Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:13](OC)=[O:14])=[CH:8]2.[H-].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([CH2:13][OH:14])=[CH:8]2
Reactant: COC(=O)C1=Cc2cccc(OC)c2CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC(CO)=C2
Reaction time: 2.5 h
Yield: 6219.6 %

Procedure:
To a solution of methyl (5-methoxy-3,4-dihydro-2-naphthyl)formate (0.75 g) in toluene (10 ml) was added dropwise a solution of diisobutylalminum hydride [1.02N in toluene (6.7 ml)] at 4° C.~6° C. under nitrogen atmosphere. The reaction mixture was stirred under same conditions for 2.5 hours. The mixture was poured into a saturated ammonium chloride solution, and the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give crude (5-methoxy-3,4-dihydro-2-naphthyl)methanol as a colorless oil 40.66 g).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:31])=[O:30])=[O:21])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)C1CCCCC1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CCCCC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclohexanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C18H24FN2O6S: 415.1; found: 415.0. 1H NMR (500 MHz, CDCl3) δ: 1.19 (overlapping m, 30,1.63 (overlapping m, 3), 1.90 (br m, 2), 2.17 (m, 2), 3.51 (m, 1), 3.69 (s, 3), 4.78 (s, 2), 6.53 (s, 1), 7.00 (m, 2), 7.26 (m, 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([OH:32])=[O:31]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (10 mg), Pd(PPh3)4 (3 mg), Cs2CO3 (24 mg) and 4-carboxybenzeneboronic acid (CAS Reg. No. 14047-29-1, 8 mg) in dioxane (2 ml) was heated for 30 min at 160° C. in a microwave oven. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (3 mg) as a light yellow solid. MS (m/e)=450.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[NH2:1])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(N)cc(CO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N)cc(CO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of (3-amino-5-methylphenyl)methanol (prepared according to: Behrens, C.; Egholm, M.; Buchardt, O. Synthesis 1992, 12, 1235-1236, 750 mg, 5.47 mmol) in CH2Cl2 (25 mL) was added imidazole (447 mg, 6.56 mmol) then TBDMSCl (989 mg, 6.56 mmol) at room temperature. After 72 hours the mixture was diluted with H2O. The layers were separated and the aqueous extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (20% EtOAc/hexanes) gave 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-methylaniline as a clear oil. 1H-NMR (300 MHz, CDCl3) δ 6.58 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.24 (s, 3H).
Reaction SMILES: Cl.Cl[CH:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[N:14]1([CH:3]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClC1CCCCc2cccnc21
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCCCC2N1CCCC1
Reaction time: 5 h

Procedure:
5 g of 9-chloro-6,7,8,9-tetrahydro-5H -cyclohepta[b]pyridine hydrochloride were dissolved in 12.5 ml of water and 8 ml of pyrrolidine were added. The mixture was refluxed with vigorous stirring for 5 hours and the excess pyrrolidine was evaporated off under reduced pressure. 25 ml of a saturated solution of sodium bicarbonate and then 50 ml of water were added followed by extraction with methylene chloride. The combined organic phases were washed with water, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and methanol (9-1) to obtain 2.25 g of the expected product with an Rf=0.20. 2.25 g of the product were crystallized from petroleum ether (b.p. 40°-70° C.) to obtain 2 g of the expected product melting about 62° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:20][N:21]1[C:25]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=2)=[CH:24][C:23]([CH3:37])=[N:22]1>>[CH3:20][N:21]1[C:25]([NH:26][C:27]([C:28]2[CH:29]=[C:30]([C:34]#[C:35][C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=3)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH:31]=[CH:32][CH:33]=2)=[O:36])=[CH:24][C:23]([CH3:37])=[N:22]1
Reactant: C#Cc1cccc(C(=O)Nc2cc(C)nn2C)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1cc(NC(=O)c2cccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)c2)n(C)n1
Yield: 60.6 %

