 g of S-methyl-N-nitro-N'-(n-propanesulfonyl)isothiourea as a pale yellow crystal, m.p. 91°-93° C.