Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(Cl)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(Cl)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 2-amino-2-methyl-propionic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 373.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]([CH3:28])=[N:21]1>>[CH3:19][N:20]1[C:24]([C:25]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:26])=[CH:23][C:22]([CH3:28])=[N:21]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(C)n1
Yield: 26 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (20 mg, 26%). 1H-NMR (δ, ppm, DMSO-d6): 2.19 (s, 3H, Mepyrrazole,3), 3.98 (s, 3H, Mepyrrazole,1), 6.48 (d, 1H, HPy,5, J=6.0 Hz), 6.81 (s, 1H, Hpyrrazole), 6.91 (d, 1H, Harom, J=8.0 Hz), 7.41 (t, 1H, Harom, J=8.0 Hz), 7.56 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=8.0 Hz), 7.80 (d, 1H, HPy,6, J=6.0 Hz), 10.19 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C18H17N6O3: 365.1362; found: 365.1356.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25](C=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25]1[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester, 3,5-dimethylpyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave {3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-carbamic acid tert-butyl ester as a pale beige sticky solid. 1H NMR (CDCl3) δ 1.75 (m, 4H), 2.18 (br t, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.37 (br, 1H), 2.56 (t, 1H, J=10.5 Hz), 2.83 (m, 4H), 3.38 (br, 1H), 3.68 (d, 1H, J=15.0 Hz), 3.84 (br, 1H), 4.04 (d, 1H, J=15.0 Hz), 7.13 (m, 1H), 7.26 (s, 1H), 7.41 (d, 1H, J=7.0 Hz), 8.33 (s, 1H), 8.53 (d, 1H, J=4.5 Hz). Deprotection with TFA using General Procedure F gave N′-(3,5-dimethyl-pyridin-2-yl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>>[F:15][C:2]([F:14])([F:1])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2ccc(C(F)(F)F)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: MS (ES) m/z 359 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][N:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([O:24]C(C)C)[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]>C(Cl)Cl.O>[NH2:6][N:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O

Procedure:
Conc. sulfuric acid (3 ml) was added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.5 g) in methylene chloride (50 ml) stirred at 0C . After 1 hour the mixture was diluted with water and processed. The oily product was chromatographed on silica gel eluting with ethyl acetate:hexane, 2:3, to give 1-amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione as a pale yellow amorphous solid (3.6 g,). 1H NMR (CDCl3,TMS): 7.27(1H, d, J=8.8 Hz), 6.88(1H, d, J=6.5 Hz), 6.28(1H, s), 5.86(1H, br. s), 4.61(2H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:24]([S:26]([C:29]1[S:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:34]([C:32]5[S:33][C:29]([S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=5)=[O:35])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 71.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 5-(ethylsulfonyl)thiophene-2-carboxylic acid (110 mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (180 mg, 71%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])C.[OH-].[K+]>CO.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:16])=[C:6]2[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c2ccc(F)cc2c1CC(=O)O
Reaction time: 2 h

Procedure:
This ester (4.5 g, 0.019 mol.) was added to a solution of KOH (2.13 g, 38 mmol.) in methanol (100 ml), and the mixture was heated at reflux for 30 min. For working up, the mixture was diluted with water (100 ml) and methanol was distilled off using a rotary evaporator. The aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 h at 4° C. The white solid that precipitated was filtered off with suction and washed with methanol. (5-Fluoro-2-methyl-1H-indol-3-yl)acetic acid was obtained in a yield of 3.25 g (m.p. 136–138° C.).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18](O)[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH:18]([N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(O)c1nc2ccccc2cc1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(c1nc2ccccc2cc1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-ol 13 (102 mg, 1 eq.) in dry tetrahydrofuran (3 ml) at 0° C., was added phthalimide (154 mg, 3 eq), triphenylphosphine (138 mg, 1.5 eq.), and DIAD (1.5 eq., 104 μl). The reaction was allowed to warm to room temperature and stirred overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The material was purified by flash chromatography to yield 91 mg of 2-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione 14 as yellow oil.
Reaction SMILES: [C:1]([N:4]1[CH2:27][CH:26]([OH:28])[CH2:25][C@H:5]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)=[O:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CO>[C:1]([N:4]1[CH2:27][CH:26]([O:28][C:35](=[O:37])[CH3:36])[CH2:25][C@H:5]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC1C[C@@H](C(=O)Nc2ccc(-c3ccc(C(=O)O)c(=O)[nH]3)cc2)N(C(C)=O)C1

