Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[N:4][CH:3]=[N:2][CH:7]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)Cc1cncnc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1cncnc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrimidin-5-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 250, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrimidin-5-yl)acetamido)propanamide. 1H-NMR (400 MHz, CDCl3): σ 9.17 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.42-7.21 (m, 7H), 7.06-6.91 (m, 5H), 6.68 (d, 1H), 4.70-4.63 (m, 3H), 4.57 (d, 1H), 3.98 (dd, 1H), 3.60-3.54 (m, 3H). MS (EI) for C28H25FN4O4. found 501.2 (MH+).
Reaction SMILES: Br.N[C:3]1[C:4]([OH:12])=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O.[Cu].C(Cl)(Cl)Cl>[OH:12][C:4]1[C:3]([I:22])=[CH:8][CH:7]=[CH:6][C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: [I-]
Reactant: CC(=O)c1cccc(N)c1O
Agent: [Cu]
Agent: Br
Agent: O=N[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1cccc(I)c1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
A suspension of 3'-amino-2'-hydroxyacetophenone hydrobromide (2.5 g, 10.8 mmol) in water (10 ml) at 0° C. was added successively with concentrated sulfuric acid (0.70 ml) and sodium nitrite (0.783 g, 11.3 mmol) dissolved in water (1.5 ml) and the mixture was left under stirring at 0° C. for 20 min. After that, concentrated sulfuric acid (0.2 ml) was added and the resulting mixture was poured onto a solution of potassium iodide (2.2 g) in water (2 ml) cooled at 0° C. Copper powder (11 mg) was added in a few minutes and the mixture was left at 75° C. for 2 h. After this time the mixture was left to cool at room temperature, then extracted with chloroform (3×50 ml), the organic phase was washed with a 5% sodium thiosulfate solution, dried and the solvent was evaporated off under reduced pressure. The resulting residue was purified by column chromatography eluting with petroleum ether:chloroform, 6:4, thereby recovering 1.95 g of title compound (69% yield).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[CH2:13]([N:20]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[N:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 52.4 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.081 g, 0.437 mmol) was reacted with benzyl azide (0.071 g, 0.533 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine hydrochloride (0.073 g, 53%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.93 (s, 1H), δ 7.37-7.27 (m, 5H), δ 6.63 (s, 2H), δ 6.44 (s, 1H), δ 2.61 (t, 2H), δ 2.40 (t, 2H), δ 1.82 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.5, 148.1, 147.4, 135.9, 129.4, 128.7, 128.5, 128.4, 122.8, 122.8, 115.9, 109.9, 53.3, 28.5, 25.0; HRMS (ESI) calcd for C15H18N6 (M+) 282.1665. found 282.1674.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1sc(-c2ccccc2)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 92 %

Procedure:
Intermediate 62 was prepared as described above for the preparation of intermediate 52. From 3.27 g of N-(Boc)-L-Tyrosine methyl ester and 2.43 g of Intermediate 9C was prepared 5.07 g of BOC-protected intermediate methyl ester (92% yield; 1H NMR (CDCl3, 300 MHz) δ7.89-7.86 (m, 2H), 7.42-7.38 (m, 3H), 7.01 (d, 2H, J=6.3), 6.94 (d, 2H, J=6.3), 5.11 (s, 2H), 4.94 (d, 1H, J=6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m, 2H), 2.90 (q, 2H, J=5.7), 1.39 (s, 9H), 1.30 (t, 3H, J=5.7); From 5.05 g of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 62 as in example 52. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 4.28 g of intermediate 62; 1H NMR (DMSO-d6, 400 MHz) δ7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H), 6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 3.05-3.02 (m, 1H), 2.91-2.81(m, 4H), 1.21 (t, 3H, J=7.4); low resolution MS (ES+)m/e 382.94 (MH+); TLC Rf=0.33 (4/1, DCM/MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].ClC(OCC)=O.Cl.[NH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[I:34])[C:29]#[N:30].Cl>CN(C)C=O.C(N(CC)CC)C>[I:34][C:33]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:14])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(I)c(OCCN)c1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(C(=O)NCCOc2cc(C#N)ccc2I)cc1
Reaction time: 0.08 h

