Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:40])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:41].C(OCC)C>C(Cl)Cl>[ClH:41].[NH2:8][C@@H:9]([CH3:40])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)N)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol) in DCM (2 mL) at −20° C. was added HCl in diethyl ether (2.0 ml, 2.0 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Kinetex C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 40% solvent B over 7 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 4.7 mg (16%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-aminopropanoate hydrochloride, the titled compound of example 4 as an off-white solid. LC-MS (Method A) RT=1.762 min, (M+H)+=454. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=9.0 Hz, 2H), 7.24-7.10 (m, 6H), 5.10-4.85 (m, 1H), 4.45-4.22 (m, 4H), 4.04-3.94 (m, 1H), 3.34-3.18 (m, 4H), 3.06 (d, J=12.0 Hz, 2H), 2.43-2.31 (m, 1H), 2.27 (s, 3H), 2.24-2.14 (m, 1H), 2.13-2.01 (m, 1H), 2.01-1.85 (m, 1H), 1.58 (d, J=7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −183.778.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][C:33]=4[F:34])[N:30]=[CH:29][CH:28]=[CH:27]5)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)C)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:34][C:33]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[CH2:23][C:20]1[N:18]2[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]3)[CH:15]=[CH:16][C:17]2=[N:22][CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-{1-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (Stage 260.1, 179 mg, 0.376 mmol) was dissolved in DCM (7.5 mL) and TFA (3 mL). The RM was stirred at rt for 1 h. A basic work up (1 M Na2CO3) followed by a crystallization in Et2O afforded the title compound as white crystals (tR 2.28 min (conditions 13), MH+=377, 1H-NMR in DMSO-d6: 8.83 (m, 1H); 8.30 (d, 1H); 7.93 (d, 1H); 7.75 (m, 2H); 7.48 (dd, 1H); 7.35 (s, 1H); 6.74 (d, 1H); 4.37 (s, 2H); 3.52-3.35 (m, 3H); 3.23-3.17 (m, 2H); 2.27 (s, 3H); 2.07 (m, 1H); 1.86 (bs, 1H); 1.80 (m, 1H)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[CH:10][C:9]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]=1[CH3:7]>CO.[Pd]>[Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Agent: [Pd]
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)OCC)c(C)c1Cl
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a 30 mL pressure flask containing 10% Pd/C (59 mg, 0.055 mmol) was added a solution of 1-benzyl 3-ethyl 4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)isophthalate (153 mg, 0.28 mmol) in MeOH (5.0 mL). The reaction mixture was stirred under H2 at 5 psi for 1 h, then filtered through a pipette containing a plug of CELITE® and concentrated in vacuo to give the title compound (110 mg, 85%) as a colorless oil. 1H NMR (CDCl3) δ 8.72 (d, J=2.0 Hz, 1H), 8.35 (dd, J=8.1, 2.0 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 4.21 (q, J=7.3 Hz, 2H), 3.56-3.49 (m, 2H), 3.46-3.38 (m, 2H), 2.20-2.13 (m, 3H), 1.71-1.60 (m, 2H), 1.59-1.50 (m, 1H), 1.47-1.33 (m, 2H), 1.30-1.15 (m, 5H), 0.96 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 464.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:21][C:20](=[O:29])[NH:1][C:2]([C:3]#[N:4])([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). Reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (8.12, 89%) as a yellow oil. MS (ESI, m/z): 297.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH3:19])[C:12]2([C:15](O)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:18][CH3:19])[C:12]2([C:15]([NH:47][CH2:46][C:44]3[CH:43]=[CH:42][N:41]=[C:40]([C:37]4[CH:36]=[CH:35][C:34]([O:33][C:32]([F:49])([F:31])[F:48])=[CH:39][CH:38]=4)[CH:45]=3)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Acid 15B (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 295 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 100 mg of a white solid. Yield=18% 1HNMR (DMSO, 200 MHz) δ 1.12 (2H, bs), 1.22 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=4.8 Hz), 4.41 (2H, d, J=5.4 Hz), 7.26 (1H, dd, J=3.8 Hz), 7.49 (2H, d, J=8 Hz), 7.65 (2H, dd, J=8.6 Hz), 7.84 (2H, dd, J=6.8 Hz, J′=1.6 Hz), 7.90 (1H, bs), 8.20 (2H, dd, J=6.8 Hz, J′=1.8 Hz), 8.28 (1H, t), 8.59 (1H, d, J=5.2 Hz) [M+1] 553.9 (C25H23ClF3N3O4S requires 553.98).
