Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=O)[CH2:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C(=O)N(c1cc(C(=O)NC3CC3)ccc1C)C(=O)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ccn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.8 %

Procedure:
To a solution of N-cyclopropyl-3-(7-methoxy-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylbenzamide (1 g) in Methanol (20 ml) and methylene chloride (45 ml) under an atmosphere of argon was added NaBH4 (114 mg) portionwise and the reaction stirred at room temperature for 17 hours. Concentrated hydrochloric acid (0.2 ml) was added and the reaction stirred for a further 4 hours. The reaction mixture was concentrated and the resultant solid triturated with ethyl acetate and air dried to yield N-cyclopropyl-3-(7-methoxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a white solid (849 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.86 (m, 1H), 3.39 (s, 3H), 6.72 (d, 1H), 7.21 (d, 1H), 7.41 (d, 1H), 7.50 (d, 1H), 7.67 (s, 1H), 7.71 (d, 1H), 7.89 (d, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH:6][C:7]1[C:15]2[O:14][CH:13]([CH3:16])[CH2:12][C:11]=2[C:10]([CH3:17])=[C:9]([Cl:18])[CH:8]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.COC(NNC1C2OC(C)CC=2C(C)=CC=1)=O>>[CH3:1][O:2][C:3]([N:5]=[N:6][C:7]1[C:15]2[O:14][CH:13]([CH3:16])[CH2:12][C:11]=2[C:10]([CH3:17])=[C:9]([Cl:18])[CH:8]=1)=[O:4]
Reactant: COC(=O)NNc1cc(Cl)c(C)c2c1OC(C)C2
Agent: COC(=O)NNc1ccc(C)c2c1OC(C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)N=Nc1cc(Cl)c(C)c2c1OC(C)C2

Procedure:
5 was prepared, as a red solid, m.p.: 112°-114° C., by treating 5A with MCPBA, according to the procedure described in Example 1 for preparing 1 from 1F.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].B>CN(C)C=O.CO>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][CH2:2]1
Reactant: Clc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ccccc1CN1CCC2CNCCN2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of 1-(bromomethyl)-2-chlorobenzene (37.2 mg, 0.181 mmol). The reaction mixture was stirred overnight. The solution was concentrated. To the concentrate was added tetrahydrofuran (10 mL) followed by borane (1M in tetrahydrofuran, 1 mL, 1 mmol). The solution was heated in an 80° C. oil bath for 4 hours. Methanol (20 mL) was added and heating of the resultant solution was continued in the 80° C. bath for 1 hour before concentration. To the concentrate was added dichloromethane (10 mL), methanol (1 mL) and HCl (4M in dioxane, 2 mL) Once LC/MS analysis indicated the reaction was complete the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.46 (d, J=8.85 Hz, 1H) 7.28-7.38 (m, 3H) 6.95 (dd, J=7.93, 1.53 Hz, 1H) 6.87-6.92 (m, 1H) 6.82-6.87 (m, 1H) 6.70 (dd, J=7.78, 1.37 Hz, 1H) 4.56 (d, J=16.17 Hz, 1H) 4.36 (d, J=16.48 Hz, 1H) 3.46-3.56 (m, 1H) 3.35-3.43 (m, 2H) 3.06-3.28 (m, 4H) 2.93-3.02 (m, 2H) 1.89-1.99 (m, 1H) 1.70-1.79 (m, 1H) MS (ESI) m/z 328.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:17][CH3:18])C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNOCc1ccccc1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
151 (616 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 152 as an oil (324 mg, 88%). 1H NMR (DMSO): δ 0.99 (t, 3H, J=7.3 Hz), 2.82 (m, 2H), 4.61 (s, 2H), 6.50 (t, 1H, J=5.8 Hz), 7.32 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13]([O:27][CH3:28])=[N:12][C:11]([CH2:29][CH3:30])=[C:10]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([NH:14][C@@H:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[CH3:10])=[O:17])[C:13]([O:27][CH3:28])=[N:12][C:11]([CH2:29][CH3:30])=[C:10]2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Solvent: C1CCOC1
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)N[C@H](C)c2ccccc2)C(OC)=N1
Reaction time: 12 h
Yield: 60 %

