Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28](=[O:40])[NH:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[C:14]([CH3:41])[CH:13]=1)(=[O:8])[O:5]CC)[CH3:2].C[Si](Br)(C)C>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28](=[O:40])[NH:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[C:14]([CH3:41])[CH:13]=1)(=[O:5])[OH:8])[CH3:2]
Reactant: CCOP(=O)(CCCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCOP(=O)(O)CCCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of (3-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propyl)-phosphonic acid diethyl ester (40 mg, 0.07 mmol) in CH2Cl2 (5 mL) was added TMSBr (0.045 mL, 0.35 mol). The solution was stirred at ambient temperature until monohydrolysis occurred (5 h). The solvent was removed under reduced pressure and the residue was purified by HPLC to give the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.41 (m, 3H), 8.08 (dd, 1H), 7.94 (dd, 2H), 7.81 (d, 1H), 7.77 (m, 1H), 7.56 (m, 1H), 7.10 (s, 2H), 3.97 (m, 2H), 2.75 (t, 2H), 2.18 (s, 6H), 1.97 (m, 2H), 1.68 (m, 2H), 1.29 (t, 3H). MS (m/z) 543.2 (M+1); Retention time: 1.17 min (method 10).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[Cl:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:41][CH:42]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 2-chloro-5-pyridine-boronic acid (315 mg, 2 mmol) to give 5-{4-[2-[4-(6-chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.C(OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1-c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.5 %

Procedure:
A solution of 4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol) and 3,4-dihydropyran (1.8 mL, 20.1 mmol) in methylene chloride (50 mL) under a nitrogen atmosphere was treated with pyridinium p-toluenesulfonate (336 mg, 1.34 mmol). After stirring for 3 hours at room temperature, thin layer chromatography indicated that no starting material remained. The reaction mixture was diluted with ethyl ether (300 mL). The ether extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to give 4.47 g of the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20]CC)=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[CH:2]=1.[ClH:23]>Cl.N1(CCC2CCCC3C(C(O)=O)=CC=CC2=3)C=CN=C1>[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1cccnc1)C2
Agent: Cl
Agent: O=C(O)c1cccc2c1CCCC2CCn1ccnc1
Product: O=C(O)c1ccc2c(c1)CCC(Cc1cccnc1)C2

