Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[C:11]2[CH:19]=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>C1COCC1>[C:4]1([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[C:11]2[CH:19]([OH:20])[CH3:1])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nc2cnccc2n1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc2cnccc2n1-c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 2.1 mL, 6.36 mmol) was added to a stirred solution of 1-phenyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde (0.71 g, 3.18 mmol) in THF (25 mL) at −78° C. under nitrogen. The resulting mixture was stirred at −78° C. for 2 h then at −10° C. for 20 minutes, then re-cooled to −78° C. and additional methyl magnesium bromide (3.0M in diethyl ether, 1 mL, 3.00 mmol) added. The resultant mixture was stirred at −10° C. for 30 minutes then poured into saturated aqueous ammonium chloride solution (25 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in THF (25 mL) and cooled to −78° C. and methyl magnesium bromide (3.0M in diethyl ether, 2.1 mL, 6.36 mmol) added, then stirred at −78° C. for 30 minutes followed by −10° C. for 1 h. The mixture was then poured into saturated aqueous ammonium chloride solution (25 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (0.36 g, 47%). LCMS (method H): Rt 1.42 min, [M+H]+ 240.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)C(C)(C)C)CC1
Temperature: 60 °C

Procedure:
To 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-[2-(2,2-dimethylpropionyloxy)ethyl]-piperidine-1-carboxylic acid tert-butyl ester as an oil, which was deprotected in CH2Cl2/TFA, employing the standard procedure. This yielded the crude title compound as an oil (94 mg, 0.44 mmol, 34%), which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.Br.Br.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:15][CH:16]=1.[CH2:24]([C:26]1([CH2:32][CH:33]=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:24]([C:26]1([CH2:32][CH2:33][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([CH3:10])=[CH:16][N:15]=3)[CH2:19][CH2:20]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:25]
Reactant: CCC1(CC=O)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC1(CCN2CCC(Nc3ccc(C)cn3)CC2)CCCCC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
After adding triethylamine (1.30 mL, 9.06 mmol) to a solution of 4-(5-methylpyridin-2-yl)aminopiperidine dihydrobromide (1.60 g, 4.53 mmol) in 1,2-dichloroethane (7 mL) and stirring the mixture for 30 minutes, a solution of (1-ethylcyclohexyl)acetaldehyde (1.54 g, 4.53 mmol) in 1,2-dichloroethane (8 mL) was added and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.96 g, 4.53 mmol) was then added while cooling on ice, and after stirring the mixture for 5 minutes, it was further stirred at room temperature for 1 hour. A 25% aqueous ammonium chloride solution, chloroform and 3N aqueous sodium hydroxide were added to the reaction mixture, extraction was performed with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (100 g Merck Art. 9385, chloroform:methanol=95:5) to obtain the title compound as a brown oil (1.37 g, 4.16 mmol) (2 steps, 92% yield).
Reaction SMILES: C(N(C)[C:9]([Cl:11])=[O:10])C1C=CC=CC=1.[CH:13]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14]1.CC#N.O.CC#N>O>[C:17]1([N:16]([CH:13]2[CH2:15][CH2:14]2)[C:9]([Cl:11])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Reactant: c1ccc(NC2CC2)cc1
Solvent: O
Solvent: CC#N
Product: O=C(Cl)N(c1ccccc1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-methyl-carbamoyl chloride from cyclopropyl-phenyl-amine prepared according to 0 Synlett 2003, 14, 2139. MS (LC-MS): [M+H]+=196.2. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.44 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[C:9]([Cl:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)(C)(C)[CH3:2]>C(O)C.Cl>[CH2:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[C:9]([Cl:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)[CH3:2]
Reactant: Cc1ccc2ccc(Cl)c(CC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C)nc12
Temperature: 90 °C
Yield: 63.3 %

Procedure:
(7-Chloro-2-methyl-quinolin-8-yl)-acetic acid tert-butyl ester (650 mg, 2.23 mmol) was dissolved in ethanol (13 ml) saturated with HCl gas. The solution was heated to 90° C. for 10 minutes. After cooling, volatiles were removed in vacuo, and the residue was purified via flash chromatography (gradient of hexane: EtOAc 95:5 to 80:20) to afford the title compound (372 mg, 63%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=8.00 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H); 4.52 (s, 2H), 4.19 (q, J=7.3 Hz, 2H), 2.81 (s, 3H), 1.27 (t, J=7.3 Hz, 3H). MS (ES+): 264.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20]C(=O)CC)(=[O:19])[CH2:17][CH3:18]>>[CH3:18]/[C:17](=[CH:12]\[C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)/[C:16]([OH:20])=[O:19]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Product: C/C(=C\c1ccc(Oc2ccccc2)cc1)C(=O)O
Yield: 68 %