Reaction SMILES: [CH2:1](N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][OH:22])[C@H:17]([CH2:19][CH3:20])C)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O>[C:8]([O:12][C:13]([NH:15][C@H:16]([CH:21]=[O:22])[CH2:17][CH:19]([CH3:20])[CH3:1])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101 %

Procedure:
9.59 ml (69.0 mmole) of triethylamine and 11.0 g (69.0 mmole) of a pyridine/sulfur trioxide complex were added to a solution of 5.0 g (23.0 mmole) of N-(t-butoxycarbonyl)-L-isoleucinol in 50 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 15 minutes. At the end of this time, the reaction mixture was poured onto ice-water, and extracted with diethyl ether. The organic extract was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order. It was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 5.0 g of N-(t-butoxycarbonyl)-L-leucinal as an oily substance.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2>C(O)C>[CH3:1][CH:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[CH2:5][CH2:6][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8]1
Reactant: C=C1CN(C(=O)OCC)CCc2sccc21
Solvent: CCO
Product: CCOC(=O)N1CCc2sccc2C(C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Compound 1030 (310 mg, 1.31 mmol) was dissolved in ethanol (50 mL). The solution was degassed three times before addition of 10% Pd/C (100 mg). The flask was charged with hydrogen at atmospheric pressure (H2 balloon) and stirred at RT for 14 hours. The catalyst was removed by filtration through diatomaceous earth and the volatiles removed under reduced pressure to yield ethyl 4,5,7,8-tetrahydro-4-methylthieno[3,2-d]azepine-6-carboxylate (Compound 1031), which was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=O)=O.OS(O)(=O)=O>[Zn].C1(C)C=CC=CC=1>[Cl:9][C:5]1[CH:4]=[C:3]([SH:10])[C:2]([Cl:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(O)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Oc1cc(Cl)c(S)cc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a mixture of 2,5-dichloro-4-hydroxy-benzenesulfonyl chloride (1.28 g, 4.92 mmol) and a solution of 25% of H2SO4 (17 mL), Zinc dust (1.64 g, 24.56 mmol) was added slowly at room temperature. The reaction mixture was allowed to stir at 120° C. overnight. The mixture was then cooled at room temperature and toluene was added. The layers were separated and the aqueous phase was dried over, MgSO4 filtered and concentrated in vacuo to give 514 mg (54%) of the title compound as a white solid, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][C:13](=[O:15])[CH3:14])[C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cccc2ccc(C)nc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCCc2ccc(C)nc21
Yield: 56.7 %

Procedure:
Reaction of N-(2-methyl-quinol-8-yl)acetamide (159 mg, 0.795 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (92 mg, 57%): 1H NMR δ 1.57-1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-2.57 (m, 1H), 2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s, 1H), 6.92 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz); 13C NMR 67 21.6, 25.4, 25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2, 172.2; MS m/z: 227 (M+Na+). N-(2-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)acetamide also was isolated (25 mg, 15%) as a tautomeric mixture of acyclic and cyclized isomers in an approximately 1:2 ratio which exhibited the following data: 1H NMR δ 1.21-1.25 (m), 1.45-1.61 (m), 1.90 (s), 1.90-1.95 (m), 2.20 (s), 2.71-2.91 (m), 3.32-3.43 (m), 4.00 (br s), 6.56 (dd, J=8, 8 Hz), 6.63 (dd, J=8, 8 Hz), 6.66 (br s), 6.83 (d, J=8 Hz), 6.87 (d, J=8 Hz), 6.94 (d, J=8 Hz), 7.02 (d, J=8 Hz), 7.06 (br s); MS m/z: 205 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])([CH3:10])[C:6](=[O:24])[NH:5][C:4]1=[O:25])[CH3:2].NC1(C)C(=O)N([CH:34]2[CH2:39]CC[CH2:36][CH2:35]2)C(=O)NC1=O>>[CH:1]1([N:3]2[C:8](=[O:9])[C:7]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=3[F:22])([CH3:10])[C:6](=[O:24])[NH:5][C:4]2=[O:25])[CH2:36][CH2:35][CH2:34][CH2:39][CH2:2]1
