Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.C1C[O:9]CC1.C(#N)C.[N+](C1C=CC(COC(C2N3[C@H](SC=2)C([CH:33]([O:43][C:44](=O)[CH3:45])[C:34]2[CH:42]=[C:41]4[N:36]([CH2:37][S:38][CH2:39][CH2:40]4)[N:35]=2)(Br)C3=O)=O)=CC=1)([O-])=O>[Zn].C(OCC)(=O)C>[CH2:44]([O:43][C:33]([C:34]1[CH:42]=[C:41]2[N:36]([CH2:37][S:38][CH2:39][CH2:40]2)[N:35]=1)=[O:9])[CH3:45]
Reactant: CC(=O)OC(c1cc2n(n1)CSCC2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: C1CCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CSCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
Freshly activated Zn dust (21.4 g) was added rapidly with 0.5 mol/L phosphate buffer (pH 6.5, 112 mL) to the THF (76 mL) and acetonitrile (36 mL) solution of crude (5R)-6-[acetoxy-(4,5-dihydro-6-thia-1,7a-diazainden-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution was cooled at 0° C., and then the pH was adjusted to 8.0. ethyl acetate (56 mL) was added to the mixture and filtered through a pad of Celite. The pad was washed with water (150 mL). The aqueous layer was separated and then the organic layer was extracted with 0.5 mol/L phosphate buffer (pH 6.5, 2×30 mL). The combined aqueous layers were cooled at 0° C., and then the pH was adjusted to 8.0. The mixture was concentrated to 236 g, and then applied to Diaion HP-21 resin (480 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water (960 mL) and then acetonitrile aqueous solution (5%; 960 mL, 10%; 960 mL, 20%; 960 mL). The combined active fractions were concentrated under high vacuum at 35° C. and lyophilized to give the titled compound as a yellow amorphous solid (1.28 g, 40.5%, pH 7.45).
Reaction SMILES: CO[C:3]([C:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:9][CH:10]=1)=[O:4].Cl.[CH3:18][NH:19][O:20][CH3:21].C([Mg]Cl)(C)C>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:3]([C:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:9][CH:10]=1)=[O:4]
Reactant: CNOC
Reactant: COC(=O)C1=CCN(c2ncccn2)CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1=CCN(c2ncccn2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a suspension of 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methyl ester (73.8 mg, 0.337 mmol) and N-methyl-O-methyl hydroxylamine hydrochloride (51.0 mg, 0.552 mmol) in THF (3 ml), was added isopropyl magnesium chloride (2.0 M in THF, 0.505 ml) at −20° C. over 15 minute-period. The mixture was stirred at −10° C. for another 30 minutes before it was quenched with the addition of saturated ammonium chloride (10 ml). The mixture was extracted with EtOAc (2×15 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (4% MeOH/CH2Cl2) to give 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methoxy-methyl amide (48 mg, 58%) as white crystals: 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=6.4 Hz, 2H), 6.53 (t, J=6.4 Hz, 1H), 6.43 (m, 1H), 4.35 (m, 2H), 3.99 (t, J=5.6 Hz, 2H), 3.66 (s, 3H), 3.27 (s, 3H), 2.55 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=[O:16])[CH3:15].[OH-].[K+].O>C(O)C>[C:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
A mixture containing 36.2 g (0.2 mole) of 4'-hydroxy-3'-nitroacetophenone, 15.7 g of acetyl chloride, 22 mL of 50% KOH solution, 200 mL of H2O and 300 mL of 95% ethanol is stirred and heated to reflux for 18 hours. The mixture is evaporated to remove ethanol, and the aqueous mixture is extracted with CHCl3 to solubilize the product. The CHCl3 extract is evaporated to dryness to afford 4'-acetoxy-3'-nitroacetophenone, which is brominated with an equimolar quantity of Br2 in CHCl3 (100 mL) to afford 2-bromo-4'-acetoxy-3-nitroacetophenone. This phenacyl bromide is then reacted in 100 mL of ethanol with 2 equivalents of isopropylamine to afford 4'-acetoxy-3'-nitro-2-isopropylaminoacetophenone, which isolated as the hydrochloride by the procedure reported by Larson et al. in Journal of Medicinal Chemistry, 10, 467 (1967) for a related compound. This ketoamine is then hydrogenated in 90% aqueous ethanol with 0.5 g of 10% Pd-C/3.5 kg/cm2H2 pressure in a Parr hydrogenator until the uptake of H2 is completed. The mixture is filtered, and the filtrate is evaporated to dryness to afford the crude title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)C(=O)NCC2c1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A diastereomeric mixture. of tert-butyl 1-oxo-4-phenyl-2,8-diazaspiro[4.6]undecane-8-carboxylate (step 4) (669.5 mg; 1.944 mmol) in THF (19.5 ml) under nitrogen was cooled in an ice/brine bath. 1M LHMDS (2.5 ml, 2.53 mmol) was added and the mixture was stirred at 0° C. for 40 minutes. Iodomethane (182 ul, 2.92 mmol) was added and the mixture was allowed to warm slowly to RT overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with EtOAc afforded the title compound;
