Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34](=O)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.00 g, 9.1 mmol) in anhydrous DCE (60 mL) were added hexanal (Aldrich, 1.80 mL, 14.6 mmol) and sodium triacetoxyborohydride (6.17 g, 29.1 mmol). The resulting mixture was stirred at 70° C. overnight. Then the reaction mixture was poured into water (60 mL) and extracted with DCM (2×60 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil. Purification by flash chromatography on silicagel (c-Hex/EtOAc (9/1)) gave 4.41 g (92%) of the title compound as a yellow oil. HPLC, Rt: 6.2 min (purity: 100%). LC/MS, M+(ESI): 524.1. 1H NMR (CDCl3) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.25 (d, J=3.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.86 (dd, J=9.0, 3.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 4.51 (s, 2H), 3.37 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.71 (s, 6H), 1.61 (m, 4H), 1.40-1.25 (m, 8H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=NO)[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCC(=NO)c2ccc(N3CCCC3)c(C(C)(C)C)c2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: COC(=O)c1ccc(OCC(=O)c2ccc(N3CCCC3)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to that of Example 1.h, by reaction of 210 mg (0.5 mmol) of methyl 4-[2-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-2-hydroxyiminoethoxy]benzoate with 100 mg (2.5 mmol) of sodium hydroxide. A white solid is obtained after recrystallization (m.p.=235° C., m=44 mg, yield=22%); (1H NMR (DMSO): 1.35 (s, 9H); 1.86 (s, 4H); 2.89 (s, 4H); 5.29 (s, 2H); 7.04-7.06 (d, J=7.65 Hz, 2H); 7.40-7.42 (d, J=7.4 Hz, 1H); 7.49-7.51 (d, J=7.4 Hz, 1H); 7.65 (s, 1H); 7.86-7.88 (d, J=7.4 Hz, 2H); 11.9 (s, 1H); 12.6 (s, 1H)).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 75.1 %

Procedure:
16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are added to a mixture of 160 ml of methanol and 30 ml of an aqueous 2N sodium hydroxide solution, and the mixture is refluxed for 30 minutes under heating. After cooling, crystalline precipitates are collected by filtration and washed with methanol. The crystals are suspended in 30 ml of water. Then, the suspension is adjusted to pH 3 with 2N hydrochloric acid. Crystalline precipitates are collected by filtration and dried. 11.4 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:30])=[C:14]([O:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[C:26]([F:29])([F:28])[F:27])[CH3:18])[CH:15]=2)=[CH:6][CH:5]=1.O.[Li+].[OH-]>CC(O)C.CCOC(C)=O>[NH2:30][C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)=[CH:15][C:14]=1[O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]([F:29])([F:28])[F:27])[CH3:18]
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OC(C)c3cccc(F)c3C(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Oc1cc(-c2ccc(C(=O)O)cc2)cnc1N)c1cccc(F)c1C(F)(F)F
Yield: 87.5 %

Procedure:
To a stirred solution of 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid methyl ester (1.4 g, 3.2 mmol) in warm IPA (72 mL) was added H2O (38 mL) containing LiOH (0.68 g, 16.2 mmol). The reaction was heated to reflux for 3.5 hr. The reaction was neutralized and diluted with EtOAc (200 mL) and extracted upon cooling. The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated under vacuum to yield 4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid (1.2 g, 2.8 mmol, 88%). 1H NMR (MeOD, 300 MHz) δ 1.75 (d, 3H, J, 6.2 Hz), 4.88-4.93 (m, 1H), 7.01 (d, 1H, J, 1.8 Hz), 7.39 (d, 2H, J, 8.3 Hz), 7.52-7.67 (m, 3H), 7.80 (d, 1H, J, 1.8 Hz), 7.97 (d, 2H, J, 8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[N:17]=[CH:16]2)[C@@H:9]([NH2:11])[CH3:10].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[N:17]=[CH:16]2)[C@@H:9]([NH:11][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:10]
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Product: C[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl) 1H-indazol-5-yloxy)propan-2-amine (300a, 18 mg, 0.05 mmol) and Pivaloyl chloride (17 μl, 0.14 mmol). Yield 22 mg (100%).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [OH-]
Product: Nc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 150 °C
Yield: 98 %

