Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].S([N:13]1[C:17]([CH3:18])=[C:16]([CH2:19]Cl)[N:15]=[CH:14]1)(C1C=CC(C)=CC=1)(=O)=O.S(N1C(CCl)=C(C)N=C1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]2[C:49](=[O:53])[CH2:50][CH2:51][CH2:52][C:41]=12.[Li].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(O)(=O)C.O1CCCC1.CCCCCC>[CH3:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]2[C:49](=[O:53])[CH:50]([CH2:19][C:16]3[N:15]=[CH:14][NH:13][C:17]=3[CH3:18])[CH2:51][CH2:52][C:41]=12
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCl)c2C)cc1
Reactant: Cc1c2n(c3ccccc13)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)n2cnc(C)c2CCl)cc1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Under nitrogen stream, sodium iodide (97.8 g) and a mixture of 1-tosyl-4-chloromethyl-5-methyl-imidazole and 3-tosyl-4-chloromethyl-5-methyl-imidazole (186 g) in tetrahydrofuran (1,000 ml) were agitated vigorously at an interior temperature of 18~23° C. for 2 hours, and after carrying out halogen exchange, the reaction solution was cooled to an interior temperature of -40~-50° C. In a separate reaction vessel, under nitrogen stream, 8,9-dihydro-10-methyl-pyrido[1,2-a]indol-6(7H)-on (100 g) was dissolved in tetrahydrofuran (900 ml), cooled to -40~-50° C. and a 1.35 N solution of lithium hexamethyldisilazit/tetrahydrofuran-n-hexane (409 ml) were dripped therein while maintaining at same temperature. After dripping was completed, the reaction was carried out under the agitate at same temperature for an additional 30 minutes and thereafter the solution was dripped into the halogen exchange reaction solution prepared above while maintaining a temperature of -40~-50° C. The reaction was carried out at the same temperature for 15 minutes, and acetic acid (12.1 g) was added thereto. An interior temperature was raised to 5~10° C., then 5% aqueous sodium thiosulfate (1,000 ml) was added thereto, and the upper layer was collected. It was concentrated under vacuum until the volume is approximately 800 ml. After the concentrating is completed, the mixture of methanol (400 ml), water (200 ml), and concentrated hydrochloric acid (100 ml) was added thereto, and were agitated for 3 hours after the interior temperature was raised to 48~53° C. After the reaction is completed, the solution was adjusted to pH 7.8-8.2 with 12% aqueous sodium hydroxide solution, and was concentrated under vacuum until volume is approximately 800 ml. Ethyl acetate (300 ml) was added thereto, adjusted to pH 10.5±0.2 with 12% aqueous sodium hydroxide, thereafter was cooled to a temperature of not higher than 10° C., and the precipitated crystals were collected by filtration. They were washed with ethyl acetate (300 ml) and water (500 ml), and then dried overnight under vacuum to obtain (±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one as yellowish-brown crystals (129.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1.C(OC(C)C)(C)C.C1CCCCC1>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:21]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OCC4CC4)c3)c(Cl)c12
Yield: 58 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(b) except for using 254 mg (0.496 mmol) of 3-chloro-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 36-(a) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, diisopropyl ether and cyclohexane were added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained crude solid was applied to silica gel column chromatography (Eluent; chloroform:methanol=9:1 (V/V)), the fractions containing the desired compound were concentrated, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred at room temperature for 3 hours. Then, the solution was concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether and dried under reduced pressure to obtain 100 mg of the title compound as a white solid. (Yield: 58%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:13].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:19][C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])[N:14]=2)=[CH:7][C:6]=1[CH3:13]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)ccc1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(C)c3)nc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde (1.46 g, 8.08 mmol) and 2-amino-4,6-dimethoxybenzamide (1.58 g, 8.08 mmol) in N,N-dimethylacetamide (20 mL) were added NaHSO3 (58.5 wt %, 2.20 g, 12.12 mmol) and p-toluenesulfonic acid monohydrate (0.38 g, 2.02 mmol). The reaction mixture was stirred at 110° C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was triturated with water (50 mL). The resulting slurry was filtered and solid was washed with water, ether, and hexanes to obtain 2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a beige solid. Yield: 2.75 g (95%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1

