Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]2[O:15][N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[N:12]=2)=[CH:4][C:3]=1[Cl:27].[OH-].[K+]>CC(O)C>[Cl:27][C:3]1[C:2]([NH2:1])=[C:7]2[CH2:8][CH2:9][O:10][C:6]2=[C:5]([C:11]2[O:15][N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]=2)[CH:4]=1
Reactant: CCOC(=O)N1CCC(c2noc(-c3cc(Cl)c(N)c4c3OCC4)n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1c(Cl)cc(-c2nc(C3CCNCC3)no2)c2c1CCO2
Yield: 62.9 %

Procedure:
A mixture of intermediate 3 (10 g) and potassium hydroxide (14 g) in 2-propanol (200 ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled and the solvent evaporated. Water was added to the residue and evaporated again. The residue was stirred in water and the resulting precipitate was filtered off, washed with water and purified by column chromatography on silica gel (eluent: CH2Cl2 /(CH3 OH/NH3) 90/10). The pure fractions were collected and the solvent evaporated, yielding 5.14 g (64%) of 5-chloro-2,3-dihydro-7-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-4-benzofuranamine (intermediate 4; mp. 219.0° C.).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=409.11.
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C@H:6]([C@@H:8]1[C@:16]2([CH3:17])[C@H:11]([C@@H:12]([OH:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:1][C:2]([CH3:19])([CH3:20])[CH2:3][CH2:4][O:5][C@H:6]([C@@H:8]1[C@:16]2([CH3:17])[C@H:11]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C[C@H](OCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](OCCC(C)(C)O)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Yield: 92.1 %

Procedure:
The compound of Example 8F (70 mg, 0.25 mmol) was dissolved in 1.5 mL of dichloromethane; 350 mg of pyridinium dichromate and 15 mg of pyridinium p-toluenesulfonate were added, and the resultant mixture was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in ethyl acetate and filtered through diatomaceous earth washing with ethyl acetate. The filtrate was concentrated and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 10% to 40% ethyl acetate in hexanes, to isolate the titled compound (65 mg, 73%).
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]([CH2:17][C@H:18]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:13]2)C1C=CC=CC=1.Cl>[Pd].CO>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C@@H:18]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:17][N:12]2[CH2:13][CH:14]3[CH:9]([NH:8][CH3:1])[CH:10]([CH2:16][CH2:15]3)[CH2:11]2)=[CH:26][CH:25]=1)#[N:28]
Reactant: CN(Cc1ccccc1)C1C2CCC1CN(C[C@@H](COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1C2CCC1CN(C[C@@H](COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C2
Yield: 60.3 %

Procedure:
A mixture of tert-butyl (1S)-2-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}-1-[(4-cyanophenoxy)methyl]ethylcarbamate (0.8 g, 1.6 mmol), 1 M HCl (0.8 mL) and MeOH (30 mL) was hydrogenated over 5% Pd/C. The reaction was stopped when the amount of H2 calculated for complete reaction had been consumed. The mixture was filtered through silica and the filtrate evaporated. The resulting crude product was purified on silica gel, eluting with DCM:ammoniacal methanol (9:1), to yield 0.4 g (61%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[CH:3]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1cccnc1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(Oc2cccnc2)c1
Yield: 70 %

Procedure:
1-Bromo-3-chloro-5-fluorobenzene (1.0 g, 4.8 mmol, 1.0 eq), 3-hydroxypyridine (454 mg, 4.77 mmol, 1.00 eq), K2CO3 (792 mg, 5.73 mmol, 1.20 eq) and DMF (15 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 950 mg (55%) of the title compound as a golden oil: 1H NMR (400 MHz, CDCl3) δ 8.45-8.44 (m, 2H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.52 (t, J=1.7 Hz, 1H), 7.47 (dd, J=8.5, 4.6 Hz, 1H), 7.25 (t, J=2.1 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H); [M+1]+: 284.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:14][CH2:15][CH3:16])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[C:3]([CH2:14][CH2:15][CH3:16])=[C:4]([CH2:10][C:11]([O:13][CH3:22])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCCc1c(O)cc(OC)cc1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCc1c(O)cc(OC)cc1CC(=O)OC