Procedure:
In a manner similar to that described in Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.141 g, 0.418 mmol) and N-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.1 g, 0.418 mmol) were reacted to give the title compound (0.126 g, 61%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]2[N:16]([C:20]3[CH:25]=[C:24]([S:26][C:27]([CH3:35])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:28])[C:23]([O:36][CH3:37])=[CH:22][C:21]=3[Cl:38])[C:17](=[O:19])[NH:18][C:13]2=[C:12]([O:39][CH3:40])[CH:11]=1)(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:38][C:21]1[CH:22]=[C:23]([O:36][CH3:37])[C:24]([S:26][C:27]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])=[CH:25][C:20]=1[N:16]1[C:14]2=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]([O:39][CH3:40])=[C:13]2[NH:18][C:17]1=[O:19]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO[Si](C)(C)C(C)(C)C)nc32)cc1SC(C)(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO)nc32)cc1SC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxy)methyl-3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylthio)phenyl]-7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (24 mg) in tetrahydrofuran (2 mL) was added tetra(n-butyl)ammonium fluoride hydrate (31 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (10 mg).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:22]2[CH:21]=[N:20][N:19]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]3[CH:24]=[CH:25][CH:2]=[CH:3][CH:4]=3)[CH:23]=2)=[CH:29][CH:28]=1
Reactant: Brc1ccc(C(c2ccccc2)(c2ccccc2)n2cccn2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a suspension of 4-bromo-trityl-1H-pyrazole (0.7 g) in N,N-dimethylformamide (14 ml) was added 4-fluorophenylboronic acid (0.377 g), cesium carbonate (1.758 g), and tetrakis triphenylphosphine palladium (0.208 g). The resulting suspension was stirred at room temperature for 10 min. The irradiation of microwaves at 160° C. for 10 min was sufficient to complete a reaction in the suspension. The product was filtered through silica gel, diluted in ethyl acetate (30 ml) and washed with saturated ammonium chloride solution (30 ml) and then with brine (30 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained was separated using silica gel chromatography to produce 4-(4-fluorophenyl)-1-trityl-1H-pyrazole (yield 51%).
Reaction SMILES: [CH:1]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pd].C(O)(=O)C>[CH2:1]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCc1ccc(N)cc1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
A mixture of 4-(1-decenyl)nitrobenzene (12.2 g), acetic acid (120 ml) and palladium black (0.84 g) was hydrogenated at room temperature and at 3-4 atm for 12 hours. The catalyst was changed and the reaction was continued under the same conditions for 12 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 10.9 g of 4-decylaniline.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:8]=2[N:7]=1)([OH:5])[CH3:4].[CH2:18]([SH:20])[CH3:19].C[O-].[Na+]>CO>[Cl:16][C:14]1[C:13]([Cl:17])=[CH:12][C:9]2[N:10]([CH3:11])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:20][CH2:18][CH3:19])=[N:7][C:8]=2[CH:15]=1
Reactant: CCS
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (141 mg) in MeOH (4 mL) at room temperature was added a solution of ethanethiol (34 mg) and sodium methoxide (0.132 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:17][NH2:18]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(Cl)n1
Reactant: NN
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-2-chloro-4-(4-chlorophenyl)-6-methylpyridine (0.18 g, 0.56 mmol) in dioxane (4 mL) at room temperature was added anhydrous hydrazine (0.4 mL). The resulting mixture was stirred at 65° C. for 1 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional anhydrous hydrazine (0.3 mL) was added, and the reaction mixture was stirred at 65° C. for 4 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting suspension was sonicated for 5 min. The resulting slurry was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 160 mg (90%) of the title compound as a white solid. HPLC/MS: retention time=2.53 min, [M+H]+=312.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(F)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:24]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([O:22][CH3:21])[N:24]=[C:25]([NH:31][C:32](=[O:33])[NH:18][S:17]([C:9]2[CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:20])=[O:19])[N:26]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
2.6 g (8.6 mmol) of methyl 4-isopropylcarbamoyl-2-sulfamoylbenzoate and 2.8 g (10.3 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate were initially charged in 50 ml of acetonitrile. At room temperature, 2.9 g (19 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added dropwise, and the mixture was stirred at this temperature for 3 h. The mixture was poured into ice-water and the pH was adjusted to 1 using 2N hydrochloric acid. The precipitated solid was filtered off with suction and washed with water. After drying, 3.9 g (94% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-4-isopropylcarbamoylbenzoate of m.p. 149-151° C. (decomp.) were obtained.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[OH-].[Na+]>O1CCOCC1.O>[S:18]1[C:17]2=[CH:16][N:5]=[CH:4][CH:3]=[C:21]2[CH:20]=[CH:19]1
Reactant: COC(CN(Cc1cccs1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: c1cc2ccsc2cn1
Temperature: 25 °C

