Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=[O:18])=[CH:10][C:11]=2[O:13]C(=O)C)[C:6]([CH2:20][CH3:21])=[N:5]1)(=O)C.[H-].[Na+].[CH2:24](O)[CH3:25]>CCOC(C)=O>[CH2:20]([C:6]1[C:7]2[C:12](=[C:11]([OH:13])[CH:10]=[C:9]([C:17]([O:19][CH2:24][CH3:25])=[O:18])[CH:8]=2)[NH:4][N:5]=1)[CH3:21]
Reactant: CCO
Reactant: CCc1nn(C(C)=O)c2c(OC(C)=O)cc(C(=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Yield: 87 %

Procedure:
To a solution of 1-acetyl-7-(acetyloxy)-3-ethyl-1H-indazole-5-carboxylate (4.0 g, 13 mmol) in ethanol (450 mL) was slowly added 60% NaH (0.50 g, 12.6 mmol). The mixture was stirred for 1 hour before concentration and removal of the majority of the ethanol. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was back extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The solid was triturated with CH2Cl2 to provide ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate as an off-white solid (2.9 g, 87%).
Reaction SMILES: [C:1](=[N:14]/[N:15]=[CH:16]/[C:17]1[S:18][CH:19]=[CH:20][C:21]=1Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([C:29](=[N:36][NH2:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:29](=[N:36][NH:37][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[CH:16]=[N:15][N:14]=[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccsc1/C=N/N=C(c1ccccc1)c1ccccc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C(=NN=C(c1ccccc1)c1ccccc1)c1sccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
To a solution of N-benzhydrylidene-N′-[1-(3-bromo-thiophen-2-yl)-meth-(E)-ylidene]-hydrazine (10.8 g, 29.2 mmol) in toluene (200 mL) was added (diphenylmethylene)hydrazine (6.9 g, 35.1 mmol), cesium carbonate (16.2 g, 49.7 mmol), Pd(OAc)2 (1.31 g, 5.85 mol), and 1,1′-bis(diphenylphosphino)ferrocene (2.43 g, 4.4 mmol). The reaction mixture was heated at 100° C. for 8.5 h then cooled to room temperature, diluted with EtOAc and filtered over Celite, rinsing with EtOAc. The filtrate was concentrated and the residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane to give 12.8 g of N-benzhydrylidene-N′-[2-(benzhydrylidene-hydrazonomethyl)-thiophen-3-yl]-hydrazine as a viscous brown oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2CN(C)[CH2:11][N:10](C)[C:9]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1.C([O-])(O)=O.[Na+].CO.O>C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([NH:10][CH3:11])=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1
Reactant: CN1CN(C)C(=N[N+](=O)[O-])N(Cc2cnc(Cl)s2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g of 1-(2-chlorothiazol-5-ylmethyl)-2-nitroimino-3,5-dimethyl-1,3,5-triaza-cyclohexane, 0.3 g of NaHCO3, 20 ml of methanol and 20 ml of water is stirred for 16 hours at 50° C. The reaction mixture is poured onto 100 ml of ethyl acetate and the aqueous phase separated. The organic phase is concentrated by evaporation and the residue purified on silica gel with dichloromethane/methanol 95:5 as the eluant. This yields the title compound with a melting point of 167-169° C. (compound 2.45).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[C:16]([NH:23][C@H:24]([C:33]([OH:35])=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.O>[C:19]([O:18][C:16]([NH:23][CH:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])=[CH:28][CH:27]=1)[C:33]([OH:35])=[O:34])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccccc2C=O)cc1)C(=O)O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
Potassium carbonate (7.36 g, 53.31 mmol) and -2-fluorobenzaldehyde (9.3 mL, 88.85 mmol) were added to a solution of Boc-tyrosine (5.0 g, 17.77 mmol) in anhydrous DMF (20 mL). The resulting suspension was refluxed at 75±5° C. under an atmosphere of argon. After 48 hr, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×50.0 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.0 and extracted with EtOAc (2×100 mL). The resulting EtOAc layer was extracted with water (1×100 mL) and brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired aldehyde, 58, as a low melting solid (6.4 g, ˜99%). 1H NMR (400 MHz, DMSO-d6): 12.62(s, 1H), 10.38 (s, 1H), 7.84 (dd, J=8.0 and 2.0 Hz, 1H), 7.64 (dt, J=7.2 and 1.6 Hz, 1H) 7.31 (d, J=8.8 Hz, 1H), 7.27 (t, J=7.6 Hz, 2 Hz), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H) 6.89 (d, J=8.4 Hz, 1H), 4.09 (ddd, J=12.8, 10.8 and 4.4 Hz, 1H), 3.02 (dd, J=13.6 and 4.4 Hz, 1H), 2.81 (dd, J=13.6 and 10.4 Hz, 1H) 1.32 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:18]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=4)[C:11]=3[CH2:19]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (130 mg, 0.44 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (98 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.66 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (50 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:10]([OH:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:37][CH2:38]Cl)[CH:34]([CH3:36])[CH3:35]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]3[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[C:10]([O:24][CH2:38][O:37][CH2:33][CH:34]([CH3:36])[CH3:35])[C:9]=2[CH3:25])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(-c2c(O)c(C)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Reactant: CC(C)COCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(-c2c(OCOCC(C)C)c(C)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