Procedure:
Into a stirred mixture of 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H)-pyrimidinedicarboxylate (12.6 g, 22.86 mmol) in THF (150 mL) was added a solution of R-(+)-α-methyl benzylamine (3.53 mL, 27.44 mmol) at room temperature. The stirring was continued for 12 h and the solvent was removed in vacuo. The yellow residue was dissolved in chloroform (200 mL) and was washed with 10% K2CO3 solution (2×30 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting mixture of diastereomers was separated by column chromatography over silica gel with 9:1 pet. ether:ether to 4:1 pet. ether:ether. First major product to elute was (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate: Colorless oil, Rf=0.31(4:1 pet ether:ether); wt.=3.8 g (60% yield); [α]D=+267.05 (c=0.76, CHCl3); 1H NMR (CDCl3) δ 1.22 (t, J=7.5 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.99 (s, 3H), 4.99 (m, 1H), 5.09 (ABq, 2H), 6.66 (s, 1H), 6.99-7.36 (m, 13H); The second major product to elute was (−)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate: Colorless oil; Rf=0.22 (4:1 pet ether:ether); wt.=3.2 g (51.2% yield); [α]D=−146.89 (c=0.38, CHCl3); 1H NMR (CDCl3) δ 1.22 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.6 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.94 (s, 3H), 5.03 (m, 1H), 5.11 (ABq, 2H), 6.68 (s, 1H) 6.91-7.34 (m, 13H).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:18]2[C:27]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:26]([CH:40]([CH3:42])[CH3:41])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:45])[CH2:21][C:22]([CH3:44])([CH3:43])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[C:12]1([C:18]2[C:27]([C:28]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)=[O:39])=[C:26]([CH:40]([CH3:41])[CH3:42])[CH:25]=[C:24]3[C:19]=2[CH:20]([OH:45])[CH2:21][C:22]([CH3:43])([CH3:44])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
80 μl (450 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.51 mg (17 μmol) of (1R,2S)-1-aminoindan-2-ol in 2.6 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 53 mg (112 μmol) of 5-cyclohex-1-en-1-yl-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethyl)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 37A) in 2.6 ml of tetrahydrofuran is slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 20:1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([NH2:26])=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.3 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (60 mg, 0.36 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (455 μL, 3.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (79 mg, 79%) as an off white solid. MS: m/e=329.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC(C)(O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCn1cc2nccc(I)c2n1
Temperature: 120 °C

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (342 mg, 1.396 mmol), 4-bromo-2-methylbutan-2-ol (233 mg, 1.396 mmol) and Cs2CO3 (455 mg, 1.396 mmol) were combined in DMF (5 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction was cooled, filtered, and concentrated to give a residue which was purified by silica column eluted using a step gradient of EtOAc (0-90%) in hexanes to give 4-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylbutan-2-ol.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](OC)[C:3]=1[C:12](=[O:14])C.C(O)C>CS(C)=O>[CH:12](=[O:14])[C:3]1[CH:2]=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Solvent: CS(C)=O
Solvent: CCO
Product: COc1ccc(C=O)cc1
Yield: 105.1 %

Procedure:
To a mixture of 34.7 g of the 2'-hydroxy-4',6'-dimethoxyacetophenone obtained in Production Example 7, 25.3 g of p-anisaldehyde, 150 ml of ethanol and 150 ml of dimethylsulfoxide was added 150 of a saturated solution of potassium hydroxide in ethanol at 0° C., and the mixture was stirred at room temperature for 4 hours to effect reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid to obtain a precipitate. The precipitate was washed with water and recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 43.4 g (yield=78.4%) of 2'-hydroxy-4,4',6'-trimethoxychalcone in the form of a yellow needle.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Yield: 98.7 %

