Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]([C:20]3([CH3:34])[CH2:25][CH2:24][N:23]([C:26](=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH:21]3[CH3:33])[CH:17]=[CH:18][CH:19]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([S:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]([C:20]3([CH3:34])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH:21]3[CH3:33])[CH:17]=[CH:18][CH:19]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)N1CCC(C)(c2cccc(-c3c[nH]c(SCc4ccccc4)n3)c2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CCC(C)(c2cccc(-c3c[nH]c(SCc4ccccc4)n3)c2)C(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a solution of 4-(3-(2-(benzylsulfanyl)-1H-imidazol-4-yl)phenyl)-1-hexanoyl-3,4-dimethylpiperidine (Preparation 41, 101 mg, 0.21 mmol) in tetrahydrofuran (2 mL) at 0° C. was added lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 0.32 mL, 0.32 mmol) dropwise over a few minutes. The solution was stirred at room temperature under a nitrogen atmosphere for 1 h and then cooled back to 0° C. The reaction was cautiously quenched by the addition of 1 N sodium hydroxide (0.5 mL) and then ethyl acetate (10 mL) and solid sodium hydrogen-carbonate (excess) were added. The mixture was stirred vigorously for 30 minutes and then filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound as a clear oil (98 mg, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1C(OCC)=O>C(O)(=O)C.O>[O:1]=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCn2c1cc1ccccc12

Procedure:
A solution of 2,3-dihydro-1-oxo-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole in 400 mL of acetic acid and 25 mL of water was heated at reflux under N2 for 16 hr. The resulting solution was cooled and concentrated to dryness. The residue was treated with water and methylene chloride. The organic layer was washed with NaHCO3, brine, dried and concentrated to give solid which was purified by column chromatography to give the title compound. HNMR (CDCl3)δ 2.17 (t, 2H), 4.38 (t, 2H), 6.95 (s, 1H), 7.06-7.2 (m, 1H), 7.2-7.4 (m, 2H), 7.7 (d, 1H) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.[CH3:16][N:17]([CH3:23])[C@H:18]([C:20](O)=[O:21])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:16][N:17]([CH3:23])[C@@H:18]([CH3:19])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:21]
Reactant: C[C@@H](C(=O)O)N(C)C
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@H](C)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (2 g, 8.67 mmol) in N,N-dimethylformamide (100 mL) was added N,N-dimethyl-L-alanine (1.524 g, 13.01 mmol), PyBOP (13.54 g, 26.0 mmol), and DIPEA (15.14 mL, 87 mmol). After stirring overnight at rt, the solvent removed, residue suspended in dichloromethane (150 mL), washed with water (100 mL), concentrated on the rotovap, and purified by column chromatography (DCM to 5% MeOH/DCM) to give (2S)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 86%). ESIMS (M+H)+=294.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)[O-].[Na+].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([O:19][CH3:20])[CH3:17])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccnc1Cl
Yield: 87.2 %

Procedure:
To a solution of 2-chloro-nicotinoyl chloride (7.00 g, 39.8 mmol) and sodium bicarbonate (10.0 g, 119 mmol) in 1:1 THF/H2O (110 mL) at 0° C. was added N,O-dimethyl hydroxylamine hydrochloride (4.68 g, 47.7 mmol). The resultant solution was stirred 2 h at 0° C., neutralized with 10% HCl to pH ˜7, and the aqueous layer was extracted two times with EtOAc. The combined organics were dried with sodium sulfate and concentrated in vacuo to produce 6.96 g (87%) of the crude nicotinamide, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:28])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:28])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOC(=O)CCC(=O)c1ccc(N)cc1
Yield: 95.6 %