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24]OS(C)(=O)=O)=[N:22][CH:23]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:31]1[CH:35]=[C:34]([CH2:36][NH2:37])[CH:33]=[N:32]1>CN(C=O)C>[F:30][C:14]1[CH:13]=[C:12]([N:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]2=[O:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[N:22][C:21]([CH2:24][NH:37][CH2:36][C:34]2[CH:33]=[N:32][O:31][CH:35]=2)=[CH:20][CH:19]=1
Reactant: NCc1cnoc1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)nc3)c(F)c2)C(=O)O1
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4cnoc4)nc3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
A solution of the methanesulfonic acid 5-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridin-2-ylmethyl ester 106 (220 mg, 0.5 mmol) in DMF (4.0 mL) was treated with C-isoxazol-4-yl-methylamine (68 mg, 0.5 mmol, 1.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 60° C. and stirred for 6 hours. When TLC and MS showed the reaction to be complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (0-5% MeOH/CH2Cl2 gradient elution) to afford the desired N-{3-[3-Fluoro-4-(6-{[(isoxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4252 (22 mg, 10%) as off-white solids. LCMS (EI): 440 (M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:28]#[N:29])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=3)[N:14]2[CH2:17][CH3:18])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:28]#[N:29])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=3)[N:14]2[CH2:17][CH3:18])=[CH:10][CH:9]=1
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(NC(=O)OC(C)(C)C)cc3n2CC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Yield: 96 %

Procedure:
Compound 832 prepared in step A above (0.63 g, 1.56 mmol) is treated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 h, and the volatiles are removed in vacuum. The residue is treated with saturated NaHCO3 and the precipitate is collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g, 96%), compound 833.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:30])([OH:29])[CH2:17]OS(C1C(C)=CC=CC=1)(=O)=O.[OH-].[Na+].C(Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]1([CH3:30])[O:29][CH2:17]1
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)COS(=O)(=O)c2ccccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
177 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluenesulphonyloxy-2-butanol are dissolved in 1 ml of ethanol and the solution is treated with 0.3 ml of alcoholic sodium hydroxide solution (1.5N). The mixture is left to stand at room temperature for 10 minutes, 30 ml of methylene chloride are then added and the mixture was dried over sodium sulphate and concentrated. There are obtained 105 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane. M.p. 47°-48° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].CC([O-])=O.[Na+]>O.CCO>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:12][OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)nc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(F)nc1
Temperature: 50 °C

Procedure:
To a 200-ml, round bottom flask was added, 1-(6-fluoropyridin-3-yl)ethanone (Method 65, 2.5 g, 17.9 mmol), hydroxylamine hydrochloride (2.5 g, 35.8 mmol), and NaOAc (3.7 g, 44.8 mmol) in a solution of water-EtOH (65 ml, 3.3:1). The resulting mixture was heated to 50° C. for 1 hour. The reaction was then allowed to cool to room temperature, partitioned with EtOAc, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound in quantitative yield. 1H NMR: 11.49 (s, 1H) 8.47 (s, 1H) 8.17-8.27 (m, 1H) 7.21 (dd, J=8.29, 3.01 Hz, 1H) 2.17 (s, 3H).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:23]([NH2:25])[CH3:24].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]1[C:20](=[O:22])[NH:25][CH2:23][CH3:24])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
15.25 ml of triethylamine and subsequently a solution of 10.48 ml of ethyl chloroformate in 50 ml of dry tetrahydrofuran were added at -25° C. to a solution of 23.13 g of (2S, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 350 ml of dry tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. At the end of this time, a 70% by volume aqueous ethylamine solution was added at -22° C., the reaction temperature was allowed to rise gradually and the reaction finished when the temperature reached 10° C. The reaction mixture was then mixed with a small amount of an aqueous solution of sodium chloride, after which it was extracted thrice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 23.60 g of the title compound as a colorless oil.
