Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:11]=[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[N:9]=2)=[CH:4][CH:3]=1.[Cl:31]N1C(C)(C)C(=O)N(Cl)C1=O>C(#N)C.O>[Cl:31][C:11]1[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:13]([F:14])[C:12]=1[N:15]=[C:16]1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1
Reactant: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CCOC(OCC)c1nc(-c2ccc(Cl)cc2)c(F)c(N=C2C=CC(=O)C=C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxy-phenyl)pyridin-4-amine (0.862 g, 2 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.788 g, 4.00 mmol) in 1:1 acetonitrile/water (20 mL) was stirred at room temperature. After 2 h, the orange solid was collected by filtration, washed with 1:1 acetonitrile/water (5 mL), dried at room temperature and recrystallized from ether/hexane. 4-((3-Chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone (0.272 g, 30% yield) was isolated as orange crystals: mp 134-136° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.44 (m, 3H), 6.76 (m, 2H), 6.58 (dd, J=10.2, 2.1 Hz, 1H), 5.79 (s, 1H), 3.90 (m, 2H), 3.72 (m, 2H), 1.31 (t, J=7.1 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ −134.18; HRMS-ESI (m/z) [M+H]+ calcd for C22H19Cl2FN2O3, 448.0757; found, 448.0761.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.O1CCCC1>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 0.5 h

Procedure:
A solution of n-butyl-lithium (15% w/w, 36 ml, 0.05 mole) in hexane was added portionwise to a stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mole) in dry tetrahydrofuran (50 ml.) at 0° under nitrogen. After the addition the solution was stirred for 0.5 hour to give a dark red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[CH2:9]([N:16]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:22])[CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>O.O1CCCC1>[NH2:33]/[C:31](=[N:32]\[C:41](=[O:42])[O:43][CH2:44][CH3:45])/[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:19]2[CH:18]=[N:17][N:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:20]=2)=[O:22])=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide diacetate and 65 mg of potassium carbonate were dissolved in 0.75 ml of water and 3.75 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.015 ml of ethyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer was removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[OH:53])[O:7]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:73](O)/[CH:74]=[CH:75]\[CH2:76][OH:77].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[O:53][CH2:73]/[CH:74]=[CH:75]\[CH2:76][OH:77])[O:7]1)(=[O:3])[CH3:2]
Reactant: OC/C=C\CO
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC/C=C\CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-5-(4-ethoxybenzyl)-2-hydroxyphenyl)tetrahydro-2H-pyran-2-yl)methyl acetate (45, 2.19 g, 2.97 mmol) from Step 1 in tetrahydrofuran (30 mL) were added triphenylphosphine (1.57 g, 5.94 mmol) and cis-2-butene-1,4-diol (0.5 mL, 5.94 mmol) at 0° C., and diisopropyl azodicarboxylate (1.35 mL, 6.53 mmol) was added dropwise thereto. The reaction mixture was stirred at ambient temperature for 0.5 h and warmed up to room temperature for 4 h. After cooling to 0° C., the reaction mixture was quenched with H2O, extracted with ethyl acetate and dried over magnesium sulfate. The crude residue was purified on Biotage® purification apparatus (silica gel, 10 to 45% tetrahydrofuran in hexanes) to yield the title compound (46, 2.08 g, 2.57 mmol, 87%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[CH3:13][N:14]([CH:16]=O)[CH3:15]>CC#N.C(Cl)Cl>[CH3:13][N:14]([CH2:16][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=1)[CH3:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cn1ccc(C)n1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cn1cc(CN(C)C)c(C)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (94 mg) and DMF (1.5 mL) in MeCN (3 mL) was added N,N-dimethylmethyleneiminium iodide (390 mg). The reaction mixture was stirred at 90° C. overnight. After cooling down, the reaction mixture was diluted with DCM and washed with sat. NaHCO3 and water. The aq. layers were extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo to afford ethyl 2-(4-((dimethylamino)methyl)-3-methyl-1H-pyrazol-1-yl)acetate (112 mg, brown oil). LC-MS (B): tR=0.39 min; [M+H]+: 226.23.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][C:3]=1[CH3:11].Cl[CH2:13][C:14](=O)[CH3:15]>C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:13]=[C:14]([CH3:15])[N:8]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C(N)=S)ccc1Br