Procedure:
A solution of dodecyl 4-(4-nitrophenyl)-4-oxobutyrate (0.42 g, 1.1 mmol), in ethyl acetate (50 ml) and 10% palladium on carbon (0.10 g) were shaken under hydrogen (30-40 psi) for 10 minutes. The mixture was filtered and the filtrate concentrated in vacuo to give dodecyl 4-(4-aminophenyl)-4-oxobutyrate (0.38 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 0.86 (t, J=6.5 Hz, 3H, ester CH3), 1.10-1.37 (m, 18H, ester CH2 's), 1.47-1.60 (m, 2H, ester CH2), 2.57 (t, J=6.5 Hz, 2H, CH2), 3.10 (t, J=6.5 Hz, 2H, CH2), 3.98 (t, J=6.5 Hz, 2H, ester CH2), 6.04 (br s, 2H, NH2), 6.56 (d, J=8.5 Hz, 2H, Ar), 7.68 (d, J=8.5 Hz, 2H, Ar). Anal. Calculated for C22H35NO3.1/20H2O: C, 72.91; H, 9.76; N, 3.86. Found: C, 72.86; H, 9.83; N, 3.82.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([O:23]C(C)(C)C)=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([OH:23])=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350 mg, 0.465 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with toluene (10 mL) and solvent removed. The residue was dissolved in EA (50 mL), THF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL). The aqueous layer was removed and acetic acid (5 mL) was added. The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed and residual acetic acid was removed under high vacuum overnight. The material was dissolved in DCM (5 mL) and ACN (5 mL) was added. The material was stirred under a flow of air for 1 hour and the suspension was filtered and the solid washed with additional ACN (5 mL) and iso-hexanes (20 mL) to give 134 mg (41%) of (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound 328 as a yellow powder. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.3 [M+H]+, tR=10.59 min (Method 10). The chiral purity was calculated at >93% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz, 1H), 8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H), 7.57-7.48 (m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H), 4.94-4.86 (m, 1H), 4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.86-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H), 0.93-0.85 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1I.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:27]1[CH:28]=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
4-Bromo-3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 117.2, 3 g, 6.17 mmol), pyrimidin-5-ylboronic acid (841 mg, 6.79 mmol), Pd(PPh3)2Cl2 (217 mg, 0.309 mmol) and Na2CO3 (1.963 g, 18.52 mmol) in a mixture of DME (17.28 mL), water (4.94 mL), EtOH (2.469 mL) was degassed and stirred at 80° C. for 23 h under argon. Additional pyrimidin-5-ylboronic acid (76 mg, 0.613 mmol) was added to the RM and stirring was continued for 5 h. The RM was treated with Si-Thiol (Silicycle, 1.27 mmol/g, 1.215 g, 1.543 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 80 g, cyclohexane/EtOAc, from 10% to 45% EtOAc) to yield the title compound as a white crystalline solid. UPLC-MS (condition 1) tR=2.80 min, m/z=437.9-439.9 [M+H]+, m/z=436.0-438.0 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[NH2:25][CH2:26][CH2:27][NH:28][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:10]2[NH:11][C:12](=[O:14])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:24])[CH:4]=3)[CH:9]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(C(=O)NCCN)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a solution of 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid obtained from step 2 of Example 57 (16.9 mg, 48 μmol) and tert-butyl 2-aminoethylcarbamate (6.4 mg, 40 μmol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, taken up in methanol (1 mL) and 4.0 N hydrochloric acid in dioxane (1 mL), and stirred at room temperature for 4 hours then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-(2-aminoethyl)-3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzamide (3.4 mg, 23%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])C(O)=O.[NH2:7][CH2:8][CH2:9][C@@H:10]([O:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[CH2:11][O:12]C.[BH4-].[Li+].CO>O1CCCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH:22]=1)[O:14][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][NH:7][C:1](=[O:5])[O:6][C:16]([CH3:19])([CH3:17])[CH3:15]
Reactant: COC[C@@H](CCN)Oc1cc(Cl)ccc1C#N
Reactant: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@H](CO)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.6 %

Procedure:
The product from step (c) (881 mg, 2.39 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and lithium borohydride (2M solution in tetrahydrofuran, 2.6 ml, 5.26 mmol) added dropwise. The mixture was stirred at room temperature for 18 h. Methanol (5 ml) was added and the reaction stirred for 15 minutes. The solvent was removed in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:2, then 1:1) to give the title compound as a colourless oil (605 mg, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1)([CH3:7])[CH3:6])[CH3:2].Cl[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>>[CH2:1]([O:3][C:4](=[O:43])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][N:27]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Yield: 72 %