Procedure:
1.8 g of ethyl 6-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 50 ml of 6 normal hydrochloric acid and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was recrystallized from methanol to give 1.04 g of 6-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid hydrochloride as colorless crystals with m.p. 222°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:11]=1)[C:5]([O:7]C)=O.[OH-].[Na+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:57][CH2:58][C:59]1[C:60](=[O:67])[NH:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65]>O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:11]=1)[C:5]([NH:57][CH2:58][C:59]1[C:60](=[O:67])[NH:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65])=[O:7]
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CN(C)C)cc2)c1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc(-c3ccc(CN(C)C)cc3)c2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
To a solution of methyl 2-chloro-6-(4-((dimethylamino)methyl)phenyl)isonicotinate (0.48 g, 1.578 mmol) methanol (5 mL), NaOH (0.094 g, 2.368 mmol), dissolved in water (1 mL), was added and reaction mass heated at 60° C. for 1 h. On completion, solvent was evaporated under reduced pressure. Residue was washed with ether and acidified with 1N HCl till pH 8 and then with citric acid till pH 5-6. Aqueous layer was extracted with 20% MeOH/DCM and combined organic layers were concentrated under reduced pressure to afford the acid (0.47 g, crude) which was used in next step without further purification. To a solution of this acid (0.47 g, 1.64 mmol) in DMSO (4 mL), PyBOP (1.26 g, 2.43 mmol) was added and reaction stirred at rt for 15 min. Then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.49 g, 3.28 mmol) was added and reaction stirred overnight. On completion, water was added and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were concentrated and residue purified by silica gel column chromatography affording 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-((dimethylamino)methyl)phenyl)isonicotinamide (0.3 g, 43.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][C:3]=1[C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][C:3]=1[C:19]([C:20](=[CH:29][N:30]([CH3:32])[CH3:31])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:26]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
A solution of 3.88 g (crude) of ethyl 3-[2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)phenyl]-3-oxopropionate and 1.22 g (0.10 mmol) of dimethylformamide dimethyl acetal in 10 ml of toluene were heated to reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Purification on silica gel (petroleum ether) (45-70° C.)/ethyl acetate, 8 minutes isocratic 35% ethyl acetate, then to 60% ethyl acetate in 7 minutes, flow rate 400 ml/minute) afforded 3.59 g (82% over the two stages) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH3:20])[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)ccc2C)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)ccc1C)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (3.01 g, 10.6 mmol) and ytterbium(III) triflate hydrate (0.66 g, 1.06 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.96 mL, 10.6 mmol) and water (190 mg, 10.6 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-fluoro-2-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethylester (3.78 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24FNO3 M+: 357.4, observed: 340.3.
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=C(C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[S:49]1C=CC=C1CC(O)=O>>[S:49]1[CH:1]=[CH:2][CH:4]=[C:5]1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2cccs2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-thiopheneacetic acid, mp 133°-136° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][C:65]1[S:69][C:68]([SH:70])=[N:67][N:66]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C)C=O>[CH3:34][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:68]1[S:69][C:65]([CH3:64])=[N:66][N:67]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:19]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Cc1nnc(S)s1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)s1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
N,N-Diisopropyl-N-ethylamine (0.309 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (800 mg) and 4-(N,N-dimethylamino)pyridine (18 mg) in methylene chloride (40 ml) at -30° C. To this mixture was added a solution of trifluoromethanesulfonic anhydride (0.261 ml) in methylene chloride (2.35 ml). After the mixture was stirred at -30° C. for 30 minutes, to the reaction mixture was added N,N-diisopropyl-N-ethylamine (0.772 ml) at -30° C., and further a solution of 5-methyl-1,3,4-thiadiazole-2-thiol (205 mg) in N,N-dimethylformamide (10 ml) was added. The mixture was allowed to warm to ambient temperature over a period of 30 minutes and stirred at the same temperature for 2.5 hours. The resultant mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (10 g), eluting with a mixture of benzene and acetone (50:1 to 20:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (824 mg) as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]1[N:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]=2[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]1[N:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1cccc(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1cccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(6-(dibutylamino)pyridin-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (75 mg, 0.15 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was added 2N NaOH (0.75 mL, 1.50 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. At 0° C., the reaction mixture was neutralized to pH 4-5 with 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (69 mg, 95%). MS(ESI+) m/z 486.4 (M+H)+.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([Cl:13])(Cl)=[O:11].[C:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[Cl:27][C:23]1[CH:22]=[C:21]([N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([Cl:13])=[O:11])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1

Procedure:
Other of the novel ureas and thioureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or thiophosgene to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a secondary amine to yield the urea or thiourea. The preparation of this intermediate is conducted in an aprotic solvent such as toluene or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example, N,N-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with N-phenyl-3-chloroaniline to yield the intermediate N-(3-chlorophenyl)-N-phenyl carbamyl chloride which is then reacted with N-benzyl-n-butylamine to yield 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[C:8]2[CH:17]=[C:18]([C:21]#[C:22][Si](C)(C)C)[CH:19]=[CH:20][C:7]=2[N:6]=1.[F-].[K+]>CO>[C:21]([C:18]1[CH:19]=[CH:20][C:7]2[N:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:8]=2[CH:17]=1)#[CH:22]
Reactant: C[Si](C)(C)C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Yield: 87.2 %

Procedure:
A solution of 4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (100 mg, 0.27 mmol) and potassium fluoride (64 mg, 0.68 mmol) in methanol (3 mL) was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under vacuum and the residue was diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 3×10 mL of water and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 70 mg (87%) of 4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid: LC-MS: m/z=+298 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][Si:9]([CH3:15])([CH3:14])[O:10][CH2:11][C:12]#[CH:13]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:7][C:6]1[C:2]([C:13]#[C:12][CH2:11][O:10][Si:9]([CH3:15])([CH3:14])[CH3:8])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: C#CCO[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCC#Cc1cscc1Br
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 19.6 %

