Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2C[CH:14]2[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:9][CH:8]=1>ClCCl.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1CC1c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C=CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.2 %

Procedure:
Boron tribromide (246 mL, 1 M) in dichloromethane was added slowly to a solution of ethyl 1-(p-methoxyphenyl)cyclopropane-2-acetate (60 g, 246 mmol) in dichloromethane (1L) at 0° C. and the reaction mixture was stirred at room temperature for 18 h. It was cooled to 0° C. and was quenched with excess ethanol. The reaction mixture was concentrated and the residue in ethyl acetate (1 L) was washed with saturated sodium bicarbonate (500 mL), washed with brine (500 mL), dried and was concentrated. The residue was purified by passing through a thick pad of silica and eluting with 20% ethyl acetate in hexane to afford 50.2 g (89%) of the desired product. 1H NMR (CD3OD) δ 6.93 (d, 2H, J=8.6 Hz), 6.71 (d, 2H, J=8.6 Hz), 4.15(q, 2H, J=7.1 Hz), 2.37 (d, 2H, J=7.2 Hz), 1.66-1.71 (m,1H), 1.23-1.28 (m, 4H), 0.87-0.91 (m, 1H), 0.75-0.79 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][N:10]=1
Reactant: Cc1cccc(-c2n[nH]c(=O)c3ccccc23)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2nnc(Cl)c3ccccc23)n1
Temperature: 0 °C

Procedure:
A dry RBF set up with stirring bar and reflux condenser was charged with 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (780 mg, 3.29 mmol) and POCl3 (10.7 ml, 115 mmol). This was stirred under reflux for 18 h. Excess POCl3 was removed under vacuum with an aid of toluene. The residue was cooled to 0° C. and basified with cold 6 N NaOH until pH=9. Occasionally, ice was added to keep the mixture cold to prevent the hydrolysis. Stirring, agitation, and sonication eventually provided a solid material at basic pH. The solids were filtered, washed with ample amount of water and dried under vacuum to afford a white solid. MS Calcd for C14H10ClN3: [M]+=255. Found: [M+H]+=256.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[S:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([C@@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:38][CH2:39]1)=[S:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (579 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. The solution was stirred for 5 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g) using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent to give 201 mg of (2R)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([CH:9]=[C:10]([O:12]C)[CH:11]=1)[C:5]([O:7]C)=[O:6]>Br>[Cl:1][C:2]1[C:3]([OH:14])=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(OC)cc(Cl)c1O
Agent: Br
Product: O=C(O)c1cc(O)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
9.95 g of methyl 3-chloro-2-hydroxy-5-methoxybenzoate were taken up in 300 ml of hydrobromic acid (48% strength in water). 1.79 g of red phosphorus were added, and the mixture was then stirred at 85° C. for 15 hours. After cooling, the reaction mixture was poured into about 1 liter of ice-cold water and extracted with ethyl acetate. The crude product obtained after drying and concentration of the ethyl acetate phase was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1CCCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1CCCO

Procedure:
A solution of [2-(3-hydroxypropyl)phenyl]acetic acid (48.6 g., 0.25 mole) and sulfuric acid (3 ml.) in ethanol (400 ml.) is heated at reflux for 6 hours. Workup as described in Example 25, Step A(3) yields the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.O>CN(C)C=O>[Br:1][C:24]1[N:25]=[C:21]([C:11]2[C:12]([Cl:20])=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[Cl:9])[NH:22][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Reaction time: 7 h
Yield: 13.1 %

Procedure:
A solution of N-bromosuccinimide (0.63 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (1.0 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml) and stirred for 7 hours. The mixture was poured into water (180 ml) and extracted with dichloromethane (5×30 ml). The combined extracts were washed with water (3×50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (3:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (0.17 g), m.p. 224°-225° C., as an off-white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(O)(=O)=O.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cool a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole (387.00 g, 1.08 mol) in DCM (2.50 L) and THF (1.00 L) to 10° C. in a 10 L jacketed reactor vessel. To the resulting mixture add methanesulfonic acid (14.0 mL, 216.02 mmol), followed by 3,4-dihydro-2H-pyran (296 mL, 3.24 mol) over 0.5 hours, observing a slight exotherm. Stir the mixture at RT for 3 hours. Cool the reaction to 10° C. and quench with saturated aqueous sodium bicarbonate (2 L). Dilute the mixture with water (2 L) and extract the aqueous layer with DCM (2 L). Wash the combined organic extracts with water (2 L) and brine. Dry the organic mixture over anhydrous sodium sulfate, filter and concentrate in vacuo. Elute the residue through a silica gel pad with eluent (0 to 10% EA/hexanes) to give the title compound. Yield: 150 g (31%). MS (ES) m/z 459 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:19][N:18]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:26]([O:28]CC)=[O:27])=[N:3]1.CO.[OH-].[Li+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:19][N:18]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:26]([OH:28])=[O:27])=[N:3]1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)C3CN(c4cccnn4)C3)cc2)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)cc1-c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1
Temperature: 60 °C