Procedure:
The procedure is performed in an analogous manner to that described in Example 17 (step A), starting from 4-phenoxybenzaldehyde and using 5 equivalents of propionic anhydride. Yield: 68% IR (nujol): 1665 cm-1 m.p. 133° C. 1H NMR (CDCl3 /TMS): 11.95 (broad s, 1H); 7.80 (s, 1H); 7.60 to 6.85 (m, 9H); 2.15 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][NH:32][C:33]([NH2:35])=[S:34]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:31][NH:32][C:33](=[S:34])[NH2:35])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: NC(=S)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reaction time: 8 h

Procedure:
To a solution of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (360 mg; 1.01 mmol) was added 1,1′-carbonylbis(1H-imidazole) (196 mg; 1.21 mmol). The mixture was stirred overnight. The dark yellow colored solution was treated with thiosemicarbazide (110 mg mg; 1.21 mmol). The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added, and extracted with ethyl acetate. Concentrated and purified on Flashmaster to obtain 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine carbothioamide. (300 mg, 69%) MS m/z: 432 M+1
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1nc(-c2ccc(N)cc2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2)nc1Cl
Yield: 55.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.17 g, 1 mmol), thionyl chloride (5 mL), methyl 2-(4-aminophenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (97d) (0.15 g, 0.65 mmol) and pyridine (5 mL), to obtain 0.14 g of the title compound as a light pink solid (56%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:36])[F:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OCC(F)(F)F)c1

Procedure:
4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 697.4 [(M+H)+]
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([S:13][CH3:14])=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[N:4][CH:3]=1.C[C:16]([N:18](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][S:11][C:8]1[N:7]=[C:6]([S:13][CH3:14])[C:5]2=[N:4][CH:3]=[C:2]([C:16]#[N:18])[N:10]2[N:9]=1
Reactant: CC(=O)N(C)C
Reactant: CSc1nc(SC)c2ncc(Br)n2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: CSc1nc(SC)c2ncc(C#N)n2n1
Temperature: 100 °C

Procedure:
(I2A): A mixture of 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (6 g, 20.61 mmol), zinc cyanide (1.694 g, 14.42 mmol) and zinc powder (0.270 g, 4.12 mmol) in DMA (150 mL) in a 350 mL round bottom pressure flask was degassed by evacuating with vacuum and back filling with nitrogen three times. bis(tri-t-butylphosphine)palladium (0) (1.053 g, 2.061 mmol) was added and the above process was repeated three times. The reaction mixture was heated at 100° C. for 4 hours. LCMS showed completion of reaction with small amount of de-bromination byproduct and mostly product. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (330 g column, eluting with 0-10% ethyl acetate/dichloromethane). 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.35 g) was obtained as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].[C:28]([C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1)([CH3:31])([CH3:30])[CH3:29]>C(OCC)(=O)C.O>[C:28]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:38][CH2:25][C:24]([NH:23][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])=[O:27])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 29.9 %