Procedure:
Into a 250 mL 4 necked RB flask equipped with a magnetic stirring bar, thermometer, rubber septum, argon inlet and reflux condenser with argon outlet (tubed to a silicon oil bubbler) is added 48.3 g (229 mmol) of 3,4-dibromothiophene, 13.0 g of triethylamine, 20.1 g (157 mmol) of 3-trimethylsiloxypropyne, 130 mg of triphenylphosphine, 147 mg of copper iodide and 470 mg of dichlorobis(triphenylphosphine) palladium(II). The mixture is heated with a silicon oil bath to 70° C. under argon with stirring for 5.5 hrs. The cooled mixture is then concentrated on a rotary evaporator at reduced pressure and the residue taken up in 200 mL of hexanes and washed with 2×25 mL of water and the pentane phase dried over sodium sulfate and then concentrated on a rotary evaporator. The residue was chromatographed through neutral silica gel eluted with 2/1 methylene chloride/ethyl acetate to yield 8.9 g of 3-bromo-4(trimethylsiloxypropynyl)thiophene as a light yellow oil which was used directly to prepare 2-hydroxymethylselenolo[2,3-c]thiophene.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1.FC(F)(F)COC1C2C(OCCC3CCN(CC4(C(OC)=O)CCOCC4)CC3)=NOC=2C=CC=1>>[CH:28]1([CH2:27][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: BrCC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 7 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and (bromomethyl)cyclobutane instead of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate (Step 7 of EXAMPLE 7).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]=3[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:29].CO.Cl>O>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]=3[CH2:25][CH2:26][CH2:27][CH3:28])[OH:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:29]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(O)c1ccc2c(Br)c(O)ccc2c1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Sodium borohydride (0.33 g, 8.98 mmol) was added into a mixture of 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol (1.9 g, 4.49 mmol) and methyl alcohol (10 mL). The reaction mixture was stirred for 1 hour poured into water, acidified with HCl (2 N) and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtOAc 2:1) gave an off-white solid(1.65 g): MS m/e 424 (M+);
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[O:7][CH3:8].[NH2:9][C:10]1[C:15]2[CH:16]=[C:17](Br)[S:18][C:14]=2[C:13]([C:20]([NH2:22])=[O:21])=[CH:12][N:11]=1>>[NH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:2]3[CH:6]=[CH:5][S:4][C:3]=3[O:7][CH3:8])[S:18][C:14]=2[C:13]([C:20]([NH2:22])=[O:21])=[CH:12][N:11]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: COc1sccc1Br
Product: COc1sccc1-c1cc2c(N)ncc(C(N)=O)c2s1

Procedure:
92 was prepared from 3-bromo-2-methoxythiophene 91 (Zhang, Y.; Homfeldt, A.-B.; Gronowitz, S.; Stalhandske, C. Acta Chemica Scand. 1994, 48, 843–849) and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide in a similar manner to that described for Example 14. 1H NMR (400 MHz, d6-DMSO) δ: 4.10 (s, 3H), 7.13 (d, J 6.0 Hz, 1H), 7.28 (d, J=6.0 Hz, 1H), 7.69–7.78 (br s, 1H), 8.19 (s, 1H), 8.20–8.30 (br s, 1H), 8.40 (s, 1H), 8.60–8.80 (br s, 2H). MS (EI) m/z (M+H+) 306, (2M+H+) 611.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:38])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[N:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.1 %

Procedure:
A mixture of ethyl{2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (690 mg), 1M aqueous sodium hydroxide solution (5 mL), ethanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 15 hr. To the reaction solution was added 1M hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crystals were washed with hexane-ethyl acetate mixed solvent to give the title compound (610 mg, yield 95%) as brown crystals.