Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH:9](P(=O)([O-])[O-])[F:10])=[C:5](CC)[C:4]=1[Br:17])C.[Li+].CC([N-]C(C)C)C.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.O>C1COCC1>[Br:17][C:4]1[CH:5]=[C:6](/[C:9](/[F:10])=[CH:26]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCc1ccc(C(F)P(=O)([O-])[O-])c(CC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A solution of diethyl(3-bromophenyl)fluoromethylphosphonate (2.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature methyl 4-formylbenzoate (1.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (Z)-methyl 4-(2-(3-bromophenyl)-2-fluorovinyl)benzoate (0.73 g, 33.6%) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(Cl)Cl.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(I)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a solution of methyl 4-iodo-2-nitrobenzoate (2.3 g, 7.4 mmol) in DCM (5 mL) and EtOAc (5 mL) was added SnCl2-2H2O (10.8 g, 89.7 mmol). The mixture was allowed to stir for 12 h at rt. The solvents were evaporated, and the residue was partitioned between 200 mL of saturated aqueous NaHCO3 and 200 mL of DCM. The organic solution was separated and the aqueous solution was extracted with DCM (2×100 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give methyl 2-amino-4-iodobenzoate (1.85 g, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC(C)=O>O>[F:18][CH:17]([F:19])[C:9]1[N:8]([C:6]2[N:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:3]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:7]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CC(C)=O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
For example, a mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), piperazine (3.45 g, 40 mmol), and acetone (50 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and precipitated crystals were filtered, and washed with methanol to afford 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine (3.87 g, 9.3 mmol) in a yield of 93% as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1N(c2cc(Cl)c(O)c(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(Br)cc3)C2=O)cc1Cl
Temperature: 80 °C
Yield: 89.2 %

Procedure:
Ethyl 4-bromobutyrate (28 mg) was added to a mixture of the compound from Example 135 (55 mg) and K2CO3 (18 mg) in 2 mL anhydrous DMF and the resulting mixture was heated at 80° C. for 5 hours. The solution was partitioned between EtOAc/H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to yield the titled compound (61 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1c(OCCN(Cc2ccccc2)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1c(N)cccc1OCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a mixture of N-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg) in ethanol (40 mL) at 50° C. was added a solution of hydrazine hydrate (1.3 g) in ethanol (10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and the solvent removed. Purification by chromatography (30% ethyl acetate-hexane) afforded 380 mg (78.9%) of a clear oil; MS EI m/e 371 (M+); IR (film) 3400, 3350, 1680 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 66 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.047 g (66%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:34][CH2:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCc1ccccn1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCc3ccccn3)ncc2Cl)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (150 mg, 0.36 mmol) obtained in Example 54 and 2-pyridin-2-ylethylamine (400 μl) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (126 mg, 70%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>C(O)C>[NH:22]1[CH:26]=[N:25][C:24]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Reactant: Nc1nc[nH]n1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2nc[nH]n2)n1
Temperature: 160 °C
Yield: 4 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (0.326 mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) was heated at 160° C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). 1H NMR (500 MHz, CDCl3) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H), 7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m, 1H). LC-MS (ES+) 356.16 (M+H); HPLC-Method D,—Rt 3.55 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:38])=[CH:40][CH:41]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cc1

Procedure:
The title compound, white solid (113 mg, 89%), MS (ISP) m/z=507.4 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1>CC(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1ncc(Br)cn1
Solvent: CC(C)O
Product: O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1

Procedure:
As shown in step 6-i of Scheme 6, to a mixture of 5-bromo-2-fluoro-pyrimidine (1 g, 5.651 mmol) in iPrOH (10 mL) was added TEA (1.143 g, 1.574 mL, 11.30 mmol) and trans-4-aminocyclohexan-1-ol (650.8 mg, 5.651 mmol). The mixture was microwaved for 20 min at 150° C., concentrated under reduced pressure, diluted with EtOAc, washed with water, and dried over Na2SO4. After removal of the volatiles under reduced pressure, the residue was purified by medium pressure silica gel chromatography (0-80% EtOAc/hexanes gradient) to provide (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexanol (compound 1013, 1.2 g): 1H-NMR (300 MHz, CDCl3) δ 8.28 (s, 2H), 5.03 (d, J=8.1 Hz, 1H), 3.91-3.49 (m, 2H), 2.31-1.90 (m, 4H), 1.56-1.19 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:27])=[O:26])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)C.[OH-].[K+]>CO.O>[OH:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[N:20]1[CH2:24][C:23](=[O:25])[NH:22][S:21]1(=[O:27])=[O:26])[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])[CH:18]=[CH:17]2
Reactant: CCOC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[6-hydroxy-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid ethyl ester (Example 8, 0.025 g, 0.053 mmol) in MeOH/H2O (3 mL) is added KOH (0.009 g, 0.159 mmol). This is stirred at 50° C. for 18 h. LC/MS reveals the desired product, so the reaction solution is acidified using 1 N HCl, extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid as a white solid: 1H NMR (MeOD) δ7.88 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.31 (dd, J=8.46, 1.64 Hz, 1H), 7.21 (s, 1H), 4.61 (s, 2H), 2.75 (t, J=7.33 Hz, 2H), 2.32 (t, J=7.07 Hz, 2H), 1.61 (m, 4H). Retention time=0.87 min (Method A); (M−H)−=377.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>CO.O>[OH:28][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: NO
Reactant: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 89.9 %