Procedure:
A mixture of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (example 188, 40 mg, 0.08 mmol) and ammonium hydroxide (2M solution in water, 8 mL) was heated in an autoclave at 150° C. for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% methanol in chloroform) to yield the desired product as a white solid (36 mg, 98%). MS (ESI): 471.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[B:11]1(B2OC(C)(C)C(C)(C)O2)[O:15]C(C)(C)C(C)(C)[O:12]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:10][C:4]1[CH:3]=[C:2]([B:11]([OH:15])[OH:12])[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1ncc(Br)cc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ncc(B(O)O)cc1N

Procedure:
5-bromo-2-methoxypyridin-3-amine (2 g, 9.85 mmol, commercially available), Bis(pinacolato)diboron (11.82 mmol), potassium acetate (1.4 g) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (200 mg, commercially available) was dissolved in dioxane (75 mL) under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (75 mL) and filtered. The filtrate was concentrated. The crude product was purified over silica gel using 0-10% ethyl acetate in petroleum ether to obtain the titled boronic acid derivative.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].Cl>O>[CH2:20]([NH:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[C:6]([OH:8])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCC(C(=O)O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CCNCc1ccccc1)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
To a solution of 26 g of the amino acid hydrochloride prepared in Example 5 (0.1 mole), in 80 ml of water, was added 8.4 g of sodium hydroxide (0.21 moles), in 42 ml of water, followed by 11.7 g (0.11 moles) of benzaldehyde. The initially turbid mixture immediately cleared. After one hour, the mixture was evaporated to a thick syrup on the rotary evaporator, the syrup dissolved in 75 ml of ethanol, and the evaporation to syrup repeated. The residue was dissolved in 500 ml of methanol and 6.5 g of sodium borohydride (0.17 moles) added in several portions. After stirring for 1.5 hours, the solvent was removed on the rotary evaporator, leaving a grayish solid. This residue was dissolved in 200 ml of water and 10 percent hydrochloric acid added to pH 7. The precipitate which formed was collected by filtration, washed with water, and dried to yield the above-named product, m.p. 217°-218° dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.BrC1C=CC(C(CC(C)([S@@](N)=O)C)C2CCCCC2)=CC=1.[CH3:43][PH:44]([O-])([O-:48])[O:45][CH2:46][CH3:47].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:16]1([C@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]2[CH:6]=[CH:7][C:2]([P:44]([CH3:43])(=[O:48])[O:45][CH2:46][CH3:47])=[CH:3][CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@](=O)N[C@H](c1ccc(Br)cc1)C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(CC(c1ccc(Br)cc1)C1CCCCC1)[S@@](N)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)C2CCCCC2)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(cyclohexyl)methyl)-2-methylpropane-2-sulfinamide, 27-b. (4.887 g, 13.13 mmol), ethyl methylphosphite (2.84 g, 26.26 mmol) and Et3N (3.98 g, 39.4 mmol) in THF (100 ml) was added PdCl2(dppf) (1.5 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (diluting with ethyl acetate) to provide the product, 27-c, (5.0 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Yield: 64.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (99 mg, 0.22 mmol) and N-bromosuccinimide (43 mg, 0.24 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.23, 533.18 (M-1, 79/81Br).
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)C(=O)O
Yield: 66 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 66% yield as a pale yellow solid. MS: (M−H)− 433.2.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[N:15]1([CH2:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[NH2:21])[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:21][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:30])([F:31])[F:32])[CH:23]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: N[C@H](CN1CCC1)c1ccc(F)c(C(F)(F)F)c1
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(F)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 12 was prepared following general synthesis scheme 7 wherein 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide was reacted with (S)-2-(azetidin-1-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid. LC-MS [435 (M+1)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous cesium carbonate (3.26 g, 10 mmol), 5 ml of dimethylsulfoxide that is dried over 4A molecular sieve, and 15 ml 1,2-dichloroethane are combined and stirred at about room temperature. After 15 hours the mixture is heated to reflux and more cesium carbonate (about 1 more equivalent). HPLC shows the ratio of product to bis alkylated biproduct to starting material is 93.1:6.2: non-detectable. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The aqueous layer is extracted with 15 ml of methylene chloride and then the combined organics are filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling to give 2.00 g of product. (94.8%). HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:18][CH3:19])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[OH-].[Li+].Cl>CO.O>[NH2:11][C:5]1[C:4]([S:18][CH3:19])=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CSc1cc(C)cc(C(=O)O)c1NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1cc(C)cc(C(=O)O)c1N
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
22.0 g (75.0 mmol) of 5-methyl-3-(methylthio)-2-(trifluoroacetylamino)benzoic acid and 9.44 g (225 mmol) of lithium hydroxide monohydrate were heated under reflux in a mixture of 200 ml of methanol and 30 ml of water for 4 h. For work-up, the contents were cooled and freed of the solvents. The residue was taken up in water and the mixture was acidified to pH<3 with dilute hydrochloric acid. The mixture was stirred at a temperature of 0° C.-5° C. for 30 minutes and then filtered. 15.0 g of 2-amino-5-methyl-3-(methylthio)benzoic acid of a purity of >95% by weight were obtained as residue.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(NCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1NCC(F)(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.76 g, pale yellow amorphous) from 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (1.27 g, 5.47 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.33 g, 10.9 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:19])([CH3:15])[CH3:16]
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.1 %