Procedure:
An acetone solution of 3-[4-(trifluoromethoxy)phenyl]-1-naphthol (50 mg, 0.166 mmol), methyl 4-(bromomethyl)benzoate (73 mg, 0.32 mmol) and K2CO3 (44 mg, 0.32 mmol) was heated at reflux until no starting material remained by HPLC analysis. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 4.64 min. (M+H)=453
Reaction SMILES: FC1C2C(=O)C3C=CN=CC=3C(=O)C=2C(O)=CC=1.[Cl:19][C:20]1[C:25]2[C:26](=[O:35])[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[C:33](=[O:34])[C:24]=2[C:23]([OH:36])=[CH:22][CH:21]=1.FC1C2C(=O)C3C=CN=CC=3C(=O)C=2C([O:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=O)=[O:56])=CC=1>C(Cl)Cl>[Cl:19][C:20]1[C:25]2[C:26](=[O:35])[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[C:33](=[O:34])[C:24]=2[C:23]([O:36][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=[O:56])=[O:54])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2cnccc2C3=O)cc1
Reactant: O=C1c2cnccc2C(=O)c2c(Cl)ccc(O)c21
Agent: O=C1c2cnccc2C(=O)c2c(F)ccc(O)c21
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2cnccc2C3=O)cc1

Procedure:
Following the procedure of Preparative Example 15 and using the mixture of 6-fluoro-9-hydroxybenzo[g]isoquinoline-5,10-dione and 6-chloro-9-hydroxybenzo [g]isoquinoline-5,10-dione obtained in Preparative Example 16 as starting material, an approximately 60/40 mixture of 6-fluoro-9-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione and 6-chloro-9-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione is obtained as a yellow powder, m.p. 193°-195° C. (from methylene chloride).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:26]
Reactant: CCI
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (40 g) obtained according to the procedure described in step (iv) above in dimethylformamide (105 ml) at 5–10° C. over a period of 15–30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1–3 h Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25–30° C. over a period of 2–3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47–48 g, 98–99%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:20])[CH2:13][CH2:14][O:15][C:16](=[O:19])[CH2:17]I)[CH2:3]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:20])[CH2:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CI)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: ClCCl
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3α-Hydroxy-21-iodoacetoxymethyl-5α-pregnane-11,20-dione (230 mg) in dry dichloromethane (25 ml) was treated with morpholine (1.0 ml) and the solution was stirred at room temperature for 30 minutes. The solution was diluted with dichloromethane, washed twice with water, dried over sodium sulphate and evaporated to a colourless gum (230 mg) which was purified by preparative t.l.c. in acetone/petrol 1:1. The main band was separated to give title compound (172 mg) as a white foam, [α]D + 79° (c 0.68).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].OC1C=CC(CC(OC)=O)=CC=1.BrC(C)(C)C(OC(C)(C)C)=O.[Li+].[OH-].Cl.O>O1CCOCC1>[C:1]([O:5][C:6](=[O:22])[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Agent: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
6.27 g (20.3 mmol) of 2-(4-methoxycarbonylmethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from methyl 4-hydroxyphenylacetate and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A]) was dissolved in 100 ml of dioxane; to the stirred solution, 40.7 ml of 1N LiOH solution was added drop by drop. After 30 min., the reaction mixture was poured into crashed ice, the pH was adjusted to <3 with HCl/H2O and it was extracted twice with AcOEt. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated to give 6.01 g of the title compound as a light yellow solid.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.C1N2CCN(CC2)C1.[CH2:24]([C:34]1[CH:35]=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[N:38][CH:39]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[H-].[Na+].Cl>C1C=CC=CC=1>[CH2:24]([C:34]1[CH:39]=[N:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:4][C:3](=[O:5])[CH:2]([F:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:42][CH:41]=2)=[N:36][CH:35]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCC(F)C(=O)O
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C(F)CCCCCC)cc2)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