Procedure:
N-(2,2-Dimethoxyethyl)-4-methyl-N-(thiophen-2-ylmethyl)benzenesulfonamide (7 g, 19 mmol) was dissolved in dioxane (10 mL) and treated with concentrated HCl (10 mL). The mixture for heated to reflux for 12 h. The mixture was allowed to cool down to room temperature, diluted with water (20 mL) and brought to pH 7 with 2 N sodium hydroxide. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 60% ethyl acetate in hexanes to obtain a tan solid. Yield=1 g. MS (M+H)+ 136.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].P(Br)(Br)[Br:29]>ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:25][C:23]1[CH:24]=[C:2]([Cl:1])[C:3]([C:4]([C:6]2[C:14]3[C:9](=[C:10]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)=[O:5])=[C:21]([Cl:27])[CH:22]=1
Reactant: BrP(Br)Br
Reactant: O=C(c1c(Cl)cc(CO)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1c(Cl)cc(CBr)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Yield: 31.7 %

Procedure:
To a solution of N-{3-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (900 mg, 2.23 mmol) in dichloromethane and carbon tetrachloride (2:1) at 0° C., phosphorus tribromide (1200 mg, 0.42 mL, 4.455 mmol) was added drop wise over a period of few minutes, stirred the mixture at 0° C. to room temperature. On completion, the reaction was quenched by adding saturated solution of sodium bicarbonate and extracted with dichloromethane. Organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-{3-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (330 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17].CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:17]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(Cl)c1
Reaction time: 24 h
Yield: 33.2 %

Procedure:
A solution of methyl 2-aminobenzoate (500 mg, 3.3 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) and 3-chloro-4-methoxybenzoic acid (645 mg, 3.3 mmol) (Lancaster Synthesis Ltd., Windham, N.H.) in DMF (20 mL) was treated with EDCI (1.3 g, 6.6 mmol) and DMAP (800 mg, 6.6 mmol) at room temperature. The reaction mixture was stirred for 24 hours, and then concentrated. The crude residue was dissolved in EtOAc (50 mL) and washed with 0.1 N HCl (2×20 mL), saturated aqueous NaHCO3 (2×20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography (SiO2, 15% EtOAc in hexanes) to afford 42A as a white solid (350 mg, 33%).
Reaction SMILES: [Br:1][CH2:2][C:3](C1C=CC=CC=1NS(C)(=O)=O)=[O:4].C([C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])(=O)C>>[Br:1][CH2:2][C:3]([C:27]1[CH:26]=[C:20]([CH:19]=[CH:29][CH:28]=1)[NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[O:4]
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CBr
Reactant: CC(=O)c1ccccc1NS(C)(=O)=O
Product: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1

Procedure:
2'-(Bromoacetyl)methanesulfonanilide can be derived from 2'-acetylmethanesulfonanilide (Preparation 1) following the bromination procedure described in Example 10, Step X. In a like manner, 3'-(2-bromoacetyl)methanesulfonanilide can be obtained.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]1[O:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:15][NH2:16]>CO>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[O:6][C@@H:4]2[C:3]([NH:16][CH3:15])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Yield: 91.6 %

Procedure:
To a mixture of (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionic acid methyl ester (1.92 g) and methanol (10 ml) is added dropwise a solution of 40% aqueous methylamine solution (2.37 g) in methanol (10 ml) under ice-cooling. The reaction mixture is stirred under ice-cooling for one hour, and concentrated under reduced pressure. To the residue is added ether, and the precipitated crystals are collected by filtration, washed, and dried at 50° C. to give (2S,3R)-3-(4-methylphenyl)-2,3-epoxy-N-methylpropionamide (1.75 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (465 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N:12]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: NNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: NNC(=O)c1cc(N2CCNCC2)ccn1
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 4-chloropyridine-2-carboxylic acid hydrazide (9.37 g), piperazine (20.0 g) and sodium bicarbonate (15 g) in n-butanol (120 ml) was heated under reflux with stirring for 18 hours and then cooled and filtered. The filtrate was evaporated and the residue was chromatographed on silica gel. Elution with a mixture of chloroform, ethanol and concentrated aqueous ammonia solution (50:50:1) gave the product as a solid (8.10 g), m.p. 212°-217° C. (decomp.).