Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[ClH:13].[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[N:17]=[CH:16][N:15]=[C:14]2[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCCN1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of oxindole (259 mg, 1.95 mmol) in THF (3 ml) was added dropwise to a suspension of sodium hydride (78 mg, 1.95 mmol, prewashed with hexane) in THF (3 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 0.65 mmol) in DMF (3 ml) was added dropwise. The mixture was heated at 60° C. for 30 minutes, the THF was removed by evaporation and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by chromatography on neutral aluminium oxide eluting with methylene chloride/methanol (80/20). The purified solid was dissolved in methylene chloride containing methanol and 3M ethereal hydrogen chloride was added. The volatiles were removed by evaporation and the residue was suspended in ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(oxindol-3-yl)-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline hydrochloride (55 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH:13]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH3:16])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC(C)C)cc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OC(C)C)cc1OC
Reaction time: 12 h

Procedure:
A 1.60 g portion of methyl 2-hydroxy-4-isopropoxybenzoate was dissolved in 30 ml of 2-butanone, 1.60 g of potassium carbonate and 1.1 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, insoluble matter was removed by filtration through celite, and the solvent was again evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give 1.70 g of methyl 4-isopropoxy-2-methoxybenzoate.
Reaction SMILES: COC1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2C=1.B(Br)(Br)Br.C(N(CC)CC)C.[C:24]([O:27][C:28](=O)[CH3:29])(=[O:26])[CH3:25]>ClCCl>[CH3:10][C:8]1[O:9][C:5]2[CH:29]=[C:28]([O:27][C:24](=[O:26])[CH3:25])[CH:12]=[CH:11][C:6]=2[CH:7]=1
Reactant: COc1ccc2cc(C)oc2c1
Reactant: CC(=O)OC(C)=O
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc2cc(C)oc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of 6-methoxy-2-methyl-benzofuran (17.4 g, 107 mmol) in dichloromethane (200 mL) at 0° C. is treated with boron tribromide (1.0 M, 107 mL). The mixture is stirred at 0° C. for 60 minutes and quenched with water (50 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography eluting with 25% EtOAc/Hexanes. The appropriate fractions are concentrated under reduced pressure. The resulting material is dissolved in dichloromethane (150 mL) and triethylamine (17.0 mL, 122 mmol) at 0° C. and treated with acetic acid anhydride (7.22 mL, 76.35 mmol). The reaction is stirred for 16 hours and allowed to warm to room temperature. The reaction is quenched with MeOH (100 mL) and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (9.50 g, 82%). 1H NMR (400 MHz, CDCl3): δ 7.40-7.38 (d, 1H), 7.15 (s, 1H), 6.91-6.88 (d, 1H), 6.32 (s, 1H), 2.41 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)([Cl:14])=O>ClCCl>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:10][Cl:14])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccnc(CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccnc(CCl)c1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.6 g of 3-chloro-2-hydroxymethyl-4-methoxypyridine and 30 ml of dichloromethane at -10 to -15° C. was added dropwise a solution of 3.5 ml of thionyl chloride in 25 ml of dichloromethane, and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated off, and the residue was induced to crystallized with diethyl ether. Colorless crystals, melting point 145°-146° C.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.Cl[C:33]1[CH:56]=[CH:55][C:36]([O:37][CH2:38][C:39]2[C:43]3[CH:44]=[N:45][C:46]([C:48](OCC)=[O:49])=[CH:47][C:42]=3[N:41]([CH2:53][CH3:54])[CH:40]=2)=[CH:35][CH:34]=1.[Cl:57]C1C=CC(O)=C(C=1)CC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1>>[Cl:57][C:55]1[CH:56]=[CH:33][CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[C:43]2[CH:44]=[N:45][C:46]([C:48]([NH:21][OH:22])=[O:49])=[CH:47][C:42]=2[N:41]([CH2:53][CH3:54])[CH:40]=1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(Cl)ccc1O)cn2CC
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(COc1ccc(Cl)cc1)cn2CC
Product: CCn1cc(COc2ccccc2Cl)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(2-chloro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-chlorophenol using methods similar to step (e) of Example 54. (b) 3-(2-Chloro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-chloro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6carboxylate and ethy 3-(5-chloro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([SeH:16])[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=C(C(C)C)[N:6]=1.[H-].[Na+].[CH2:19](OCCl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([SeH:16])[C:4]([CH:10]([CH3:15])[CH3:11])=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1
Reactant: Cc1nc(C(C)C)c(-c2ccccc2)n1[SeH]
