Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C([O-])(=O)C.[Na+]>C1N(CCCS(O)(=O)=O)CCOC1>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)CCCN1CCOCC1
Agent: [Na+]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Glucose isomerase assays: TNXI and its mutants were assayed routinely with glucose as the substrate. The enzyme (1–1.5 mg/ml) was incubated in 100 mM MOPS (pH 7.0) [or 100 mM sodium acetate (pH 5.5)] containing 1 mM CoCl2 and 0.4 M glucose at 80° C. for 10 min. The reaction was stopped by transferring the tube to an ice bath. The amount of fructose produced was determined by the resorcinol-ferric ammonium sulfate-hydrochloric acid method (Schenk and Bisswanger, 1998). To determine the effect of temperature on activity, the enzymes were incubated in the reaction mixture at the temperatures of interest in a heated water (45–95° C.) or oil bath (95–110° C.) for 10 min. The effect of pH on activity was determined using the routine assay described above except that the MOPS buffer was substituted with 100 mM sodium acetate (pH 4.3–5.8), 100 mM PIPES (pH 6.1–7.0), or 100 mM EPPS (pH 7.2–8.1). All pHs were adjusted at room temperature, and the ΔpKa/Δt's for acetate, PIPES, and EPPS (0,–0.0085, and −0.011, respectively) (USB, Cleveland, Ohio) were taken into account for the results. To determine the kinetic parameters, assays were performed in 50 mM MOPS (pH 7.0) containing 10–1,500 mM glucose and 1 mM CoCl2. One unit of glucose isomerase activity is defined as the amount of enzyme that produces 1 μmol of fructose per minute under the assay conditions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.O.[CH:27](O)([CH3:29])[CH3:28]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([O:11][CH:27]([CH3:29])[CH3:28])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (0.5 g, 1.38 mmol) in isopropanol (100 mL) was added 4 drops of concentrated sulfuric acid. The reaction was heated to reflux for 48 hrs then cooled to room temperature and added to 10 mL of water before evaporating all solvent under vacuum. The residue was partitioned between ethyl acetate and 1M HCl and the organic layer dried over Na2SO4. Removal of solvent under vacuum provided 357 mg (64%) of the title compound as a white solid. MS calcd for (C18H2O3N2O6S): 404.1. MS found (ESI negative): (M−H)−=403.1. 1H NMR (DMSO-d6) δ (ppm): 9.84 (s, 1H), 9.15 (s, 1H), 7.40-7.47 (m, 2H), 7.19 (d, J=8.4, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.37 (bs, 2H), 5.91 (bs, 2H), 4.85 (m, 3H), 3.83 (s, 1H), 1.16 (d, J=6.4, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:8]([C:9]#[N:10])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccccc1F
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1F

Procedure:
Prepare by the method of example 1.1.2 using 2-fluorophenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: OC1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (ISP): 466.1 and 468.3 (M+H)+, 366.0 and 368.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].CN1CCCC1>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(OC3CCCCC3)cc2c1O
Reactant: N#C[Cu]
Agent: CN1CCCC1
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(OC3CCCCC3)cc2c1O
Temperature: 130 °C
Yield: 76.5 %

Procedure:
A mixture of 1-bromo-6-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (see U.S. Patent Application Publication No. 2004/0254215; 350 mg, 0.83 mmol), CuCN (149 mg, 1.66 mmol) and N-methyl-pyrrolidine (2.5 mL) was heated at 130° C. for 2 h. After cooled, reaction mixture was poured into water (50 mL) with stirring. Precipitate was collected and rinsed with water. Resulting solid was partitioned between ethyl acetate and 10% aqueous NH4OH (50 mL), and vigorously stirred for 15 min. The mixture was acidified by aqueous concentrated HCl and then 1 N HCl solution to pH=4. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title product (234 mg). MS-(+)-ion: M+1=369.43.
Reaction SMILES: CSC.B.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1.O.[ClH:17]>O1CCCC1.CCOCC.C(O)C>[ClH:17].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC#N)c1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1cccc(CCN)c1
Temperature: 0 °C