Procedure:
2-(3-Hydroxy-5-methoxy-2-propylphenyl)acetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3-hydroxy-5-methoxy-2-propylphenyl)acetate.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[C:11]([C:13]1[CH:14]=[C:15]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12].C(N(CC)CC)C>C(O)C>[CH2:7]([N:9]1[C:21](=[O:22])[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])[NH:10]1)[CH3:8]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Temperature: 80 °C
Yield: 122.8 %

Procedure:
Ethyl hydrazine oxalate (15.6 g, 104 mmol, 1.50 equiv) was added to a solution of ethyl 3-(3-cyanophenyl)-3-oxopropanoate (15.0 g, 69.1 mmol, 1 equiv) and triethylamine (14.4 mL, 104 mmol, 1.50 equiv) in ethanol (345 mL). The reaction mixture was heated to 80° C. for 70 min, then was removed from heat an concentrated to ˜¼ volume by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile as a light-yellow solid (18.1 g) of sufficient purity to use in the next step without further purification. Calcd (M+1)+: 214.1. Found: 214.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].CCOCC>CN(C=O)C>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCN=C=O
Reactant: Nc1nc2c(s1)C(=O)CCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A solution of 2-amino-7-oxo-4,5,6,7-tetrahydro-benzothiazole 3 (11.56 g, 68.7 mmol) in anhydrous DMF (200 mL) was treated with triethylamine (19.2 mL, 137 mmol, 2.0 eq) and ethyl isocyanate (10.9 nL, 137 mmol, 2.0 eq). The reaction mixture was heated at about 90° C. with stirring for about 3 hours. The DMF solvent was distilled off under reduced pressure. A sticky brown residue was obtained. Treatment with Et2O (100 mL) gave a precipitate, which was filtered off and washed with more Et2O (50 mL). The light brown colored solid was dried under vacuum to give 13.97 g (85%) of 4. The material was used in the following synthesis without further purification. 1H NMR (DMSO) δ 10.95 (br s, 1H, NH), 6.66 (br s, 1H, NH), 3.16 (p, 2H, J=7.2 Hz, CH2), 2.79 (t, 2H, J=6.1 Hz, CH2), 2.45 (t, 2H, J=6.5 Hz, CH2), 2.05 (p, 2H, J=6.4 Hz, CH2), 1.07 (t, 3H, J=7.2 Hz, CH3); LC/MS 240 (MH+); RP-HPLC RT 2.27 minutes.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][C:5]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C>[Cl:27][C:6]1[C:5](/[N:18]=[CH:19]/[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1Cc1c[nH]c2ncccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCn1nc(/N=C/c2ccc(F)cc2)c(Cl)c1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine (P-0165, 10.1 mg, 0.0289 mmol, prepared as described in Example 105, Scheme 162) in acetonitrile (8.0 mL) was added N-chloro-succinimide (4.18 mg, 0.0318 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0166, 1.1 mg). MS (ESI) [M+H+]+=382.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+].C(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[S:10][CH:12]=1)[CH3:19]
Reactant: NC(=S)c1ccccc1O
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Yield: 92.6 %