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(C(C)C)n1[SeH]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a solution of 400 mg of 2-methyl-4-isopropyl-5-phenylselenyl-imidazole (1.4 mmol) in 4 ml of dry dimethylformamide is added 70 mg of 60% oil suspension of sodium hydride (1.8 mmol) under ice cooling and the mixture is allowed to stand for 5 minutes followed by the addition of 270 mg of benzyloxymethyl chloride (1.7 mmol). The mixture is stirred for 30 minutes under ice cooling, mixed with ice water and extracted with diethyl ether. The extract is washed with water, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:1). The product is recrystallized from n-hexane to give 297 mg of the objective 2-methyl-4-phenylselenyl-5-isopropyl-imidazole (I-87 ) and 1-benzyloxymethyl-4-isopropyl-2-methyl-5-phenyl-selenyl-imidazole (I-37). Yield, 52%; mp. 94°-96° C.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18](O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24]C)C>>[C:1]([NH:9][CH:10]([CH2:18][N:23]([CH3:24])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: CN(C)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 26.5 g of N-benzoyl phenyalanine (XIII) in 200 ml of T.H.F. are added 11 g of triethylamine, it is cooled to 0° C. and 11 g of ethyl chloroformiate are added. After 30 mn at 0° C., a solution of 4.5 g of diethyllamine in 50 ml of T.H.F. is added, then it is left for 2 hours at ambient temperature. Then the solvent is evaporated, the residue taken up in water, extracted with chlorofrom, dried on sodium sulfate, filtered and the filtrate evaporated. Thus, the expected product was obtained with a yield of 81% Melting point: 150° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Reaction time: 0.5 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bias(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5 h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions. The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil. PMR (CDCl3): δ1.38 (6H, s), 1.42 (3H, t, J~7.0 Hz), 1.98 (2H, m), 3.07 (2H, m), 4.39 (2H, q, J~7.0 Hz), 7.20 (1H, d, J~9.0 Hz), 7.28 (2H, d, J~8.1 Hz), 7.82 (1H, dd, J~9.0, 1.8 Hz), 8.12 (2H, d, J~8.1 Hz), 8.17 (1H, d, J~1.8 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
3-Amino-1-propanol (6.92 mL, 90.5 mmol) was added dropwise to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (20.0 g, 90.5 mmol) and triethylamine (18.9 mL, 136 mmol) in DMF (300 mL) at room temperature. After 16 hours, the solvent was removed under reduced pressure and the resulting oil was partitioned between ethyl acetate (450 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL). The combined aqueous layers were back-extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was triturated with hexanes/ethyl acetate (2:1) and was isolated by filtration to yield 12.43 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[C:6]([C:21]#[N:22])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[C:6]([CH:5]=1)[C:21]#[N:22]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
To a solution of 3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (23 g, 0.070 mol) in anhydrous THF (200 mL) was added portionwise LiAlH4 (4.07 g, 0.11 mmol) at −78° C. The reaction mixture was warmed to −55° C. slowly and stirred for 20 mins, diluted with water (3 mL 0.16 mmol, slow addition), filtered and concentrated. Purification via column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 5/1) afforded the title product (12.5 g) as a colorless oil. LCMS: rt=2.81 min, [M+H+]=295.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])=[O:3].C(O)C.C(OCC(O)COC1C=CC([NH:27][C:28](=[O:32])[CH2:29][CH2:30]Cl)=CC=1)C>[OH-].[Na+]>[C:2]([NH:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7][CH2:30][CH2:29][C:28]([NH2:27])=[O:32])(=[O:3])[CH3:1]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CCOCC(O)COc1ccc(NC(=O)CCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NC(CSCCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A 1.63 g quantity of L-acetylcysteine was dissolved in 0.80 g of sodium hydroxide and 50 ml of a 70% aqueous solution of ethanol with ice cooling. To the solution was added 3.02 g of N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-chloropropionamide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was adjusted to a pH of 3 with diluted hydrochloric acid, washed with chloroform and extracted with ethyl acetate. The ethyl acetate layer was dewatered with Glauber's salt and was concentrated. The residue was purified with acetone-ether, giving 3.95 g of N-] 4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(2-acetylamino-2 carboxyethylthio)propionamide in a yield of 92.1 %. ##STR5##
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]1>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCNC1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC(CO)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 114 g. of 3-piperidinemethanol in 900 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate of 1-(4-acetylbenzenesulfonyl)-3-piperidinemethanol collected by filtration, washed with water and dried; m.p. 104°-106° C. after crystallization from aqueous ethanol.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:6])=[O:5].Cl[CH2:23][CH2:24][C:25]([OH:27])=[O:26].Cl>O.C(OCC)(=O)C>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:21][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:6])=[O:5]