Procedure:
Borane dimethyl sulphide (45 ml) was added dropwise to a stirred solution of 3-methoxyphenylacetonitrile (32.4 g) in dry tetrahydrofuran (150 ml) under nitrogen. The solution was heated under reflux for 2 hours and was then cooled to 0° C. The solution was stirred under nitrogen at 0° C. as water (74 ml) was added, followed by concentrated hydrochloric acid (149 ml) dropwise over 1 hour. The cloudy solution was heated on a steam bath for 4 hours and then allowed to cool to room temperature. The suspension was diluted with 5N hydrochloric acid (30 ml) and the acidic mixture was washed with ether then basified with 5N sodium hydroxide and extracted with ether. The extracts were washed with water, dried and evaporated to yield a residue which was dissolved in dry ether (50 ml). A saturated solution of hydrogen chloride in ethanol (30 ml) was added followed by more dry ether (150 ml) and the mixture was cooled to 0° C. to yield 2-(3-methoxyphenyl)ethylamine hydrochloride (m.p. 121°-123° C.). The hydrochloride (27.3 g) was dissolved in 5N sodium hydroxide (100 ml) and extracted with ether. The extracts were washed with water (50 ml) and dried. The solvent was removed by evaporation to give the free base.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:19])=O.ClCCl>O1CCCC1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ncccn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-pyrimidin-2-ylbenzoic acid of Step A (0.283 g, 1.41 mmol) in dry tetrahydrofuran (20 mL) at room temperature under nitrogen was added N,N-dimethylformamide (1 drop, cat) followed by a 2.0 M solution of oxalyl chloride in dichloromethane (1.41 mmol, 2.82 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to afford 4-pyrimidin-2-yl-benzoyl chloride as a yellow syrup. The crude acid chloride was dissolved in dry tetrahydrof-uran (5 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5Hpyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.49 mL, 2.83 mmol) in dry tetrahydrofuran (5 mL), and the reaction mixture stirred at room temperature under nitrogen for 20 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (10 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (2×50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave an cream foam that was crystallized from diethyl ether/hexane to afford the title compound (0.395 g, 84%) as white solid, m.p. 234-236° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][Cl:23])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:25]1C2C(=CC=CC=2)N=C(CCl)N=1.ClC1C=C(N)C=CC=1OC.Cl.ClCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1>Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][Cl:23])[N:13]=2)[CH3:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)cc1Cl
Reactant: ClCc1nc(Cl)c2ccccc2n1
Agent: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: COc1ccc(N)cc1Cl
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl

Procedure:
(3-Chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-amine hydrochloride: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (500 mg, 2.3 mmol), 3-chloro-4-methoxy-phenylamine (444 mg, 2.8 mmol) and HCl (12 M, 7 drops) in i-PrOH (8 mL) by a procedure similar to the preparation of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride in Example 203c. 1H NMR (CDCl3) δ 8.6 (d, 1H), 8.1 (t, 1H), 7.85 (m, 3H), 7.62 (d, 1H), 7.20 (d, 1H), 4.8 (s, 2H), 3.92 (s, 3H); LC-MS (ESI+; 334 ([M+H]+)).
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH2:11][C:6]3([NH:13]C(=O)OC(C)(C)C)[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[O:3]1)[CH2:9]2.[ClH:21]>O1CCOCC1>[ClH:21].[NH2:13][C:6]12[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:12][CH:4]([O:3][C:2]3=[O:1])[CH2:5]1)[CH2:7]2.[ClH:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)OC(=O)C(C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 25 °C

Procedure:
To a solution of lactone 13A (0.17 mmol) in 1,4-dioxane (2 mL) was added a solution of 4 N HCl in dioxane (1.0 mL) and the mixture was maintained at rt for 16 h. The reaction mixture was concentrated and the residue was dissolved in water (2 mL). The aqueous layer was washed with EtOAc (3×5 mL) and concentrated to provide amine 13 in 95% yield as a hydrochloric acid salt.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4](=[O:23])[CH2:3]1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC.CCOC(C)=O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4](=[O:23])[CH2:3]1
Reactant: OCc1ccccc1
Reactant: O=C(O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)OCc1ccccc1
Yield: 92 %