Procedure:
A stirred solution of 2-hydroxybenzenecarbothioamide 3a (5.36 g, 35.0 mmol), ethyl 4-chloroacetoacetate (6.34 g, 38.5 mmol) in dry THF (70 mL) was heated to reflux under nitrogen for 2.5 days. At ambient temperature, the mixture was diluted with EtOAc (200 mL), then cautiously treated with saturated aq. NaHCO3 (40 mL), and followed by adding solid NaHCO3 in small portions until CO2 evolution ceased. The organic layer was separated, washed with brine (40 mL×2), dried over MgSO4, and filtered. After concentration in vacuo, the oily residue was chromatographed on silica gel (gradient EtOAc/CH2Cl2 : 0-4%) to provide 4a (8.53 g, 93%) as a white solid, which was recrystallized from toluene/hexane at -30° C. mp 35.5°-36.5° C.; IR (neat) 3120, 1740, 1480, 1225 cm-1 ; 1H NMR (DMSO-d6) δ1.15 (3H, t, J=7.1 Hz, CH3), 3.84 (2H, s, CH2), 4.07 (2H, q, J=7.1 Hz, CH2), 6.89 (1H, t, J=7.8 Hz, Ar), 6.97 (1H, d, J=7.8 Hz, Ar), 7.26 (1H, t, J=7.8 Hz, Ar), 7.48 (1H, s), 7.93 (1H, d, J=7.8 Hz, Ar), 11.29 (1H, s, OH); FABMS m/z 263 (M+), 264 (M+ +1); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.16; H, 4.97; N, 5.50.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([CH2:17][CH:18]=O)[C:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH3:8])[CH3:7])C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:6]([CH:5]1[CH2:17][CH2:18][N:21]([C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:4]1=[O:20])([CH3:7])[CH3:8]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C(CC=O)C(C)(C)c1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Cl)cc1Cl)C1CCN([C@H]2CC[C@H](O)CC2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-(2,4-Dichloro-phenyl)-3-methyl-2-(2-oxo-ethyl)-butyric acid ethyl ester (Preparation 61) in THF and treat with trans-4-Amino-cyclohexan-1-ol (2.0 eq), acetic acid (6.0 eq) and NaBH(OAc)3 (4.0 eq). Allow reaction to stir at room temperature for 17 h and heat to 60° C. for six hours. Cool to room temperature, filter, dilute filtrate with EtOAc, wash with 0.1 N HCl, brine, dry over sodium sulfate and filter. Chromatography (silica, 1:1 to 3:7 hexanes/EtoAc) yields the titled compound in 53% yield: Mass spectrum (API-ES positive) m/z=372.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(N)cc1CC
Solvent: c1ccncc1
Solvent: O
Product: CCOc1ccc(NC(C)=O)cc1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example 30(t)] in pyridine (5 mL) was added acetic anhydride (1 mL) and the mixture was stirred 18 hours at ambient temperature. The reaction mixture was diluted with water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated to give N-(4-ethoxy-3-ethyl-phenyl) acetamide (0.6 g) as a pink foam. GC-MS one peak, RT=9.16 minutes, MS 207 (M)+. (f) N-(4-Methoxy-3-methyl-phenyl)-acetamide
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ncc(-c3ccc4cc(OCC(=O)O)ccc4c3)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of methyl ({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (254 mg, 0.925 mmol), prepared in the previous step, and 1N NaOH (925 μL, 0.925 mmol) in 30 mL of THF, 30 mL of methanol and 10 mL of H2O was stirred at room temperature for 16 h (overnight). The reaction was acidified by the addition of 1.0 mL of 1N HCl and then concentrated under reduced pressure to remove the THF and methanol. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (218 mg, 89%) as a yellow solid, mp 269-272° C. Elemental Analysis for C24H18N2O4 Calc'd: C, 72.35; H, 4.55; N, 7.03. Found: C, 71.97; H, 4.78; N, 6.73.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][NH:11][CH2:12]2.[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][NH:24][C:23]=12.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28]([N:11]3[CH2:10][CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12]3)=[O:29])=[CH:25][NH:24][C:23]=12
Reactant: c1ccc(-c2cccc3c2CCNC3)nc1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 70 h
Yield: 75.3 %