Procedure:
Ethyl 1-methyl-5-(4-(1-(pyridazin-3-yl)azetidine-3-carboxamido)phenyl)-1H-pyrazole-3-carboxylate (368 mg, 0.905 mmol) was taken up in tetrahydrofuran (3.38 mL), and methanol (3.38 mL) then 1N aqueous lithium hydroxide (1.35 mL, 1.350 mmol) was added. The mixture was heated at 60° C. for 2 hours. The mixture was concentrated to dryness, suspended in water and treated with 1N aqueous HCl to pH 2. The solution was extracted with ethyl acetate and the organic layers were dried with sodium sulfate, filtered, and concentrated to give a colorless syrup that solidified upon standing. This solid was triturated with ether and collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.67 (s, 1H), 10.32 (bs, 1H), 8.60-8.55 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.42 (dd, J=9.0, 4.5 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 6.80 (s, 1H), 4.34-4.13 (m, 4 H), 3.91 (s, 3 H), 3.83-3.74 (m, 1H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[N:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: Cc1noc(C)c1CCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has-been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z 3.96 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 19.9 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (100 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (220 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 4, the title compound (49 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[C:10](=[O:22])[C:11]2[C:16]([C:17](=[O:20])[C:18]=1Br)=[CH:15][C:14]([F:21])=[CH:13][CH:12]=2>C(O)C>[O:20]=[C:17]1[C:18]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:9]=2[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([F:21])=[CH:15][C:16]1=2
Reactant: O=C1C(Br)=C(Br)C(=O)c2cc(F)ccc21
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=C1c2cc(F)ccc2C(=O)c2c1nc1ccccn21
Yield: 24.7 %

Procedure:
1.4 g (15 mmol, 2 eq) of 2-aminopyridine are added to a suspension of 2.5 g (7.5 mmol, 1.0 eq) of 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene in 50 mL of ethanol. The reaction mixture is brought to reflux of the solvent for 20 h, then brought to ambient temperature. The tan precipitate formed is filtered and washed profusely with ethanol. The solid obtained is purified by flash chromatography on a column of silica gel (support: silica 6-35 mm; (10 cm φ, 25 cm h; eluant: dichloromethane/ethyl acetate, 70/30). 494 mg of 6,11-dihydro-6,11-dioxo-8-fluoronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or 6,11-dihydro-6,11-dioxo-9-fluoronaphtho[2',3':4,5]imidazo-[1,2-a] pyridine or 5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5] imidazo[1,2-a]pyridine are obtained in the form of yellow crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9](O)=[O:10].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9]([N:3]([O:4][CH3:5])[CH3:2])=[O:10]
Reactant: CNOC
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Yield: 73 %

Procedure:
N,O-dimethlyhydroxylamine hydrochloride (3.28 g, 33 mmol) and 2-amino-3,6-dichlorobenzoic acid (4.76 g, 22 mmol) were dissolved in DMF (110 ml). At r.t. under nitrogen and stirring, first N-methyl morpholine (10 g, 99 mmol) and then HBTU (12.5 g, 33 mmol) were added, and the reaction was stirred at r.t. overnight. The reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was treated with heptane and little diethyl ether to yield 4 g of the product. The mother liquor was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to give another batch of the title compound as an off-white solid (5.52 g, 100%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([S:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+].CCOCC>[CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH:11][C:25](=[O:26])[C:24]([CH3:28])([CH3:29])[CH2:23][S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CSCc1ccccc1)C(=O)Cl
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a stirred solution of S-benzyl-L-cysteine(11.5 g) in 2N sodium hydroxide solution(68 ml), 3-benzylthio-2,2-dimethylpropionyl chloride (14.6 g) dissolved in ether(10 ml) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 20 minutes under ice-cooling and 2 hours at room temperature. The reaction mixture was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 19.4 g(85.1%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:24])[C@H:4]([NH:20]CC#N)[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].O.C1(C)C=CC(S(O)(=O)=[O:33])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>>[CH3:1][O:2][C@H:3]([CH3:24])[C@H:4]([NH:20][OH:33])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7]
Reactant: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NCC#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NO
Temperature: 60 °C
Yield: 357.7 %