Procedure:
A mixture of 24.5 g of methyl 4,5bis(4-methoxyphenyl)-5-oxo-3-pentenoate and 51.5 g of hydroxylamine hydrochloride in a mixture of 650 ml of methanol and 72 ml of water was heated under reflux for 3 hours. During this procedure, 0.9 equivalent of sodium hydrogen carbonate was added portionwise to the reaction mixture as the reaction progressed. After completion of the reaction, the methanol was distilled off under reduced pressure. Water and ethyl acetate were added to the residue for dissolution thereof, the organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to give 23 g (yield 90%) of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate as an oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:25])=[C:22]([CH3:36])[N:21]=[C:20](S(C)(=O)=O)[N:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:25])=[C:22]([CH3:36])[N:21]=[C:20]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.3 mg (0.0798 mmol) of phenol was dissolved in DMF. 16.7 mg (0.418 mmol) of sodium hydride (60% oily substance) was added at 0° C. and stirred at the same temperature for 30 minutes. 100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-methylsulfonyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was added at the same temperature and stirred heating to room temperature for 12 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (0.99 g, 2.84 mmol) in 50 mL of CH2Cl2 was treated with 25 mL of concentrated NH4OH solution. To the rapidly stirred solution was added p-toluenesulfonyl chloride (569 mg, 2.98 mmol). After stirring for 30 min, the reaction was treated with CH2Cl2 (50 mL) and H2O (25 mL). The layers were separated and the organic portion was washed 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give a tan solid. Chromatography (SiO2, 2% MeOH/CHCl3 containing 0.5% concentrated NH4OH) followed by crystallization from propyl acetate gave N1-benzyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (148 mg) as white needles. mp 152–155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.61 (dd, J=8.2, 1.2 Hz, 1H), 7.85–7.77 (m, 1H), 7.59–7.52 (m, 1H), 7.42–7.34 (m, 4H), 7.33–7.24 (m, 2H), 6.02 (t, J=6.6 Hz, 1H), 5.39 (s, 2H), 4.43 (s, 2H), 4.40 (d, J=6.7 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 147.9, 144.9, 135.7, 129.2, 129.1, 128.6, 127.8, 126.7, 122.4, 120.7, 66.7, 65.3, 56.7, 15.0; MS m/z 348 (M+H)+; Anal. Calcd for C2OH21N5O.0.36H2O: C, 68.90; H, 6.11; N, 20.09; Found: C, 68.50; H, 6.07; N, 20.11.
Reaction SMILES: [C:1]([NH2:5])(=[S:4])[CH2:2][CH3:3].Cl[CH:7]([CH:13]=O)[C:8]([O:10]CC)=[O:9]>C(O)C>[CH2:2]([C:1]1[S:4][C:7]([C:8]([OH:10])=[O:9])=[CH:13][N:5]=1)[CH3:3]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCc1ncc(C(=O)O)s1
Reaction time: 8 h

Procedure:
a solution of 26 gm of thiopropionamide in 100 cc of ethanol is mixed with a solution of 36.5 gm of ethyl 2-chloro-3-oxo-propionate in 50 cc of ethanol. The reaction mixture is left in contact overnight, then the alcohol is evaporated off. The residue is dissolved in ether, the ethereal phase is washed with an aqueous 20% sodium carbonate solution, then with water. The oil obtained is distilled and the fraction coming off at 80° C. to 90° C. under a pressure of 0.5 mm is recovered. This fraction is saponified with an alcoholic solution of potassium hydroxide, then acidified and recrystallized from toluene. 2-Ethyl-5-thiazolecarboxylic acid is obtained in the form of colorless crystals, soluble in ethanol and sodium hydroxide, insoluble in water, melting at 157° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12]1[O:16]CCO1.[B:17]([O-])([O-:23])[O:18]CCCC.Cl>CCCCCC.CCOCC>[CH:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[B:17]([OH:23])[OH:18])=[O:16]
Reactant: Brc1ccsc1C1OCCO1
Reactant: CCCCOB([O-])[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1sccc1B(O)O
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1.1 N solution of n-butyllithium in hexane (28 ml) was added dropwise (10 mins) to a solution of 2-(3-bromo-2-thienyl)-1,3-dioxalane (3) (6.6 g, 28.1 mmol) in anhydrous ether (30 ml) at −70° C. After stirring for 10 mins, butyl borate (9.1 ml, 33.7 mmol) in anhydrous ether (20 ml) was added in a single portion. The reaction mixture was stirred for 4 hrs at −70° C. and then left to return to room temperature. 1 N hydrochloric acid (20 ml) was added, and the mixture was left for 1 hr with stirring. The aqueous phase was extracted with ether and the combined ether phases were washed with a solution of sodium bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the intermediate (4) (2.2 g, 14.1 mmol, 50% yield) as a brown solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
5.23 g of imidazole and 4.85 g of tert-butyldimethylchlorosilane were added, in this order, to a suspension of 4.02 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole in 60 ml of dimethylformamide at room temperature. The mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added 100 ml of ice water and 200 ml of ethyl acetate. The organic layer was separated, washed with 100 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to obtain 5.14 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyphenyl)thiazole.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)O1>>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:17]2[C:4]3[C:3]4[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=4[NH:7][C:6](=[O:14])[C:5]=3[S:15][CH:16]=2)=[CH:27][CH:28]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3scc(-c4ccc(C(C)=O)cc4)c3c2c1
Yield: 46.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.0 g, 3.2 mmol) was reacted with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (1.2 g, 4.8 mmol) to afford the desired product (520 mg, 46%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 8.16 (d, J=8.1 Hz, 2H), 7.61-7.54 (m, 2H), 7.45-7.39 (m, 3H), 6.05 (d, J=5.4 Hz, 1H), 3.75 (s, 3H), 2.71 (s, 3H).