Procedure:
To a 250 mL flask was added 5-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.250 g, 10.7 mmol) and 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.75 g, 9.19 mmol). The mixture was diluted with DMF (100 mL) and Hunig's Base (16.6 mL, 95 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4 g, 12.46 mmol) was added to the mixture. The mixture was stirred at rt for 70 h, quenched with water (50 mL) and the solvent removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the residue purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The residue still had impurities by 1H NMR so it was dissolved in dichloromethane (150 mL) and washed with sat. NaHCO3 (100 mL) then with sat. ammonium chloride (150 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the solution was concentrated under reduced pressure to give 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (3.40 g, 6.92 mmol, 75% yield) as a blue solid. The product still had some impurities by 1H NMR, but was used in the next step with no additional purification. LC/MS: m/z 489.14 (M+H)+, 1.169 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 10.89 (br. s., 1H) 8.62-8.80 (m, 1H) 7.64-7.95 (m, 3H) 6.98-7.49 (m, 5H) 4.66-4.99 (m, 2H) 3.60-3.87 (m, 5H) 2.87-3.12 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Li+].CO.C(Cl)(Cl)Cl>COCCOC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:3][OH:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Yield: 89 %

Procedure:
This compound was prepared in 89% yield from the ester 4d (11.2 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.50 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 1.40 (s, 9H, t-Bu), 2.00-2.53 (m, 1H, OH), 2,83 (d, J=5.4 Hz, 2H, CH2Ph), 3.33-4.08 (m, 3H, CH2OH, CHCH2), 4.48-4.94 (br d, 1H, NH), 7.22 (s, 5H, Ph). CI MS, m/e 252 (M+ +1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)=[CH:26][CH:25]=3)=[N:21][N:20]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([CH3:16])([CH3:15])[C:17]#[N:18])[CH:9]=2)=[N:4][C:3]=1[C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][CH3:32])=[CH:28][CH:29]=2)=[N:21][N:20]=1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.32 %

Procedure:
tert-butyl N-[[4-[5-[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (199.3 mg, 0.3785 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of trifluoroacetic acid (500 μL, excess). The mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to an oil. Azeotroped with dichloromethane/methanol. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 2-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrile Compound I-4 as a pale yellow powder (mono trifluoroacetic acid salt) (88.6 mg, 43.32% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.80 (s, 6H), 2.64 (t, J=5.0 Hz, 3H), 4.28 (t, J=5.4 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 8.12 (dd, J=1.5, 5.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 2H), 8.41 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.91 (s, 2H) and 9.18 (s, 1H) ppm; LC/MS m/z 427.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([CH2:13][C:14](=[O:36])[NH:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CO.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][C:14](=[O:36])[NH:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([OH:37])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of the diester of example 62 (10.5 g, 20.8 mmol) in methanol (100 mL) was cooled in an ice bath and was treated drop wise with a solution of sodium hydroxide (1N, 42 mL). Stirring was continued for 30 minutes and then for an additional 48 hours at room temperature. The methanol was evaporated in a rotary evaporator and the alkaline reaction mixture was diluted with water followed by extracting with ether. The pH was adjusted to 4 by the addition of HCl (2N) and the acidic solution was extracted several times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired product (10.2, 100%) as a white foam: 1H NMR (CDCl3, 400 MHz) 7.70 (d, 1H), 7.26-7.46 (m, 16H), 2.72-2.99 (m, 1H), 1.99-2.42 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:22]Cl)=[CH:17][CH:16]=1>O1CCOCC1.CCCCCC>[Cl-:14].[CH2:10]([P+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:22][S:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH2:11][CH2:12][CH3:13]
Reactant: ClCSc1ccc(Cl)cc1
Reactant: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCCC[P+](CCCC)(CCCC)CSc1ccc(Cl)cc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
A solution of 8.45 g of tri(n-butyl)phosphine and 8.33 g of chloromethyl 4-chlorophenyl sulfide in 25 ml of p-dioxane was stirred and refluxed (101°-102° C.) for 20 hours. The mixture was cooled to room temperature and diluted with 100 ml of hexane. The white precipitate was filtered and dried to give 1, as a solid, mp 113°-114° C.