Procedure:
A solution of 29.9 g (0.078 mol) of the above pyridone acid, 120 ml of pyridine, and 60 ml of acetic anhydride is stirred overnight at room temperature. The solution is cooled and upon adding methanol, a precipitate forms. The mixture is cooled and then filtered and the solid is air dried. The solid is recrystallized from 1800 ml of 20% water in methanol and dried at 50° under vacuum to give 21.1 g of 6-[4-[N-acetyl-4-(acetyloxy)-L-prolylamino]phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +17.3° (cl, 75% DMF/pyridine).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.IC1C=C(C=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:2]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Reactant: CCOC(=O)c1cccc(I)c1
Agent: Nc1cccc2[nH]ncc12
Product: CCOC(=O)c1cccc(-n2ncc3c(N)cccc32)c1

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and ethyl 3-iodobenzoate.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.COC[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1>[CH3:1][S:2]([CH2:5][C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3]
Reactant: COCC(=O)OC
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was addded 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen atmosphere. After stirring for 0.5 hour, a solution of methyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 2 hours in the bath and allowed to warm to room temperature over 2 hours. The mixture was partitioned between EtOAc and 4 N hydrochloric acid. The reaction was quenched by adding 4 N hydrochloric acid in EtOAc (15 mL). The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was washed with EtOAc (100 mL, five times). The organic layer was combined, and the combined extracts were dried over MgSO4, and evaporated. Flash silicagel column chromatography (EtOAc-hexane=50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].O.[OH-].[Li+].CO>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 97.6 %

Procedure:
To a stirring solution of crude methyl 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (Intermediate 62) (2.2 g, 5.01 mmol) in MeOHl (12 mL), was added lithium hydroxide monohydrate (0.144 g, 6.01 mmol) in water (12 mL) and the mixture warmed to 50° C. for 70 mins. MeOH (10 mL) was added and the mixture stirred at 50° C. for a further 50 mins. The mixture was allowed to cool to room temperature before being partitioned between saturated aqueous sodium bicarbonate (150 mL) and DCM (3×150 mL). The aqueous layer was then treated with 2M HCl until acidic (˜pH 3) before being extracted with DCM (3×150 ml). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (2.08 g, 4.89 mmol). LCMS: (Formate, 2 min), Rt=0.86 mins, MH+426.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:26]2[N:27]=[N:28][NH:29][N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:2][CH2:3][OH:4])[N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
Add 2-bromoethanol (0.093 mL, 1.25 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzyl-(2H-tetrazol-5-yl)amino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (653 mg, 1.045 mmol) and cesium carbonate (749 mg, 2.30 mmol) in dry dimethylformamide under an atmosphere of nitrogen and stir the mixture at 50° C. for 24 h. Cool to room temperature, add water, and extract with ethyl acetate. Dry the organic solvent over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford a mixture of two compounds. Separate by normal phase HPLC eluting with standard hexane/ethanol gradient to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1carboxylic acid isopropyl ester (48 mg, 7%). 1H NMR (CDCl3, 300 MHz): δ 0.95 (t, J=7.7 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H), 1.35 (d, J=6.3 Hz, 3H), 1.55-1.69 (m, 2H), 2.31-2.47 (m, 3H), 3.98-4.00 (m, 2H), 4.49-4.73 (m, 5H), 5.09 (septuplet, J=7.5 Hz, 1H), 5.41 (dd, J=11.9, 7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.81 (s, 2H), 8.39 (d, J=8.6 Hz, 1H). MS (ES+): 670 (M+H).
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:34]([S:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[CH2:42]([S:41][C:34]1[CH:35]=[C:36]([CH:40]=[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])[C:33]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]([OH:39])=[O:38])[CH2:43][CH:44]([CH3:46])[CH3:45]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CC(C)CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: CC(C)CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-isopentylthio-4-phenylbenzoic acid, and following the procedure described, 3-isopentylthio-4-phenyl-5-sulfamylbenzoic acid is obtained crystallizing with 0.5 mole of ethanol with a melting point of 70°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:9]([F:14])([F:13])([F:12])([F:11])[F:10].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.CCCCCC.CCOC(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:16]=[O:18])=[CH:4][C:3]=1[S:9]([F:14])([F:10])([F:11])([F:12])[F:13]
Reactant: Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C=Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Temperature: 72 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-(pentafluoro-λ6-sulfanyl)aniline (2.36 g, 7.92 mmol, 1.0 eq) in toluene (70 mL) was added triphosgene (1.57 g, 5.3 mmol, 0.67 eq) under N2 at room temperature. Triethylamine (1.31 mL, 9.37 mmol, 1.2 eq) was added dropwise by syringe. The mixture was stirred at 72° C. (oil bath) for 2 hrs. TLC (hexane/EtOAc=2/1, UV) indicated that starting material was consumed. The mixture was allowed to cool to room temperature. Hexane (100 mL) was added. The precipitate was removed by filtration, washed with hexane (30 mL). The combined filtrate was concentrated by evaporator in vacuo at 70° C. for 40 min to afford crude 1-bromo-4-isocyanato-2-(pentafluoro-λ6-sulfanyl)benzene as a brown liquid which was used immediately for the next reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[C:17]([O:28][CH3:29])[CH:16]=3)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[C:17]([O:28][CH3:29])[CH:16]=3)=[CH:30][CH:31]=1
Reactant: COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc2oc(-c3ccc(O)cc3)cc(=O)c2c(OC)c1OC
Yield: 93.5 %