7.1 g (20 mmol) of 6-(4-chlorophenyl)-4-hydroxy-5-methyl-3-(2,4,6-trimethyl-phenyl)-2-pyrone in 50 ml of ethyl acetate are introduced in the absence of moisture. 2.02 g (20 mmol) of triethylamine are added thereto at 20° C. and a solution of 2.4 g (20 mmol) of i-butoxychloromethane in 20 ml of ethyl acetate is added dropwise at 0° C. with cooling. The mixture is then further stirred for 20 h at 20° C. and the reaction is followed by thin-layer chromatography. The solution is filtered off from the precipitated triethylamine hydrochloride using suction and washed with ethyl acetate. The combined mother liquors are washed twice, each time with 50 ml of half-saturated common salt solution, dried over magnesium sulfate and evaporated in vacuo. 8.8 g of crude product are obtained. 5.6 g (63% of theory) of 6-(4-chlorophenyl)-4-[(2-methyl-1-propoxy)-methoxy]-5-methyl-3-(2,4,6-trimethylphenyl)-2-pyrone are obtained as an oil by flash chromatography on 500 g of silica gel 60 (35-70 μm) using toluene:acetone 50:1 as mobile phase.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].O>O1CCCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][N:11]([CH2:23][C:22]#[CH:21])[C:12](=[O:15])[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCBr
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 66.6 %

Procedure:
0.70 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.15 g of 60% sodium hydride at room temperature for 30 minutes. 0.52 g of propargyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.54 g of methyl N-(3-phenylbenzyl)N-(2-propynyl)carbamate as a yellow transparent viscous liquid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].CC(C)([O-])C.[K+].C(OCC)(=O)C>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:13][C:12]([C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=Cc2cc(Br)ccc2OC1
Temperature: 25 °C

Procedure:
To a solution of 5-bromosalicylaldehyde (10.0 g) and tert-butyl acrylate (17.5 ml) in tert-butanol (100 ml) was added potassium tert-butoxide (1.67 g) at room temperature, and the mixture was refluxed for 66 hours and cooled to room temperature. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give tert-butyl 6-bromo-2H-1-benzopyran-3-carboxylate (10.86 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CCc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=302.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (2-bromoethyl)benzene.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=1.[CH3:18]I>CN(C)C=O.O>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6.9 g (17.2 mmol) of 60% sodium hydride in oil are added portionwise to a solution of 39 g (14.3 mmol) of tert-butyl (6-bromopyrid-2-yl)carbamate in 400 ml of dimethylformamide. After stirring for 20 minutes at room temperature, 17.8 ml (28.6 mmol) of methyl iodide are added dropwise. The reaction medium is stirred at room temperature for 18 hours, taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH:34]C(OC(C)(C)C)=O)=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
TFA (1 ml, 12.98 mmol) was added to a flask of benzyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (70 mg, 0.127 mmol) in dichloromethane (1 ml) at room temperature and the reaction was allowed to stir for 1 hour. The reaction was quenched by the addition of saturated sodium bicarbonate until bubbling stopped. The aqueous layer was extracted (2×) with EtOAc. The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was then purified by reverse phase HPLC to provide the desired product. 1H NMR (DMSO-d6) δ: (10.36s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.3 Hz, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.08-7.41 (m, 1H), 5.12 (s, 2H), 5.02 (s, 2H), 4.26 (d, J=6.3 Hz, 2H) MS: cal'd 453 (MH+), exp 453 (MH+). The in vitro HDAC1 IC50 of this compound is 32 nM. The IC50 of this compound in HCT-116 cells is 590 nM. Percent Cyp inhibitions at 10 μM are 7, 25 and 24%, for Cyp3A4, 2C9, and 2D6, respectively. The inflection point for MK-499 binding is 12.2 μM.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH2:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>[OH-].[Na+].O1CCOCC1>[CH2:14]([S:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in 1N aqueous sodium hydroxide (10 ml)-dioxane (3 ml), and dioxane (7 ml) solution of benzylsulfonylchloride (1.91 g, 10 mmole) was added dropwise to the solution while cooling with ice and stirring while keeping pH value thereof to between 10 and 11 using 1N aqueous sodium hydroxide. After completion of the addition, the mixture was further stirred for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 1.5 with 1N aqueous hydrochloric acid while cooling with ice and stirring to precipitate N-benzylsulfonyl-L-alanyl-L-proline in a crystalline form[yield: 1.78 g, 52.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:27][CH:28](C)[CH:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:27][CH2:28][CH:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(CO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Temperature: -10 °C
Yield: 103.4 %

Procedure:
A stirred solution of 9.36 g of oxalyl chloride in 130 ml of methylene chloride, under an argon atmosphere was cooled to -70° C. To this was added dropwise 11.53 g of dried dimethyl sulfoxide at a rate to maintain the temperature at -65° to -70° C. After stirring 5 minutes a solution of 10 g of 3-(hexadecyloxy)-2-(phenylmethoxy)-1-butanol in 60 ml of methylene chloride was added dropwise at a fast rate. The pasty mixture was allowed to warm to -10° C. over 20 minutes providing a solution. This solution was recooled to -50° C. and 16.17 g of triethylamine was added dropwise. The reaction mixture was allowed to warm to room temperature and was then poured into 100 ml of water. The organic phase was separated, washed successively with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried and the solvents removed giving an oil. This oil was dissolved in petroleum ether, washed with water and taken to dryness, giving 10 g of the desired compound as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][CH:10]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC1N=C(NC(=O)C)SC=1)(=O)C.CC(O)=O>CC(O)=O>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=1[Br:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(COC(C)=O)cs1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(COC(C)=O)c(Br)s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
(2-Acetamidothiazol-4-yl)methyl acetate (9.00 g, 42 mmol) was dissolved in 30 mL AcOH. A mixture of Br2 (9.0 g, 56.7 mmol) in 20 mL AcOH was added dropwise to the (2-acetamidothiazol-4-yl)methyl acetate/AcOH mixture. The reaction was complete in 10 minutes. After 200 mL distilled water was added to the reaction mixture, the mixture was extracted with EtOAc. The organic layer was washed a few times with water and saturated sodium bicarbonate. The organic layer was then washed with brine solution and dried over sodium sulfate. Evaporation of the solvent provided the product as a yellow solid (10 g, yield=80%). LCMS (API-ES) m/z (%) 293.2 (100%, M++H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2C)CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c(n2-c2ccccc2C)CCNC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
5-Benzyl-2-(4-methoxyphenyl)-1-(2-methylphenyl)4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (5.6 g, 14 mmol; prepared by methods as described in Example 1) was added to a suspension of palladium hydroxide on carbon (20%, 1.52 g, 2 mmol) in dry methanol (130 mL) and tetrahydrofuran (100 mL) under argon. The mixture was degassed by vacuum, and purged by argon several times. Then, the flask was fitted with a balloon containing hydrogen gas, and the mixture was stirred under H2 at rt overnight. The reaction mixture was filtered through Celite, and the filtrate evaporated to provide the product (4.3 g, 98%). LC-MS m/z (MH+) 409.2, retention time 2.30 min (method 2).
Reaction SMILES: ClC(OCC)=O.[CH:7]1([O:12][C:13](=[O:28])[C@@H:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:16][C:17](O)=[O:18])[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[BH4-].[Na+].Cl>C1COCC1.O>[CH:7]1([O:12][C:13](=[O:28])[C@@H:14]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC1CCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC1CCCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Ethyl chloroformate (2.45 ml, 25.6 mmol, 1.2 eq) was added at −20° C. to a stirred solution of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-cyclopentyl ester (6.73 g, 21.4 mmol) and N-methyl morpholine (3.05 ml, 27.8 mmol, 1.3 eq) in THF (50 ml). The reaction mixture became very thick with precipitation of a white solid. The reaction was therefore diluted further with THF (100 ml) to aid mixing and left stirring at −20° C. for 2 hours. The precipitated mass was filtered off and the filtrate was added over a period of 20 minutes to a solution of sodium borohydride (2.43 g, 64.1 mmol, 3 eq) in THF (20 ml) and water (5 ml) at 0° C. The reaction mixture was allowed to stir to room temperature and left for 4 hours for complete reaction. The mixture was acidified to pH 5 with 1M HCl and the THF removed under reduced pressure. The aqueous solution was extracted with EtOAc (3×100 ml) and dried over magnesium sulphate. The product was purified by column chromatography (DCM-5% MeOH/DCM) and isolated as a clear oil (5.0 g, 78%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: COc1ccc(CNc2cnc(C#N)c(C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile (15 g, 49.02 mmol) was taken up in DCM (30 mL) and TFA (50 mL) was added. The resulting reaction mixture was stirred at room temperature for 3 h (until done by LC-MS). The solvent and TFA were removed in vacuo and MeOH was added to the residue. The beige solid that was not soluble in MeOH was filtered and washed with MeOH. The filtrate was evaporated to dryness and the residue was partitioned between EtOAc and a saturated solution of sodium bicarbonate. The organic layer was washed two more times with a saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in DCM and hexanes with swirling until a yellow solid precipitated. This solid was filtered and washed with hexanes to afford 7.2 g of 5-amino-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, 1H), 7.28 (d, 1H), 6.99 (bs, 2H).