Reactant: CC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Product: CC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 20h was prepared by the same method described for 20f using 5-amino-1-cyclohexyl-5-methylbarbituric acid (0.48 g, 2 mmol). The crude 1-cyclohexyl-5-methyl-5-(tetrafluorobenzamido)barbituric acid (20h) was obtained as yellow crystals and did not require further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[Cl:19][C:20]1[C:21](F)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>[Cl-].[NH4+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:21]1[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:23][N:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (740 mg, 4 mmol) in N,N-dimethylformamide (5 mL) sodium hydride (180 mg of 60% dispersion in mineral oil, 4.5 mmol) is added at room temperature. After 10 minutes, 3-chloro-2-fluoro-5-trifluoromethylpyridine (1 mL, 8 mmol) is added and the suspension stirred at room temperature. After 3 h the reaction mixture is treated with saturated ammonium chloride solution (150 mL), extracted with dichloromethane (2×100 mL). Combined extracts washed with brine (2×50 mL), water, dried over anhydrous Na2SO4 and solvent removed in vacuo. The crude is purified by chromatography over silica gel eluting with hexanes/ethyl acetate to give the title compound, ESI m/z 365 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26](S(C)(=O)=O)[N:25]=1>O1CCCC1.CCCCCC>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:14]([CH2:15][CH2:16][CH3:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])[N:25]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCC(C(=O)OCC)c1nc(OC)cc(OC)n1
Reaction time: 0.5 h

Procedure:
4,2 g (30 mmol) Diisopropylamine in 100 ml tetrahydrofuran, under nitrogen at -78° C., was treated with 19 ml (30 mmol) 1.6M butyllithium in hexane. The mixture was stirred for 30 minutes and then at -60° C., a solution of 3.5 g (27 mmol) ethyl pentanoate, dissolved in 20 ml tetrahydrofuran, was added dropwise. The mixture was stirred for a further hour and 5.9 g (27 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added, portionwise. The temperature of the mixture rose over 2 hours to +10° C. The reaction mixture was then washed with saturated aqueous ammonium chloride and sodium chloride. The aqueous phase was extracted with ethyl acetate. The organic phases were dried over magnesium sulphate and concentrated. The resulting yellow oil was finally purified on silica gel using a hexane/ethyl acetate mixture (0 to 20% ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH3:13][O:14][CH2:15]OC.B(F)(F)F.CCOCC.CCCCCC>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][O:14][CH3:15])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COCOC
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COCN1C(=O)C(=O)c2cc(Br)ccc21
Temperature: 40 °C
Yield: 49.8 %

Procedure:
To a 500 mL round-bottomed flask, was added 5-bromoisatin (5.00 g, 22.1 mmol), formaldehyde dimethyl acetal (111 mL, 22.1 mmol), and boron trifluoride diethyl etherate (16.7 mL, 133 mmol). The resulting mixture was heated at 40° C. TLC (1:1 hexane:EtOAc) showed starting material was consumed. The mixture was then diluted with EtOAc (100 mL) and washed with brine/water (60 mL), brine (60 mL) and brine/bicarbonate (60 mL). The organic layer was dried over sodium sulfate and evaporated to provide an orange solid. The solid was taken up in EtOAc (50 mL) with heating, and hexane (10 mL) was added until the mixture