Procedure:
3.76 g (19.6 mmol) of EDCl was added to 40 ml of THF solution of 1.99 g (9.79 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 2.03 g (9.79 mmol) of H-Leu-NHPh obtained in Synthesis Example 2-2, followed by stirring for 17 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 2.42 g of the product with a yield of 63.1%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.CS(C)=[O:26].OO>[OH-].[Na+].CO>[Cl:1][C:2]1[C:3]([C:22]([NH2:23])=[O:26])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][OH:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(C#N)c(Cl)cc2n1-c1ccc(CCO)cc1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (step 4, 2.4 g, 7.4 mmol), DMSO (0.7 mL, 8.8 mmol) and methanol (100 mL) was added 30% aqueous hydrogen peroxide (1.3 mL, 11 mmol) and 0.2 M aqueous NaOH (0.7 mL, 0.14 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was removed and the resulting precipitates were collected by filtration. The precipitates were washed with water and dried under reduced pressure to give 1.9 g (76%) of the title compound as pale pink solids: 1H-NMR (DMSO-d6) δ 7.69 (1H, br.s), 7.61 (1H, s), 7.33-7.40 (4H, m), 6.95 (1H, s), 4.64 (1H, br.s), 3.59 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=6.4 Hz), 2.62 (2H, q, J=7.4 Hz), 1.11 (3H, t, J=7.4 Hz).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH:5]1[C:14]2[C:9](=[C:10]([F:26])[CH:11]=[C:12]([C:16]([C:18]3[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=3[OH:23])=[O:17])[C:13]=2[Cl:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1.N1C=CC=N1.C(=O)([O-])[O-].[K+].[K+].[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>ClCCl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][CH:5]1[C:14]2[C:9](=[C:10]([F:26])[CH:11]=[C:12]([C:16]([C:18]3[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=3[O:23][S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])=[O:17])[C:13]=2[Cl:15])[S:8](=[O:27])(=[O:28])[CH2:7][CH2:6]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CCn1ncc(C(=O)c2cc(F)c3c(c2Cl)C(OCCF)CCS3(=O)=O)c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(F)c3c(c2Cl)C(OCCF)CCS3(=O)=O)cnn1CC
Yield: 60 %

Procedure:
0.69 Gram (1.6 mmol) of the 4-(2-fluoroethoxy)-5-chloro-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-8-fluorothiochroman-1,1-dioxide (corresponding to pyrazole derivative of the formula (Ia)) obtained in Preparation Example 9 was dissolved in 5 ml of dichloromethane, and a solution of 0.26 g (1.9 mmol) of potassium carbonate as a base in 2 ml of water was added. To this mixture was added 0.21 ml (1.9 mmol) of n-propanesulfonyl chloride (corresponding to compound of the formula (IV)) as a reaction reagent, and 0.05 g (0.2 mmol) of benzyltriethylammonium chloride as a phase transfer catalyst was added. The mixture was allowed to react at room temperature for 1 day. After the completion of the reaction, water and dichloromethane were added to separate the reaction mixture to two phases. The resultant organic layer was consecutively washed with distilled water, with a saturated sodium hydrogencarbonate and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel; hexane:ethyl acetate=1:1) to give 0.52 g (yield 60%) of the subject end product.