Procedure:
The reaction of 2-(2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylaminophenyl)butylamino]ethyl}-1H-indol-5-yl)-2-methylpropionic acid ethyl ester with benzyl chloroformate was carried out according to the procedure of Example 14.1 Step C, to give the titled compound in 72% yield as a stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=738 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:56]1([CH2:62][C@@H:63]([C:65]2[O:66][C:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[N:68][N:69]=2)[NH2:64])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:38])[NH:64][C@H:63]([C:65]1[O:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[N:68][N:69]=1)[CH2:62][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.2 mg (32 μmol) (1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine trifluoroacetic acid salt (intermediate 14).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(F)cc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 4-Fluoro-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(4-fluoro-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (27 mg, 53%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.28 (m, 1 H) 6.76 (m, 2 H) 6.92 (m, 3 H) 7.20 (m, 2 H) 7.76 (m, 2 H) 7.85 (d, J=8.82 Hz, 1 H) 7.96 (dd, J=8.64, 2.39 Hz, 1 H) 8.13 (d, J=2.21 Hz, 1 H) 8.88 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.30 (s, 1 H) 11.35 (s, 1 H); MS (ESI+) m/z 510 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>CC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:19]
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: Nc1c([N+](=O)[O-])ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-amino-3-nitropyridine (5.0 g; 36 mmol) in acetone (250 mL) was added a solution of m-chloroperbenzoic acid (7.5 g; 100 mmol) in acetone (50 mL). The shiny orange solution was stirred at room temperature for 3 days. The resulting precipitate was dissolved again under heating and the solution poured onto a silica gel column. Column chromatography using acetone as eluant gave the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylcarbonyl)-5-bromo-1H-indole (WO-A-92/06973; 0.67 g, 1.57 mmol) was dissolved in dry tetrahydrofuran (20 ml) and, at room temperature under nitrogen, lithium borohydride (2M solution in tetrahydrofuran; 1.2 ml, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, heated under reflux for 16 hours, then allowed to cool to room temperature. 2M Hydrochloric acid (10 ml) was added dropwise and the reaction mixture then partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (×2) and brine (×1), dried (Na2SO4), and evaporated under reduced pressure to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane, gave the title compound as an oil (0.32 g). Rf 0.20 (SS 16). Found: C,59.94; H,5.07; N,6.58. C21H21BrN2O2 ; 0.10 CH2Cl2 requires C,60.08; H,5.07; N,6.64%. δ(CDCl3)--mixture of rotamers: 1.63-1.90 (4H, m), 2.60-2.82 (1H, m), 3.10-3.28 (1H, m), 3.30-3.54 (2H, m), 4.18 (1H, m), 5.15-5.25 (2H, m), 5.30 (0.2H, s, CH2Cl2), 6.90 and 6.95 (1H, 2×s), 7.05-7.50 (7H, m), 7.70 and 7.85 (1H, 2×s), 8.25 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH2:20])[N:14](C(C)(C)C)[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[N:21]1([C:26]2[CH:35]=[CH:34][C:29]([C:30](OC)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1.C[Al](C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:20][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:35][CH:34]=3)[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Agent: C[Al](C)C
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(-n4cccn4)cc3)[nH]n2)c1
Temperature: 82 °C
Reaction time: 8 h

Procedure:
5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73 mmol) was dissolved in toluene (10 ml) and to this was added methyl 4-pyrazol-1-ylbenzoate (177 mg, 0.88 mmol) and AlMe3 (0.93 ml, 1.8 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (15 ml), quenched with damp sodium sulfite and further stirred for 20 mins before being filtered. The solvent was removed in vacuo to yield a yellow gum. This gum was dissolved in formic acid (12 ml) and heated at 82° C. overnight. The reaction mixture was evaporated to dryness and the resulting product was passed through a SCX column, eluting initially with methanol followed by 2N ammonia/methanol. After solvent removal, a yellow solid was obtained which was triturated with hot acetonitrile to afford a white solid. The solid was filtered and dried (155 mg, 55%); 1H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H), 3.74 (s, 3H), 6.48 (s, 1H), 6.60 (s, 1H), 6.77 (d, 1H), 6.84-6.82 (m, 2H), 7.20 (t, 1H), 7.81 (s, 1H), 7.96 (d, 2H), 8.14 (d, 2H), 8.63 (s, 1H), 10.69 (s, 1H), 12.18 (s, 1H); MS: m/z 388 (MH+).