Reaction SMILES: C([N:3]([C:9]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([Cl:17])=[C:11]([NH2:18])[C:10]=1[Cl:19])[C:4](=[O:8])[C:5]([O-:7])=[O:6])C.C(Cl)Cl.[OH-].[Na+].[Na]>O>[NH2:18][C:11]1[C:10]([Cl:19])=[C:9]([NH:3][C:4](=[O:8])[C:5]([OH:7])=[O:6])[CH:14]=[C:13]([C:15]#[N:16])[C:12]=1[Cl:17]
Reactant: CCN(C(=O)C(=O)[O-])c1cc(C#N)c(Cl)c(N)c1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(NC(=O)C(=O)O)c(Cl)c(N)c1Cl

Procedure:
A solution of 2.97 g. (0.01 mole) of ethyl(3-amino-2,4-dichloro-5-cyanophenyl)oxamate in 100 ml. of methylene chloride is placed in a separatory funnel. There is added a solution of 8 ml. of 1 N sodium hydroxide diluted to 100 ml. with water. There is added an additional 300 ml. of water to dissolve the sodium salt that forms. The phases are separated and the aqueous layer acidified with glacial acetic acid. To the solution is then added 5 ml. of concentrated hydrochloric acid. The precipitate is removed by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[NH:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc2[nH]ccc2c1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
A mixture of the product of Step A (0.2 g; 1.41 mmol), HCl×H2NOH (0.36 g; 5.2 mmol), and Na2CO3 (0.26 g; 2.44 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 10 min, then refluxed overnight under N2. After cooling most of the ethanol was removed under reduced pressure and the product was extracted with EtOAc (20 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.23 g; 92%), as a creamy foam. 1H-NMR (CDCl3+CD3OD) 1.71 (broad s, H2O); 4.93* (broad s, 0.5H); 6.55 (d, 1H, J=3 Hz); 7.21 (d, 1H, J=3 Hz); 7.28-7.42 (m, 2H); 7.87 (d, 1H, J=1 Hz); 8.63* (broad s, 0.3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([C:12](OCC)=[O:13])[CH:6]=[C:5]([CH3:17])[N:4]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:13][CH2:12][C:7]1[CH:6]=[C:5]([CH3:17])[N:4]=[C:3]([O:2][CH3:1])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)c1cc(C)nc(OC)c1[N+](=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1nc(C)cc(CO)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a −70° C. solution of ester from step B (5.4 g, 22.5 mmol) in 140 mL of DCM was added 56.2 mL (56.2 mmol) of DIBAL-H (1M in hexane) by dropping funnel. The resulting solution was stirred for 1 h then warrned to room temperature over an additional hour. The reaction mixture was quenched by the careful addition of saturated NaK tartrate. Stirring was continued for 30 min then the solid was filtered and washed with 100 mL of DCM. The filtrate was extracted with 2×50 mL of saturated NaK tartrate then brine (25 mL). The yellow solution was concentrated and chromatographed (2:3 EtOAc/Hexane) to afford the desired alcohol as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:30]=[CH:31][C:32]([S:35][CH3:36])=[CH:33][CH:34]=4)[C@@H:26]([NH:28][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1
Reactant: COCC(=O)Cl
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methoxyacetyl chloride (10 μL, 0.11 mmol) was added to a suspension of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine hydrochloride (40 mg, 0.09 mmol) and triethylamine (42 μL, 0.3 mmol) in THF (1 mL). The reaction was stirred at r.t. for 30 min and then quenched by adding water, the mixture was diluted with a small volume of MeCN so that a solution was obtained. This crude mixture was purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 20 min gradient of 20%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid. Yield 30 mg (69%).