Reactant: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccccc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1cc(OCCC(=O)O)ccc1Oc1ccccc1
Yield: 23.1 %

Procedure:
4 g of sodium hydroxide was dissolved in 250 ml of water. Therein was dissolved 27.9 g of 3-methylsulfonylamino-4-phenoxyphenol. Thereto was added an aqueous solution obtained by dissolving 10.9 g of 3-chloropropionic acid and 4 g of sodium hydroxide in 30 ml of water. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled and adjusted to pH 8 with 4N hydrochloric acid. 70 ml of ethyl acetate was added thereto. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid and extracted with 100 ml of ethyl acetate. The resulting extracts were washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with diethyl ether. The resulting solid was collected by filtration to obtain 8.1 g (yield: 23.1%) of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)propionic acid having a melting point of 145°-149° C.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1
Reactant: CCOC(=O)c1cn(C2CCCCO2)nc1I
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate (85 g, 242.75 mmol, 1.00 equiv) in THF (300 mL) and methanol (300 mL) was added a solution of LiOH (17.5 g, 730.69 mmol, 3.01 equiv) in water (400 mL). The resulting solution was stirred at room temperature overnight and then concentrated under vacuum to remove the organic solvent. The resulting solution was diluted with 400 mL of H2O and then acidified to pH 6.0 with 1M hydrochloric acid. The mixture was extracted with 3×800 mL of dichloromethane. The combined organic layers was washed with 3×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 75 g (96%) of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylic acid as an off-white solid. LCMS (method D, ESI): RT=1.23 min, m/z=323.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1>CN(C=O)C.O>[CH3:21][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of 2-aminopyridin-4-ol (355 mg, 3.22 mmol) in DMF (4.0 mL) at 0° C. under nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 193 mg, 4.83 mmol) and the reaction mixture warmed to RT for 2 hr, The mixture cooled to 0° C. and a solution of 4-fluoro-2-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in DMF (2.0 mL) was added, dropwise and the reaction mixture warmed to RT for 16 hr. The resulting mixture was diluted with water (20 mL) and was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (20 mL), then dried (MgSO4) and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 25% EtOAc in DCM, isocratic elution) to afford 4-(3-methyl-4-nitrophenoxy)pyridin-2-amine as a yellow solid (351 mg, 44%); Rt 1.20 min (Method 2); m/z 246 (M+H)+ (ES+).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=4[CH:29]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:52]1[CH2:71][O:70][C:54]2([CH2:59][CH2:58][CH:57]([N:60]([CH2:62][C:63]3[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=3)[CH3:61])[CH2:56][CH2:55]2)[O:53]1>CN(C=O)C.C(N(CC)CC)C>[CH2:71]1[CH2:52][O:53][C:54]2([CH2:55][CH2:56][CH:57]([N:60]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([NH:67][C:26]([C:20]4[CH2:21][CH2:22][S:23](=[O:24])(=[O:25])[C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][O:2][CH2:3][CH2:4]7)=[CH:9][CH:10]=6)=[CH:29][C:18]=5[CH:19]=4)=[O:28])=[CH:68][CH:69]=3)[CH3:61])[CH2:58][CH2:59]2)[O:70]1
Reactant: CN(Cc1ccc(N)cc1)C1CCC2(CC1)OCCO2
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (200 mg) and 1-hydroxybenzotriazole (0.12 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]aniline (0.19 g) and triethylamine (0.2 ml) in DMF (3 ml), and the mixture was stirred for 64 hours. The mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:1) to give yellow crystals of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 15) (119 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[C:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][CH:4]=[C:3]2[CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:37][CH2:38]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ncc(CN3CCC(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc23)cc1OC
Yield: 100.1 %

Procedure:
A mixture of 5.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 2.49 g of 4-(2-methoxyphenyl)piperidine, and 2.63 g of triethylamine in 50 ml of dimethylsulfoxide was heated at 80° for one hour under argon and then the cooled solution was diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated to give 7.0 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-([4-(2-methoxyphenyl)-1-piperidinyl]methyl)isoquinolin as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][C:3]1=2.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[NH:22][CH:23]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:19]3[CH:20]=[C:21]([CH:24]=[O:25])[NH:22][CH:23]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Reactant: O=Cc1cc(Br)c[nH]1
Product: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Yield: 21.7 %

Procedure:
In a similar manner to Example 3(b), by reaction of 5.9 g (25.6 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid with 3.7 g (21.3 mmol) of 4-bromo-2-pyrrolecarboxaldehyde, 1.3 g (21.6%) of the expected product are obtained, with a melting point of 211-2° C.