became cloudy. A black precipitate formed immediately that should have been removed. The mixture was heated to reflux and allowed to stand at room temperature and then at −20° C. Orange red crystals were filtered washing with hexane and manually separated from the black precipitate to provide the title compound (2.97 g, 49.7% yield) as a red crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (s, 3H), 5.08 (s, 2H), 7.19 (d, J=8.22 Hz, 1H), 7.77 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][NH:32][CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:21][CH2:20]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][N:32]([C:1](=[O:3])[CH3:2])[CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (5 μL, 0.058 mmol) was added to a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.1 mg, 0.029 mmol) and pyridine (7 μL, 0.088 mmol) in DCM (290 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.7 mg, 78%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.33 (d, J=6.6 Hz, 6H), 1.91-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.88-2.94 (m, 1.1H), 3.12 (td, J=8.5, 4.0 Hz, 2H), 3.43-3.51 (m, 2H), 3.80-3.85 (m, 1.1H), 3.86-3.91 (m, 0.9H), 4.10-4.18 (m, 1H), 4.47-4.54 (m, 1H), 4.55 (br s, 2H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.4.
Reaction SMILES: C(O[C:6](=O)[N:7]([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@@H:10]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(C)(C)C.[AlH4-].[Li+]>O1CCCC1>[Si:34]([O:33][C@H:10]1[CH2:11][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:13][C@H:9]1[CH2:8][N:7]([CH3:6])[S:41]([NH2:44])(=[O:42])=[O:43])([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C)S(N)(=O)=O
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C)S(N)(=O)=O
Temperature: 50 °C

Procedure:
tert-Butyl(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)-methyl]carbamate (108 mg, 0.000164 mol) was dissolved in tetrahydrofuran (2.0 mL) under an atmosphere of nitrogen. Lithium tetrahydroaluminate (12.5 mg, 0.000329 mol) was added and the mixture heated at 50° C. for 80 minutes. The reaction was then cooled, quenched with water and acidified to ˜pH 6 with 1M HCl. This mixture was then extracted with ethyl acetate, the separated organic phase was evaporated, and the residue was purified by silica gel chromatography, eluting with 10 to 100% ethyl acetate in hexanes, to yield the product, 25 mg (27%). LC/MS: Rt=2.34 min, ES+ 571 (AA standard).
Reaction SMILES: [NH:1]([C:21]([O:23]C(C)(C)C)=O)[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5])[CH3:3].[NH:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]C(O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>Cl.O1CCOCC1.CN(C=O)C>[NH:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:5])[CH3:3])=[O:23]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 87.9 %

Procedure:
Boc-Ala-Pro-OBzl (75.3 g, 0.2 mole) was deprotected by stirring for 1.5 h. in 4.2 N HCl in dioxane. Excess HCl and dioxane were removed under reduced pressure, triturated with ether, faltered, washed with ether, and dried (yield 100%). A solution of Boc-Gly-OH (35.04 g, 0.2 mole) and HOBt (27.02 g, 0.2 mole) in DMF was cooled to -15° C. with stirring and EDCI (38.34 g, 0.2 mole) was added. After 20 rain, a pre-cooled solution containing the above hydrochloride salt and NMM (21.98 mL, 0.2 mole) was added and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to a thick oil which was dissolved in CHCl3. This solution was extracted with water, 10% citric acid, water, 5 % NaHCO3, water, and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting oil was crystallized from ether/petroleum ether. The solid was filtered, washed with petroleum ether, and dried to obtain 76.2 g (yield 87.88%) of II. R1f 0.39; R2f, 0.44.