Solvent: CCO
Product: Cc1csc(-c2ccc(Br)c(C)c2)n1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4-Bromo-3-methylthiobenzamide (D38, 0.87 g, 0.0038 mole) was dissolved in ethanol (60 ml) and treated with chloroacetone (0.39 ml, 0.0049 mole). The reaction mixture was heated under reflux for 5 h, then more chloroacetone (0.39 ml, 0.0049 mole) was added and the mixture heated under reflux for a further 3 h. After cooling to room temperature, the solvent was removed in vacuo to leave the title compound as a pale oil (1.00 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a mixture of para-fluorophenol (15 g) and K2CO3 (18.5 g) in 100 mL acetone were added chloroacetone (10.4 mL) and of KI (22 g). After heating at reflux for 18 h the reaction mixture was cooled down and left at RT overnight. The reaction mixture was filtered, washed with acetone, and evaporated to dryness. The residue was partitioned between dichloromethane and water, the organic layer was separated and washed with water, dried over MgSO4, and evaporated to yield 15 g of 1-(4-fluoro-phenoxy)-propan-2-one as a yellow liquid.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@@H]1CC[C@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](CBr)C1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a 0° C. solution of 99 (6.6 gm, 50 mmol, 1 equi.) in 60 mL of DCM was added triphenyl phosphine (60 mmol, 1.2 equi, 15.72 gm) followed by carbon tetrabromide (60 mmol, 1.2 equi. 19.86 gm). The reaction mixture was stirred overnight allowing the temperature to rise to room temperature. Reaction was concentrated to dryness and the residue was diluted with ether/DCM (1:1, 20 ml) and filtered through a pad of celite. The filtrate was concentrated to dryness and the residue was purified by silica gel chromatography with (5% to 20% EtOAc in hexanes) to provide 3.5 g of (1R,3S)-methyl 3-(bromomethyl)cyclopentanecarboxylate 100.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.CN(C=[O:23])C>>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:4](=[O:23])[CH2:3][O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: COCCNCCOC
Reactant: CN(C)C=O
Reactant: BrCc1ccc(Br)cc1
Product: COCCN(Cc1ccc(Br)cc1)C(=O)COC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Di-(2-methoxyethyl)amine (6 ml) was added to a solution of 4-bromobenzylbromide (5 g) in DMF (20 ml) at ambient temperature. After stirring at ambient temperature for 2 h, the mixture was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic phase was dried, the solvent removed under vacuum to yield a yellow oil which was purified by column chromatography using a 0 to 20% ethyl acetate/isohexane gradient to yield the title compound as a clear oil (4.83 g). MS (M+H)+302. 1H NMR (CDCl3) 2.72 (t, 4H), 3.3 (s, 6H), 3.45 (t, 4H), 3.64 (s, 2H), 7.21 (d, 2H), 7.41 (d, 2H). b) 2-[(Aminocarbonyl)amino]-5-{4-[(bis-(2-methoxyethyl)amino)methyl]phenyl}-thiophene-3-carboxamide A solution of N-(4-bromobenzyl)-2-methoxy-N-(2-methoxyethyl)ethanamide (1.6 g) in THF (15 ml) was cooled to −60° C. under argon. Butyl lithium (5 ml, 1.6M solution in hexane) was added dropwise and the mixture was stirred at −60° C. for a further 20 min Triisopropylborate (1.8 ml) was added before allowing the mixture to warm to room temperature. After stirring at room temperature for 3.5 h, the THF was removed under vacuum and DME (20 ml), water (2 ml) and 2-(aminocarbonyl)amino-5-bromo-thiophene-3-carboxamide (0.47 g) were added. The mixture was degassed by purging with argon and sonicating for 15 min, sodium hydrogen carbonate (0.445 g) and Pd(Ph3)4 (0.1 g) added and heated to 90° C. for 18 h under argon. The solvent was removed under vacuum and the residue was partitioned between 2N sodium hydroxide solution and DCM. The combined phases were filtered and the aqueous phase was taken to pH 7 by addition of 5N aqueous hydrochloric acid. A precipitate formed which was purified by preparative hplc to yield the product as a solid (0.01 g). MS (M+H)+407. 1H NMR (DMSO-D6) 2.62 (t, 4H), 3.19 (s, 6H), 3.39 (t, 4H), 3.61 (s, 2H), 6.87-6.95 (bs, 2H), 7.22-7.31 (m, 3H), 7.44 (d, 2H), 7.61-6.9 (m, 2H), 10.97 (s,1H).