Procedure:
A mixture of methyl ({6-[2-(2-naphthylmethyl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (184 mg, 0.433 mmol), prepared in the previous step, and 1N NaOH (650 μL, 0.65 mmol) in 10 mL of THF, 10 mL of methanol and 5 mL of H2O was refluxed for 2 h. The reaction was acidified by the addition of 700 μL of 1N HCl and then concentrated under reduced pressure to remove the THF and methanol. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (175 mg, 99%) as a white solid, mp 258-260° C. Elemental Analysis for C26H19NO4+0.20 H2O Calc'd: C, 75.61; H, 4.73; N, 3.39. Found: C, 75.41; H, 4.91; N, 3.22
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2].[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C(O)(=O)C>[CH2:1]([NH:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:23])[CH3:2]
Reactant: CCNC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Yield: 34.4 %

Procedure:
To a slurry of ˜1.0 mmol ethyl benzamide from Step 3 in 3 mL acetic acid was added 0.15 g (2.0 mmol) glycine. The reaction was mixed at 90-102° C. for 5.5 hr and allowed to cool. The solution was concentrated and and the residue was purified by 6Gilson preparative HPLC to afford 120 mg of [2-(4-ethylcarbamoyl-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid [5LC-MS data molecular ion and retention time): m/z 349 (M+H); 2.36 min] as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.Cl.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C(O)C>[CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH2:8])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=3)[N:18]=2)[CH2:4][CH2:3]1
Reactant: CC1(C(=O)CC#N)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cc1

Procedure:
Heat to reflux a solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (60 g, 487.2 mmol) and p-tolyl-hydrazine hydrochloride (78 g, 478.2 mmol) in ethanol (975 mL) for 4 hours. Evaporate the solvent and dissolve the remaining solid in water. Increase pH of the solution to pH 8 using a 1.0 N solution of sodium hydroxide. Filter the precipitate to obtain 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine as a white solid. 1H NMR (DMSO): 7.39 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 5.12 (s, 2H), 2.31 (s, 3H), 1.30 (s, 3H), 0.80 (q, J=4 Hz, 2H), 0.61 (q, J=4 Hz, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:11]=[CH:10][C:8]=2[CH:9]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:1]3[NH:30][N:29]=[N:28][N:2]=3)[O:6][C:7]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCc3nnn[nH]3)oc2c1
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.20 g), sodium azide (1.09 g), ammonium chloride (0.90 g) and N,N-dimethylformamide (30 ml) was stirred at 130° to 140° C. for 16 hours. The reaction mixture was poured over water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with methanol-chloroform (5:95, v/v), 5-[2-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]ethyl ]-1H-tetrazole (1.05 g, 78%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)[CH3:6])[CH3:2].C1COCC1.[Li+].C[Si]([N-:24][Si](C)(C)C)(C)C.C1(P(ON)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:24][C:5]([C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CCOC(=O)C(C)c1noc(C)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(N)c1noc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-propionic acid ethyl ester (CAN168704-76-5, 0.5 g, 2.71 mmol) in a mixture of dry THF (15 ml)/dry DMF (4 ml) cooled down to 0° C. under an argon atmosphere was slowly added LiHMDS 1.0M solution in THF (2.85 ml, 2.85 mmol). The reaction mixture was stirred at 0° C. for 30 minutes followed by addition of O-(diphenylphosphoryl)hydroxylamine (696 mg, 2.99 mmol). The resulting suspension was let to warm up to room temperature and stirred at room temperature overnight (a white suspension formed). The reaction mixture was filtered through a pad of Celite and the filter cake was washed twice with THF. The filtrate was concentrated in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with 5 mL aqueous Na2CO3 2M. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of dichloromethane/methanol to yield the title compound (450 mg, 83%). MS (ESI, m/z): 200.2 (M+H+).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)=O)(C)(C)C.[ClH:28]>CO>[ClH:28].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:16]([O:18][CH3:19])=[O:17])[CH2:10]1
Reactant: COC(=O)[C@H](c1c(F)cccc1F)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](c1c(F)cccc1F)N1CCC[C@@H](N)C1