Procedure:
600 mg (3.1 mmol) of 4-dimethylcarbamoylbenzoic acid and 1.25 g of triethylamine were stirred in dimethylformamide. 336 mg (3.1 mmol) of ethyl chloroformate was added to the resultant mixture, and they were stirred for 5 minutes. 3-(2-aminoethoxy)-4-iodobenzonitrile monohydrochloride was added to the mixture. The temperature was elevated to room temperature. After stirring for 2 hours, 1 N hydrochloric acid was added to the mixture. After extracting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl a solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with ethyl acetate to obtain the title compound. Further, the residue obtained after the evaporation of the solvent from the wash solution was purified by the silica gel chromatography (ethyl acetate/methanol) to obtain the title compound.
Reaction SMILES: [CH:1](OC)(OC)OC.[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([NH:22][NH2:23])[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:8][C:9]1[N:21]2[CH:1]=[N:23][N:22]=[C:20]2[CH:19]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH:10]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(NN)c1
Product: CC(C)(C)OC(=O)c1cc(Cl)n2cnnc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
Trimethyl orthoformate (100 mL, 903 mmol) was added neat to tert-butyl 2-chloro-6-hydrazinoisonicotinate (10.0 g, 41.0 mmol). The mixture was heated to 85° C. After 5 h, the mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (4.55 g): LC-MS [M+1]=254.1.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>O.C(O)C>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:25])=[O:24]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 67.8 g of N-acetyl-L-cysteine and 100.8 g of sodium bicarbonate in 300 ml of water is added to 55.4 ml of o-fluoronitrobenzene in 1 l of ethanol. The reaction is heated to reflux for 3 hr with mechanical stirring and allowed to cool to room temperature. After removing the solids by filtration, the solution is concentrated to one fourth of the original volume and diluted with 1 l of water. The aqueous suspension is washed with 200 ml of ether and acidified to pH 1 with 12N aqueous hydrochloric acid. The resulting yellow precipitate is collected by filtration and dried in vacuo at 70° C. over phosphoruos pentoxide to afford S-(o-nitrophenyl)-N-acetyl-L-cysteine; m.p. 175°-176° C.; [α]D =+87.8° (c=1.15, absolute ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:30]#[N:31])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(C#N)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
3-Bromo-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (Example 63, step 2) (214 mg, 0.445 mmol), zinc cyanide (26.1 mg, 0.222 mmol) and Pd(PPh3)4 (20.5 mg, 0.018 mmol) were dissolved in DMF (4 ml) and the vial flushed with nitrogen. The mixture was heated in the microwave at 150° C. for 10 mins, then cooled and diluted with EtOAc (30 ml). This was washed with a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography on a 4 g silica column using 0-50% EtOAC/hexanes as eluent gave the title compound.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:26][C:27]#[CH:28])[CH3:25]>N1CCCC1.C(Cl)Cl>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[C:27][CH2:26][N:24]([CH3:25])[CH3:23])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(Nc2ccc(I)cc2)nc1Nc1ccccc1
Reactant: C#CCN(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN(C)CC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A solution of 4-anilino-5-bromo-2-(4-iodoanilino)pyrimidine (Method 12; 200 mg, 0.40 mmol), N,N-dimethylpropargylamine (0.09 ml, 0.85 mmol) and tetrakis (triphenylphosphine)palladium (0) (25 mg, 0.02 mmol) in pyrrolidine (3 ml) was stirred for 60 hours and then heated at 80° C. for 2 hours. The mixture was diluted with DCM (10 ml) and silica (2 g) was added. Volatile material was removed by evaporation and the residue was loaded onto a Varian Mega Bond Elut column. Elution with 0–10% 2.0 M methanolic ammonia solution in DCM gave the product (30 mg, 17%). NMR: 2.2 (s, 6H), 3.4 (s, 2H), 7.2 (m, 3H), 7.4 (m, 2H), 7.6 (m, 4H), 8.2 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); MS (MH+): 422.3, 424.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2]>C1CCCCC=1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1CC
Yield: 69.6 %

Procedure:
A solution of cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7C) (18.0 g, 40 mmol) in 150 mL each of cyclohexene and ethanol was treated with 10% palladium on carbon (10.0 g, 50% water by weight). After heating at reflux for 1 h, the cooled mixture was filtered through Celite® and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 25-50% ethyl acetate/hexanes as eluent to afford 8.8 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.25 (m, 4H), 1.45 (m, 1H), 1.6 (m, 1H), 2.49 (m, 1H), 3.81 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 7.47 (m, 2H), 7.69 (s, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:4])=O.O=P(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1>[CH3:4][C:2]1[O:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:1]=1
Reactant: CCOC(=O)C(=O)NCC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(C)o1
Yield: 61.9 %

Procedure:
To a stirred solution of ethyl 2-(acetonylamino)-2-oxo-acetate (9.2 g, 53.12 mmol) in toluene (100.0 mL), is added POCl3 (4.95 mL, 53.12 mmol) and the reaction mixture is refluxed for 16 hours. The reaction mixture is cooled, added portionwise to water (100.0 mL) and stirred vigorously. The organic layer is washed with saturated NaHCO3 solution (2×50 mL), water (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (8.0:2.0) to give the title compound (5.1 g, 61.9%) as a yellow oil. ESI/MS m/z 156.2.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([O:8][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][N:4]([CH3:19])[C:3]1=[O:20].Cl>CCO>[OH:8][CH:6]1[CH2:5][N:4]([CH3:19])[C:3](=[O:20])[N:2]([CH3:1])[CH2:7]1
Reactant: CC(C)[Si](OC1CN(C)C(=O)N(C)C1)(C(C)C)C(C)C
Agent: Cl
Solvent: CCO
Product: CN1CC(O)CN(C)C1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 1,3-dimethyl-5-triisopropylsilanyloxy-tetrahydro-pyrimidin-2-one (Step P8) (9.1 g, 28 mmol) in EtOH (70 mL) was added a 1M HCl (140 mL, 140 mmol) and the mixture was stirred for 3 h at 70° C. The mixture was concentrated, and the pH of the resulting aqueous phase was adjusted to 5 with a saturated aqueous NaHCO3 solution. The aqueous layer was saturated with NaCl and was extracted with CH2Cl2/isopropanol 3:1. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: tR=0.33 min, [M+H]+ 145.1 (LC-MS 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][CH2:10][C:11]1[C:12]([CH3:26])=[CH:13][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:15][C:16]=1[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:9][CH2:10][C:11]2[C:12]([CH3:26])=[CH:13][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:15][C:16]=2[CH3:17])=[O:8])=[CH:2]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cc[nH]c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 1H-pyrrole-3-carboxylic acid (1.40 g, 12.60 mmol), tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (3.48 g, 13.86 mmol) and DIPEA (6.60 ml, 37.8 mmol) in DCM (100 ml) was added HBTU (5.73 g, 15.12 mmol) at rt and was stirred at rt for 12 hours. The suspension was filtered off. The solid was washed with DCM and dried under reduced pressure to afford pure tert-butyl 5-((1H-pyrrole-3-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate. HPLC (Method G) Rt=1.35 min; MS [M+H]+=345.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:28])=[C:9]([CH:27]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1)=[O:11])([CH3:4])[CH3:3].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:28][C:35]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:36])=[C:9]([CH:27]=1)[C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)=[O:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)(C)c1ccc(OC(=O)N2CCOCC2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 95 %