Reaction SMILES: Br.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][CH2:10][CH2:11][OH:12].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O-])=O.CO.O.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([OH:35])(=[O:34])=[O:33].[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][O:12][C:19]1[CH:20]=[CH:21][C:16]([NH2:13])=[CH:17][CH:18]=1
Reactant: C[C@@H]1CCCN1
Reactant: OCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCCOc1ccc(N)cc1

Procedure:
4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline was obtained as a light brown oily substance by the method according to Example 138, using (2R)-2-methylpyrrolidine hydrobromide, 3-bromopropanol and 4-nitrophenol as starting materials. The obtained oily substance was dissolved in ethyl acetate, 1 Eq of a methanol solution of p-toluenesulfonic acid monohydrate was added, and the target compound was obtained as a colorless solid by filtering off the solid produced. (2R)-2-methylpyrrolidine hydrobromide was manufactured by the method described in the literature (J. Org. Chem., 1989, Vol. 54, p. 209)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][OH:19]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:19][CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCCCC1CO
Product: CN1CCCCC1COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and racemic (1-methylpiperidin-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.36 min; ESI-MS 247.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Br:1][C:2]1[CH:8]=[C:7]([I:18])[CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4]
Reactant: CC(C)(C)c1cccc(Br)c1N
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(I)cc(Br)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
In a 50 mL round-bottom flask was added 2-bromo-6-tert-butylaniline [prepared by the method of Onitsuka, et. al. Organometallics, 25(5), 2006, pp 1270-1278] (1.18 g, 5.17 mmol) and sodium bicarbonate (0.782 g, 9.3 μmol) in water (5 ml). The mixture was cooled in an ice bath and iodine (1.444 g, 5.69 mmol) was added in several portions. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was treated with aqueous sodium thiosulfate, extracted by ethyl acetate, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel eluting with 5% ethyl acetate in hexane to give an oil (1.2 g, 65%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:8]=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:5][CH:4]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[K+].CC([CH2:27][C:28]([OH:30])=[O:29])=O>CN(C=O)C.C(OCC)(=O)C>[C:19]([O:22][CH:2]([O:30][C:28](=[O:29])[CH3:27])[C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:8]=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)CC(=O)O
Reactant: CC(=O)[O-]
Reactant: O=C1c2cc(C(Br)Br)ccc2-c2cc(Br)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC(OC(C)=O)c1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 100 °C
Reaction time: 1.17 h

Procedure:
To 7-dibromomethyl-3-bromo-9-fluorenone (137.1 mg) in DMF (3.3 ml) was added potassium acetate (78 mg). The reaction mixture was stirred at 100° C. for 70 minutes. It was then diluted with ethyl acetate, washed four times with H2O, twice with brine, dried and evaporated. The residue was purified by preparative tlc using 1% ethyl acetate/methylene chloride gave a mixture of the diacetate and the ultimately desired aldehyde (68.4 mg).