Procedure:
To a suspension of 1e 4′-benzyloxy-5,6,7-trimethoxyflavone, (120 mg, 0.29 mmol) and a catalytic amount of palladium on charcoal (10%) in ethanol (15 mL) was hydrogenated at atmospheric pressure for 4 h. The catalyst was filtered off and the solvent was stripped off to produce the title compound 1h (89 mg, 95%) as slight yellow crystals. Without purification, the purity of this compound is higher than 95%. 1H NMR (DMSO, 200 M Hz), δ 7.88 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.90 (d, J=8.6 Hz, 2H), 6.60 (s, 1H), 3.93 (s 3H), 3.93 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: FC1C([O:8][C:9](=O)[C@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=C(F)C(F)=C(F)C=1F.Cl.[C:43]1([CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:58])[C@@H:54]([CH2:56][OH:57])[NH2:55])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:55][C@@H:54]([C:53]([NH:52][CH2:51][CH2:50][CH2:49][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:58])[CH2:56][OH:57])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:28]=1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reactant: N[C@H](CO)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H](CO)C(=O)NCCCc1ccccc1)OCc1ccccc1
Yield: 57.3 %

Procedure:
A solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (2.34 g.), N-(3-phenylpropyl)-D-serinamide hydrochloride (1.00 g.) and diisopropylethylamine (0.71 ml.) in tetrahydrofuran (25 ml.) was stirred at room temperature for one hour. The mixture was triturated with water, and the product was precipitated with hot ethyl acetate and recrystallized from ethyl acetate, affording (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-(3-phenylpropyl)-D-serinamide (1.35 g., m.r. 175°-177° C.).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:29]C)=[C:10]([CH:28]=1)[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])(=[O:5])CCC.N1C(C)=CC(C)=[CH:33][C:32]=1[CH3:39].[I-].[Li+].Cl>>[F:22][C:20]([F:23])([F:21])[C:18]1[CH:19]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:6]([C:1](=[O:5])[CH:32]([CH3:39])[CH3:33])[CH:7]=[CH:8][C:9]=2[OH:29])[CH:15]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:17]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: CCCC(=O)c1ccc(OC)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Product: CC(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 65.3 %

Procedure:
A mixture of 5-butyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-benzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) and crystallized (ethyl acetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) as a white crystal.