Procedure:
(S)-Methyl 2-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-2-(2,6-difluorophenyl)acetate (185 mg, 0.481 mmol) was stirred in 3 M HCl in MeOH (5 mL) at room temperature for 24 hours and at 50° C. for 5 hours. The solvent was removed in vacuo to give the bis HCl salt of (5)-methyl 2-((R)-3-aminopiperidin-1-yl)-2-(2,6-difluorophenyl)acetate as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.Br.C1C2C(=CC=CC=2)C=CC=1CS[C:31](=[NH:33])[CH3:32]>C(O)C>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([NH:1][C:31](=[NH:33])[CH3:32])[CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: CC(=N)SCc1ccc2ccccc2c1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Agent: Br
Solvent: CCO
Product: CC(=N)Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-10H-dibenzo[b,f][1,4]oxazepin-11-one (Example 4, 50 mg, 0.22 mmol) in 4 mL of ethanol at 0° C. was added thioacetimidic acid naphthalen-2-ylmethyl ester hydrobromide (65 mg, 0.22 mmol). The reaction was warmed to room temperature overnight. The mixture was concentrated at reduced pressure and partitioned between water (5 mL) and ethyl acetate (25 mL). The aqueous layer was separated and evaporated under vacuum (yield 70 mg, 92%). H1 NMR (DMSO d6) δ: 11.15 (bs, 1H), 10.68 (s, 1H), 9.44 (bs, 1H), 8.56 (bs, 1H), 7.71-7.70 (m, 1H), 7.54-7.53 (m, 2H), 7.40-7.36 (m, 1H), 7.20-7.17 (m, 3H), 2.31 (s, 3H), MS (ES): MH+ 268.3.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)=[O:4]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)Nc1ccc(CCCC(=O)O)cc1

Procedure:
4-(4-(2-aminobenzoyl)aminophenyl)butyric acid was prepared using Method F starting from isatoic anhydride and 4-(4aminophenyl)butyric acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:16]1
Reactant: CC1CCCC(N)C1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Product: CC1CCCC(NC(=O)c2cnc3ccccc3n2)C1
Yield: 78.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 3-methylcyclohexylamine (119 mg, 0.90 mmol), and pyridine (5 mL) yielding 190 mg (78%) of (161):
Reaction SMILES: OC(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([NH2:29])[N:28]=4)[N:25]=3)[CH3:19])=[N:16][N:17]=2)[CH:14]=1.CCN(C(C)C)C(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([NH:29][C:42]([CH:39]5[CH2:41][CH2:40]5)=[O:43])[N:28]=4)[N:25]=3)[CH3:19])=[N:16][N:17]=2)[CH:14]=1
Reactant: CC(c1ccc2nc(N)cn2n1)c1nnc2ccc(Br)cn12
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-amine TFA salt (250 mg, 0.52 mmol) in CH2Cl2 was added DIEA (0.65 g, 5.0 mmol) followed by cyclopropanecarbonyl chloride (0.16 g, 1.5 mmol). The reaction was stirred at ambient temperature for 30 min. Solvent was removed via rotary evaporation and the resulting residue was reconstituted in MeOH (10 mL). NH4OH (0.5 mL) was added and the reaction was stirred at ambient temperature for 1 hr. The reaction was then concentrated to dryness and the resulting material was dissolved in EtOAc, washed with saturated NaHCO3, dried with MgSO4, filtered and concentrated to dryness. The crude material was purified via MPLC (5% MeOH/0.1% NH4OH/EA) to provide the title compound, N-(6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide 48 (0.22 g, 0.52 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.87 (m, 4 H) 1.83-1.99 (m, 4 H) 5.17 (d, J=7.07 Hz, 1 H) 7.38-7.57 (m, 3 H) 7.80 (d, J=9.60 Hz, 1 H) 7.99 (d, J=9.09 Hz, 1 H) 8.78 (s, 1 H) 11.14 (s, 1 H). ESI-MS:m/z 426.2 (M+H)+.