Reaction SMILES: FC(F)(F)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.C(OC(N[C@@H](CC1C=CC([Cl:45])=CC=1)C(O)=O)=O)(C)(C)C.C(OC(N[C@@H](CC1C=CC(C(F)(F)F)=CC=1)C(O)=O)=O)(C)(C)C>>[Cl:45][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O

Procedure:
A 60% dispersion of sodium hydride in mineral oil (9.6 mg, 251 μmol) was added to a mixture of 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (44 mg, 209 μmol) and (S)-tert-butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (109 mg, 314 μmol) in DMF (1 mL) at ambient temperature and the mixture was stirred at ambient temperature for 1.5 hours. H2O (15 mL) was added, and the mixture was extracted with DCM (4×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM (3 mL), TFA (2 mL) was added, and the mixture was stirred at ambient temperature for 2 hours. Toluene (3 mL) was added, and the mixture was concentrated under reduced pressure. The resulting orange oil was dissolved in DCM, evaporated onto a silica gel plug, and purified by flash chromatography (Biotage Si 25+M, 5% to 10% 2 N NH3 in MeOH/DCM) to provide N-((S)-2-amino-3-(4-chlorophenyl)propyl)-1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (18 mg, 23% yield) as an off-white solid. LCMS (API-ES) m/z (%): 412.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (br s, 3H), 2.62 (dd, J=13.1, 8.1 Hz, 1H), 2.79-2.94 (m, 2H), 3.15 (dd, J=11.8, 2.6 Hz, 1H), 3.25 (d, J=4.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H) 7.45 (s, 2H), 7.64 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 8.00 (s, 2H), 8.51 (d, J=5.5 Hz, 1H), 9.20 (s, 1H). (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434)) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][OH:8]>CO>[ClH:4].[NH2:5][C@@H:6]([CH2:7][OH:8])[C:9]([O:11][CH3:1])=[O:10]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CO
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanol (450 mL) in a round-bottom flask was cooled to 0° C. and acetyl chloride (55 mL, 0.77 mol) was added dropwise. After completion of the addition, the mixture was stirred at ambient temperature for 10 min and H-Ser-OH (30 g, 0.29 mol) was added in three portions. The reaction mixture was heated at 80° C. for 2 h and then concentrated. The residue was dried under vacuum to afford (S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (quantitative) as a colorless solid, which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6]/[C:5](=[N:8]\O)/[CH2:4][C:3]1([CH3:11])[CH3:10].C(Cl)Cl>CO.[Ni]>[NH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[C:3]([CH3:11])([CH3:10])[CH2:4]1
Reactant: CC1(C)C/C(=N/O)CCC1O
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(N)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (E)-4-hydroxy-3,3-dimethylcyclohexanone oxime (1.0 equiv.) in MeOH (0.8 M) was added Raney-Ni (10 equiv.). The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-2,2-dimethylcyclohexanol (92% yield), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22].N12CCN(CC1)CC2.CN(C)C=O>CO>[C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])[C:20]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:25]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1N
Temperature: 120 °C
Yield: 75.9 %

Procedure:
Into a 4 liter beaker equipped with magnetic stirrer, dropping funnel, and thermometer, was charged stearyl alcohol (270.0 grams, 1.0 mol; obtained from Sigma-Aldrich), isatoic anhydride (244.0 grams, 1.5 mol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (56 grams, 0.5 mol), and dimethylformamide (750 milliliters). The mixture was stirred and heated to 120° C. for a period of about 2 hours. The mixture was then cooled to 50° C., and methanol (3 liters) was added. A thick white precipitate formed, which was filtered and then washed with 3×1 liter portions of methanol and oven dried at 60° C. to yield 295.8 grams of a beige solid at 76 percent yield.
Reaction SMILES: CC(CC(C)C)=O.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Br:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](Cl)=[O:28]>O>[CH3:8][C:9]([NH:17][C:27](=[O:28])[CH:26]([Br:25])[CH:30]([CH3:32])[CH3:31])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)C(Br)C(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), α,α-dimethylbenzylamine (27.0 g) and triethylamine (21.2 g), and α-bromo-isovaleryl chloride (40.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-isovaleramide (51.9 g).