Procedure:
(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetic acid (8.0 g, 25.78 mM) and benzyl alcohol (3.35 g, 31 mM) were dissolved in 200 ml of toluene and 0.5 g of p-toluenesulfonic acid were added and resulting mixture was refluxed until TLC (Hexane/AcOEt 8/12) showed completion of reaction. Organic layer was washed 3 times with sodium bicarbonate solution, dried and toluene evaporated providing 9.5 g of product.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].C([O-])(O)=O.[Na+].[C:18](=[O:25])([O:22][CH2:23]I)[S:19][CH2:20][CH3:21]>O.C(Cl)Cl>[C:18](=[O:25])([S:19][CH2:20][CH3:21])[O:22][CH2:23][O:5][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCSC(=O)OCI
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CCC(=O)OC(C)(C)C
Reaction time: 0.42 h
Yield: 82 %

Procedure:
To a mixture of acid 1 (1.0 g, 5.74 mmol) in H2O (14.5 mL), and CH2Cl2 (14.5 mL) was added NaHCO3 (1.00 g, 11.9 mmol) and TBAHSO4 (1.95 g, 5.74 mmol). After stirring for 25 min, S-ethyl O-iodomethyl carbonothioate (1.10 g, 4.42 mmol, prepared according to Synthesis 1990, 1159) in CH2Cl2 (5 mL) was added. The biphasic reaction was stirred vigorously for 2 h 35 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with water, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over Na2SO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using 20% EtOAc in hexanes as eluent to furnish compound 2 (1.06 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 9H), 2.54-2.58 (m, 2H), 2.63-2.66 (m, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.62 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]2[CH2:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]=[CH:7][C:6]2[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1cc2c(cn1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc2c(cn1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 6-Trifluoromethyl-2-trityl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and trifluoroacetic acid. Off white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>C(OCC)(=O)C>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:10][CH:11]=1
Reactant: CO
Reactant: NCc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (1 g, 7 mmol) in MeOH (10 mL) was added dropwise concentrated H2SO4 (1 mL). Upon completion of addition, the reaction mixture was heated to 60° C. where it stirred for 12 h. After this time, the reaction mixture was concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate and then carefully neutralized with a 10% NaOH solution. The organic layer was separated and washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-(aminomethyl)benzoate (2.5 g) as a white solid. LCMS Method O: retention time 0.49 min, [M+1]=166.2.
Reaction SMILES: [CH3:1][C:2]1([NH:13][C:14]2[C:15]([C:30]([F:33])([F:32])[F:31])=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:25][C@@H:24]1[C:23](=[O:26])[NH:22][N:21]=[C:20]2[CH2:27][O:28][C:17]3[CH:16]=[C:15]([C:30]([F:32])([F:31])[F:33])[C:14]([NH:13][C:2]4([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:29][C:18]=3[N:19]12
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (R)-tert-butyl 3-methyl-3-((1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (Enantiomer 1, SFC (Table 1, Method 16) Rt: 6.686 min, 0.270 g, 0.55 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (R)-1-methyl-9-((3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #100-1, Enantiomer 1, SFC (Table 1, Method 18) Rt: 9.62 min, 0.275 g, 99%) as a pale solid. LC/MS (Table 1, Method 5) Rt=2.005 min; MS m/z: 370 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:38])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
5-fluoro-3-(5-fluoro-4-methylsulfanyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 24a, (2.30 g, 5.32 mmol) was dissolved in dichloromethane (107 mL) and treated portionwise with 3-chloroperbenzoic acid (1.19 g, 5.30 mmol), keeping the temperature below 20° C. After stirring for 2 hours, another portion of 3-chloroperbenzoic acid (0.18 g, 0.80 mmol) was added, and stirring was continued for another hour. A third portion of 3-chloroperbenzoic acid (0.07 g, 0.05 mmol) was added and stirring was continued for 30 minutes. The reaction mixture was treated with an aqueous 15% K2CO3 solution (30 mL) and the layers were separated. The organic layer was washed with 15% K2CO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 2.3 g (96%) of the desired product as a yellow solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.67 (dd, J=9.1, 2.8 Hz, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH:12]1([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:18]#[N:19])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:15]2[CH:16]=[C:17]([CH2:18][NH2:19])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:14][CH2:13]1
Reactant: COc1ccc(C#N)cc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride in diethyl ether (17.3 ml, 1.0 M, 17.3 mmol, 3.0 eq) was carefully added over twenty minutes to a solution of 3-cyclopropyl-4-methoxybenzonitrile (8-2, 1.0 g, 5.77 mmol, 1.0 eq) in tetrahydrofuran (28.9 ml) at 0° C. under nitrogen atmosphere. The resulting dark orange mixture was allowed to stir at 0° C. for 30 min, then carefully quenched in the following order: water (1.0 ml), 15% NaOH aqueous (1.0 ml) and water (3.0 ml). The resulting emulsion was stirred at room temperature for 30 min. Several spatula amounts of magnesium sulfate was added to the mixture to remove any water. The entire mixture was filtered through a pad of sodium sulfate, washing with ethyl acetate. The collected filtrate was concentrated to give the product (8-3) as a yellow oil. ESI+MS [M-16]+ C11H15NO: 161.1 found, 161.2 required.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C[O:22][C:23](=[O:30])[C:24]([NH2:29])([CH2:27][CH3:28])[CH2:25][CH3:26]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:29][C:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]([OH:30])=[O:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)OC
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O