Procedure:
1.59 g (11.5 mmol) of potassium carbonate was added to a DMF (20 mL) solution comprising 1.00 g (3.82 mmol) of methyl 5-chloro-2-[(chloroacetyl)amino]benzoate and 574 mg (3.82 mmol) of 3-tert-butylphenol. The mixture was stirred at 80° C. for 7 hours, and then cooled to room temperature. Water and ethyl acetate were added thereto, and extraction was performed. Thereafter, the organic layer was separated, washed with saturated saline, dried over sodium sulfate, and filtered. After the filtrate was condensed, the obtained crude product was separated and purified by silica gel column chromatography, thereby giving 429 mg of methyl 2-{[(3-tert-butylphenoxy)acetyl]amino}-5-chlorobenzoate (yield: 30%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:28])=[O:29])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:37]=[CH:38][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:41][CH:42]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.432 mL, 3.44 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.3 g, 2.87 mmol) and sodium hydrogen carbonate (0.482 g, 5.73 mmol) in dioxane (20 mL) at RT. The resulting slurry was stirred at RT for 1 hour and then the reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 0%-20% ethyl acetate in DCM, to give the desired material as a yellow dry film (1.62 g).
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 39.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2-bromophenylisocyanate (64 μL, 0.52 mmol) were coupled to form the desired urea (0.1 g, 39%). LC-MS m/z 488(M+).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:21]2[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1>ClC(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:21]2[CH2:22][CH2:23][N:24]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:25][CH2:26]2)=[CH:10][CH:9]=1
Reactant: CN1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of 180 parts of ethyl carbonochloridate in 600 parts of trichloromethane was added dropwise a solution of 110 parts of 3-[(4-fluorophenyl)(1-methyl-4-piperidinylidene)-methyl]pyridine in 600 parts of trichloromethane. Upon completion, the whole was heated till reflux and stirring at reflux was continued for 16 hours. The reaction mixture was evaporated. The residue was stirred in water and the whole was alkalized with a sodium hydroxide solution. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 100 parts (75%) of ethyl 4-[(4-fluorophenyl)(3-pyridinyl)methylene]-1-piperidinecarboxylate as a residue (intermediate 20).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:24])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:14]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[C:3]1[C:2]([NH:1][CH:22]([CH3:24])[CH3:21])=[CH:7][CH:6]=[CH:5][N:4]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1N
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1cccnc1N1CCNCC1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-amino-2-(Boc-piperazine)pyridine 7 (3.813 g, about 11.16 mmol, crude) was dissolved in dichloroethane (75 mL). Acetone (1.7 mL, 23.12 mmol) was added, followed by an addition of HOAc (1.0 mL, 17.45 mmol) at room temperature. After about 10 min, NaBH(OAc)3 (7.46 g, 33.44 mmol) was added. An additional amount of dichloroethane (25 mL) was added. The resulting mixture was stirred at room temperature for 64 h. 5% aqueous NaHCO3 was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, concentrated. The residue was purified via flash column chromatography over silica gel with 5-35% ethyl acetate in hexane to afford the product as solid in quantitative yield. 1H-NMR (CDCl3): 7.673 (dd, J=5.0 Hz and 1.5 Hz, 1 H, Ar—H), 6.904 (dd, J=8.0 Hz and 5.0 Hz, 1 H, Ar—H), 6.812 (dd, J=8.0 Hz and 1.5 Hz, 1 H, Ar—H), 4.150 (d, J=7.5 Hz, 1 H, NH), 3.569-3.517 (m, 5 H, 2CH2 and CH), 2.997 (t, J=5.0 Hz, 4 H, 2 CH2), 1.477 (s, 9 H, 3 CH3), 1.23 (d, J=6.0 Hz, 6 H, 2 CH3). (ref. Romero D. L. et al. J. Med. Chem. 37, 999-1014, 1994.)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH3:20]O>>[Cl:19][C:14]1[CH:13]=[C:12]([N:7]2[C:8]([C:9]([NH2:11])=[O:10])=[C:4]([C:1]([O:3][CH3:20])=[O:2])[CH:5]=[N:6]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Reactant: CO
Product: COC(=O)c1cnn(-c2cc(Cl)cc(Cl)c2)c1C(N)=O

Procedure:
A 1.5 g portion of the compound of Example 2 was suspended in 30 ml of methanol, and hydrogen chloride gas was bubbled through the suspension for 1 minute. Then 30 ml of methanol was added over a 5 minute period while the addition of gas was continued. Then the mixture was heated under reflux for 2 hours, and was cooled and filtered. The solids were collected and dried to obtain 1.15 g of the desired product, m.p. 220°-222°.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=O>>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c(C)s1
Yield: 112.9 %

Procedure:
A solution of 1 g (4 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 987 mg (4 mmol) of 2-bromo-4′-nitroacetophenone in a manner similar to Example 8, step (a) to give methyl 4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (1.7 g, quantitive yield) as a brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C16H12N2O4S3 393.0 (M+H), found 392.8.
Reaction SMILES: Cl[C:2]([SiH3:5])(Cl)Cl.[Si:6]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Mg]>O1CCCC1>[Si:6]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][C:2]([SiH3:5])([CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[O:13][Si:6]([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:8])[CH3:7])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr
Reactant: [SiH3]C(Cl)(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CC([SiH3])(Cc1ccccc1O[Si](C)(C)C(C)(C)C)Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reaction time: 72 h

Procedure:
A mixture of trichloromethylsilane (0.12 ml, 1.0 mmol) and Grignard reagent, which was prepared from 2-((tert-butyldimethylsilyl)oxy)benzyl bromide (IIa) (1.54 g, 5.0 mmol) and magnesium (1.2 g, 50 mmol) in tetrahydrofuran (12 mL), was stirred for 3 days. The reaction was quenched with satd. ammonium chloride (50 mL). The mixture was extracted with hexanes (3×50 mL). Purification by flash column chromatography (hexane/ethyl acetate=50:1, v/v) provided compound Ma (0.51 g, 72%) as a colorless oil.