More specifically, 0.24 mg (1.5 mmol) of 2-fluorooctanoic acid was added to 2 ml of thionyl chloride and the mixture was refluxed at 90° C. for 2 hours. Then, the excess of thionyl chloride was distilled off, and a preliminarily prepared solution of 0.34 g (3.0 mmol) of triethylenediamine and 0.47 g (1.5 mmol) of 5-n-decyl-2-(p-hydroxyphenyl)pyrimidine in 5 ml of dry benzene was quickly added thereto, followed by 2 hours of stirring at 50° C. Thereafter, 0.06 g (1.5 mmol) of sodium hydride (60%) was added, and the mixture was further refluxed for 2 hours at 90° C. After the reaction, 2N-hydrochloric acid was added to the system, which was then subjected to extraction with benzene. The extract was dried, subjected to distillation of the solvent and purified by column chromatography with benzene to obtain 0.44 g (0.96 mmol) of 5-n-decyl-2-[4-(2-fluorooctanoyloxy)phenyl]pyrimidine. Yield: 64%
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19](=[O:20])[O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, asolution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetrahydrofuran. The reaction mixture, a suspension, is stirrred at room temperature overnight. The formed solid is collected, washed with water and dried to give 5.9 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])[C:9]([OH:11])=O.Cl.C([O:33][C:34](=[O:37])[CH2:35][NH2:36])C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])[C:9]([NH:36][CH2:35][C:34]([OH:37])=[O:33])=[O:11]
Reactant: CCOC(=O)CN
Reactant: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)NCC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2S)-2-(5-chloro-2-methoxybenzyl)-3-[(2,4,6-trimethoxybenzyl)amino]propionic acid (1g) in acetonitrile (10 ml), glycine ethyl ester hydrochloride (345 mg), 1-hydroxy benzotriazole (478 mg), and triethylamine (0.35 ml) were added at room temperature, and the mixture was stirred at room temperature for 40 minutes. At room temperature, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (678 mg) was added to the reaction solution, and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo, and ethyl acetate was added to the obtained residue. Then the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, an the organic layer was concentrated. To the obtained residue, isopropyl alcohol (5 ml) and 5N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted with 5N hydrochloric acid to pH 5, then the precipitated crystals were obtained by filtration and dried to obtain the title compound (978 mg) as a colorless crystal. The various types of spectral data match with those of Example 326.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 45 mg (68% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O>CCOCCO>[CH2:8]([O:11][CH2:12][CH2:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[Cl:22])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:7]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOCCO
Product: CCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 129.8 %

Procedure:
In 80 ml ethyl cellosolve was dissolved 2.0 g (0.0057 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid, and a catalytic amount of sulfuric acid was added. The mixture was heated to reflux for 8 hours. After stopping of the reaction, ethyl cellosolve was removed by distillation, and the residue was extracted with benzene. The extract was washed with a dilute aqueous solution of caustic soda and then with water, and dehydrated with sodium sulfate. By concentration 1.8 g (0.0037 mol) of the intended product was obtained; yield 65.2%, nD25 1.5272.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[O:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[O:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)COc1cccc(OC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(OC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)acetate (38 mg, 0.091 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and stirred overnight at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 15% methanol/dichloromethane) to afford 21 mg (61%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:27]([O:26][C:25]([N:24]([CH2:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:14])=[O:15])[CH:11]=1)[CH3:32])=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol), methyl bromoacetate (40 mg, 0.26 mmol) and potassium carbonate (45 mg, 0.33 mmol) were added to 5 mL of acetonitrile, then the reaction solution was heated up to 50° C. and stirred for 16 h. The reaction solution was concentrated under reduced pressure. 50 mL of water were added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product methyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 1i (110 mg, a yellow oil), which was used directly in the next step.