Procedure:
An ice-cold stirred solution of (2S,3R)-3-methoxy-2-(N-cyanomethylamino)-1-(3-quinolylmethanesulfonyl)butane (590 mg) in MDC (20 ml) was treated with 4-toluenesulphonic acid monohydrate (50 mg) and 70% 3-chloroperoxybenzoic acid (281 mg). After 45 min the reaction was quenched with 10% sodium thiosulphate (5 ml) followed by saturated sodium hydrogen carbonate (5 ml) solution. After 5 min the organic layer was collected and the aqueous re-extracted with MDC (10 ml). The combined MDC phases were dried (MgSO4) and evaporated. The residue was redissolved in methanol (10 ml) treated with 4-toluenesulphonic acid monohydrate and hydroxylamine hydrochloride (2.36 g) and heated at 60° C. for 1.5 h. The cooled solution was evaporated, then dissolved in water (5 ml) and saturated sodium hydrogen carbonate solution (5 ml). After extraction with MDC (2×5 ml), the combined extracts were dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, step gradient: 80–100% ethyl acetate in hexane) to give the subtitle compound (305 mg). MS (APCI+ve ion) 325(MH+); 1H NMR δ(CDCl3): 8.91 (1H, m), 8.32 (1H, d, J=2 Hz), 8.14 (1H, d, J=8 Hz), 7.85 (1H, d, J=8 Hz), 7.76 (1H, t, J=8 Hz), 7.6 (1H, t, J=8 Hz), 4.83 (1H, broad), 4.58 (2H, m), 3.0–3.7 (4H, m), 3.38 (3H, s), 0.92 (3H, d, J=6.3 Hz).
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:15][SH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[CH:1]1([C:6]2[S:16][CH2:15][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CS)NC(=O)C1CCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CSC(C2CCCC2)=N1

Procedure:
Tosic acid monohydrate (0.78 g) was added to a solution of ethyl 2-(cyclopentanecarboxamido)-3-mercaptopropanoate (example 59, step a) (5 g) in toluene (40 mL). The resulting mixture was heated at reflux under Dean and Stark conditions for 6 h. The reaction was allowed to cool, then the toluene solution was washed with saturated sodium bicarbonate solution (20 mL) and the solvent evaporated. The residue was azeotroped with toluene. The resulting white solid was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.2 g.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([CH3:23])([CH3:22])[O:19][C:20](=[O:21])[C:15]=2[CH:14]=1.O>C1(C)C=CC=CC=1>[CH3:23][C:18]1([CH3:22])[O:17][C:16]2[CH:24]=[CH:25][C:13]([NH:12][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:1][C:3]4[CH:11]=[CH:10][CH:6]=[CH:5][CH:4]=4)=[O:8])=[CH:5][CH:4]=3)=[CH:14][C:15]=2[C:20](=[O:21])[O:19]1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: O=Cc1ccc(C(=O)[O-])cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C(=O)OCc4ccccc4)cc3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
A solution of 4-formylbenzoate (481 mg) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (386 mg) in toluene (20 mL) was heated at reflux for 12 h with azeotropic removal of water. The toluene was evaporated off under reduce pressure, the residue was taken up in methanol (10 mL) and cooled to 0° C. NaBH4 (114 mg) was added portionwise and the reaction mixture was stirred at 0° C. for 1 h then at rt for 2 h. The reaction mixture was poured into water and resulting mixture extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduce pressure to give the crude product as an oil. The product was purified by flash chromatography (SiO2, EtOAc/c-Hex 20/80) to give the title compound as a colorless oil (713 mg, 85%). 1H NMR (CDCl3) δ 8.07 (d, J=8.1 Hz, 2H), 7.54-7.32 (m, 7H), 7.17 (d, J=2.6 Hz, 1H), 6.89-6.78 (m, 2H), 5.37 (s, 2H), 4.41 (s, 2H), 1.70 (s, 6H). M+(ESI): 418.3; M−(ESI): 416.1. HPLC, Rt: 4.6 min (purity: 95.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([NH:32][CH2:31][CH2:29][OH:30])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (97 mg, 0.248 mmol) and ethanolamine (18 μl, 0.298 mmol). MS (ESI) m/z: Calculated: 433.1; Observed: 434.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([CH3:12])[OH:11])=[C:4]([F:13])[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:11])[CH3:12])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(C)O)c(F)cc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(C)=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A stirred solution of 10.4 g of 4-chloro-2-fluoro-5-methoxybenzaldehYde in 150 mL of anhydrous THF was cooled in a dry ice-acetone bath and treated with 35 mL of a 3M solution of methyl magnesium chloride in THF over a period of one minute. The ice bath was removed and the mixture allowed to warm to room temperature. After warming, the solution was slowly poured into ice water. The water slurry was extracted three times with diethyl ether, the ether extracts dried and concd to afford a crude oil. Crystallization from hexanes yielded 10.8 g (95.6%) of 4-chloro-2-fluoro-5-methoxy-α-methylbenzenemethanol: mp 68.5°-69.5° C. This benzenemethanol intermediate was dissolved in 100 mL of acetone, cooled in an ice water bath and treated dropwise with 50 mL of freshly prepared Jones' reagent (prepared from 6.7 g of CrO3, 6 mL of H2SO4 and 50 mL of water), keeping the temperature below 10° C. After stirring for 2 hrs, the solution was diluted with water and extracted three times with methylene chloride. The organic extracts were dried and concd to give a crude product. Recrystallization from methanol yielded 9.66 g (90.3%) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)ethanone as a white solid: mp 96.5°-98.5° C.; 1HNMR (CDCl3) δ2.50 (d, 3H, 5.4 Hz), 3.80 (s, 3H), 7.10 (d, 1H, 10.1 Hz), 7.30 (d, 1H, 6.3 Hz).