Reaction SMILES: Cl.CO.C(OC([N:11](C(OC(C)(C)C)=O)[C:12]1[C:13]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([C@@H:41]4[CH2:46][O:45][CH2:44][CH2:43][N:42]4C(OC(C)(C)C)=O)=[CH:37][CH:36]=3)[CH:31]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C>ClCCl>[CH:27]([S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:14]=[C:13]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][C:38]([C@@H:41]5[CH2:46][O:45][CH2:44][CH2:43][NH:42]5)=[CH:37][CH:36]=4)[CH:31]=3)[C:12]([NH2:11])=[N:17][CH:16]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc([C@@H]5COCCN5)cc4)no3)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
HCl in methanol (595.7 μL of 3 M, 1.787 mmol) was added to a solution of tert-butyl (3R)-3-[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]phenyl]morpholine-4-carboxylate 14 (144 mg, 0.178 mmol) in dichloromethane (5.538 mL) and the resulting solution stirred at 50° C. overnight (a yellow precipitate formed). The reaction mixture was cooled to rt and the solid was collected by filtration, washed with CH2Cl2 and dried by suction leaving product as a yellow solid. Material was recrystallised from dichloromethane and methanol (approx 3:1 ratio DCM:MeOH) to leave the product as a yellow solid (28 mg, 28% yield); 1H NMR (DMSO) d 1.18 (6H, d), 3.47 (1H, m), 3.79-3.87 (2H, m), 4.03-4.09 (2H, m), 4.57 (1H, m), 7.23 (2H, br s), 7.75 (2H, d), 7.85 (1H, s), 7.93 (2H, m), 8.12 (2H, d), 8.37 (2H, d), 8.96 (1H, s) and 9.53 (2H, br s) ppm; MS (ES+) 506.5.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:6]=2[N:5]=[CH:4]O1.C([O-])(=O)C.[NH4+:19]>[NH4+].[OH-].CO>[O:1]=[C:2]1[C:7]2[C:6](=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][NH:19]1
Reactant: [NH4+]
Reactant: O=C(O)c1cccc2c(=O)ocnc12
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2c(=O)[nH]cnc12
Temperature: 80 °C
Yield: 17529.5 %

Procedure:
4-oxo-4H-3,1-benzoxazine-8-carboxylic acid derivative (51.5 g; 251.26 mmol) was dissolved in NH4OH (360.0 ml; 6.98 V; 28% solution). Ammonium acetate (77.5 g; 1.005 mmol) was added, and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with MeOH (40 mL) then heated for 72 h at 80° C. in a pressure bottle. The reaction mixture was concentrated on the rotary evaporator then cooled on ice and filtered. The solid was dried under vacuum to provide the desired product (33.5 g, 65% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:20]=[CH:21][CH:22]=[N:23]5)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2nccnc2c1
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccc5nccnc5c4)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoxaline-6-carbaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 11.0 (brs, 1H), 8.81 (s, 2H), 8.13 (d, J=8.7, 1H), 8.01-7.92 (m, 3H), 5.01-4.94 (m, 1H), 4.01-3.88 (m, 2H), 3.37 (t, J=8.3, 1H), 3.05 (d, J=9.9, 1H), 2.86-2.85 (m, 1H), 2.70-2.68 (m, 1H), 2.49-2.44 (m, 1H), 2.07-2.01 (m, 1H). 1.48 (dd, J=15.3, 6.6 Hz, 6H), 1.20 (d, J=7.05 Hz, 3H). MS: (M+H m/z 404.1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[C:11]([CH3:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)O
Temperature: 50 °C
Reaction time: 19.5 h
Yield: 71.6 %

Procedure:
The compound (1.81 g, 6.68 mmol) obtained in Example 30b was dissolved in methanol (27 mL), a 1 N aqueous sodium hydroxide solution (26.7 mL, 26.7 mmol) was added, and the mixture was stirred at 50° C. for 19.5 hours. A 1 N aqueous sodium hydroxide solution (26.7 mL, 26.7 mmol) was added to the reaction mixture, and the mixture was stirred at 50° C. for 24 hours. Methanol was evaporated under reduced pressure, water and ethyl acetate were added to the resulting residue, and the mixture was extracted with water (×2). The resulting aqueous layer was adjusted to pH 1 with 1 N hydrochloric acid, the mixture was extracted with ethyl acetate (×2), and then the organic layer was washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and moisture was removed from the resulting residue azeotropically with toluene (×2) to give the title compound (1.23 g; yield, 62%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=N/S(C2SC=CC=2)(=O)=O)/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:38][S:35]([C:32]2[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O

Procedure:
5.2.20 Ethyl 2-(1-oxo-4-(tosylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (81) was prepared according to the procedure for 8a except using 4-methylbenzenesulfonamide, TiCl4.2THF and THF as solvent. The title compound 100.7 mg (46.9%) was obtained according to the workup procedure for 12a as a yellow solid, m.p.: ° C.