Procedure:
The title compound can e.g. be synthesized by: i) coupling of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) with 2-amino-2-ethyl-butyric acid methyl ester (CAN 70974-26-4) in analogy to Example 1; and ii) saponification of the ester group in analogy to the conditions described in Example 48 e), MS (EI): m/e=396.1 [M−H]−.
Reaction SMILES: [C@@H]12C[C@@H](CC1)C[C@@H]2OC1C(C2CC2)=CC(C(OC(C)(C)C)=O)=C(F)C=1.[C:26]12([CH2:36][O:37][C:38]3[C:50]([CH:51]4[CH2:53][C:52]4([F:55])[F:54])=[CH:49][C:41]([C:42]([O:44]C(C)(C)C)=[O:43])=[C:40]([F:56])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>>[C:26]12([CH2:36][O:37][C:38]3[C:50]([CH:51]4[CH2:53][C:52]4([F:54])[F:55])=[CH:49][C:41]([C:42]([OH:44])=[O:43])=[C:40]([F:56])[CH:39]=3)[CH2:35][CH:30]3[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]3)[CH2:33]1)[CH2:27]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Product: O=C(O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 54 %

Procedure:
Following the procedure as described in Example 283 step 3 and making variations as required to replace tert-butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoate. Purification by trituration with methanol gave the title compound as a colorless solid (0.45 g, 54%): 1H NMR (300 MHz, DMSO-d6) δ 12.91 (br s, 1H), 7.58 (d, J=8.6 Hz, 1H), 6.94 (d, J=12.7 Hz, 1H), 3.68-3.56 (m, 2H), 2.84-2.70 (m, 1H), 1.99-1.90 (m, 4H), 1.89-1.78 (m, 1H), 1.71-1.56 (m, 12H); MS (ES+) m/z 381.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[C:9]=1[C:22]([NH2:24])=[O:23])=[O:6])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[C:22]([NH2:24])=[O:23])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1cccc(OCc2ccccc2)c1C(N)=O
Agent: [Pd]
Product: CCOC(=O)C(=O)Nc1cccc(O)c1C(N)=O

Procedure:
A mixture of 3.4 g. of [2-(aminocarbonyl)-3-benzyloxyphenylamino]oxoacetic acid ethyl ester and 0.3 g. of 5% Pd on charcoal is hydrogenated until hydrogen uptake ceases. The mixture is filtered through celite; the filtrate is evaporated and the residue is recrystallized to give pure product, m.p. 200°-202° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2cn[nH]c12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cc2cccc(F)c2n1

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 35% yield, 175 mg.