Procedure:
Using 5-[(1,1-dimethyl)ethyl]-2-hydroxy-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCN(C(=O)c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 81.6 %

Procedure:
The title compound was prepared as described in Example 24.A, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol) and 4-fluorobenzoyl chloride (0.475 g, 3.0 mmol) to provide the title compound (0.786 g, 82% yield): ES−MS (m/z) 482 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=O)=O.[Br-:24].[Li+]>CC(C)=O>[CH2:6]([Br:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reaction time: 48 h
Yield: 117.2 %

Procedure:
A mixture of linoleyl methane sulfonate (26.6 g, 77.2 mmol) and lithium bromide (30.5 g, 350 mmol) in acetone (350 mL) was stirred under nitrogen for two days. The resulting suspension was filtered and the solid washed with acetone. The filtrate and wash were combined and solvent evaporated. The resulting residual was treated with water (300 mL). The aqueous phase was extracted with ether (3×150 mL). The combined ether phase was washed with water (200 mL), brine (200 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to afford 29.8 g of yellowish oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 700 mL) eluted with hexanes. This gave 20.8 g (82%) of linoleyl bromide (II).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[C:11]4[S:18][CH:19]([CH3:22])[C:20](=O)[C:9]([C:10]=34)=[C:8]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>ClCCCl.C(Cl)Cl.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[C:11]4[S:18][CH:19]([CH3:22])[CH2:20][C:9]([C:10]=34)=[C:8]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c2c3c(c(OC)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2=O
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)Cc1c2c3c(c(OC)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2

Procedure:
To a suspension of product from Step 2 (886 mg) in 1,2-dichloroethane (16 mL) there was added ZnI2 (960 mg) and NaCNBH3 (440 mg). The mixture was heated to 60° for 1 hour, cooled, diluted with CH2Cl2, washed 3× with H2O, dried over Na2SO4, filtered and evaporated to afford the title product as an oil which slowly solidified. It was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Solvent: c1ccncc1
Product: O=S(=O)(N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in pyridine (1.0 mL) at 20 C was treated with 4-chlorobenzenesulfonyl chloride (15 mg, 0.07 mmol). The reaction was shaken at room temperature for 18 hours then concentrated. The crude compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 450 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.88 (d, 1 H), 8.71 (d, 1 H), 8.53 (d, 1 H), 7.93 (d, 1 H), 7.87 (d, 2 H), 7.81 (dd, 1 H), 7.70 (d, 3 H), 6.95 (d, 1 H), 3.86 (br.s, 1 H), 3.14 (m, 1 H), 1.89 (m, 2 H), 1.74 (m, 4 H), 1.58 (m, 2 H).
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C@@H:12]1[CH3:38])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:29]([O:28][C:26](=[O:27])[N:25]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@H:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[NH:11][C@@H:12]([CH3:38])[CH2:13]1)[CH3:30]
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2cc(OC)c(OC)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Yield: 90.4 %

Procedure:
A solution of cis-4-(benzyl-ethoxycarbonyl-amino)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (Example 4) (1.0 g, 1.9 mmol) in ethanol (20 mL) was placed in a Parr bottle, charged with 10% palladium on carbon (100 mg), and agitated under 50 psi of hydrogen gas on a Parr shaker for 2 h. The mixture was then filtered through a bed of Celite®, eluting with ethyl acetate, and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography using 30% ethyl acetate/hexanes as eluent to afford 660 mg of the desired final product (89%): MS m/z 204 (M+−PhCH2NHCO2Et−H2+1); 1H NMR (CDCl3) δ1.12 (d, 3H), 1.17 (t, 3H), 3.65 (s, 3H), 3.8 (s, 3H), 6.10 (C5, s, 1H), 6.44 (C8, s, 1H), 7.1-7.3 (m, 5H).