Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[NH:8][CH:7]=1)[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH:8]1[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:6]([CH2:2][CH2:3][NH2:5])=[CH:7]1
Reactant: NC(=O)C(=O)c1c[nH]c2ccncc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCc1c[nH]c2ccncc12
Temperature: 0 °C

Procedure:
A solution of 2-oxo-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)-acetamide (1 eq.) in ether is treated with lithium aluminum hydride (4 eq.), refluxed for 8 h, cooled to 0° C. and quenched by addition of Rochelle's salt solution. The reaction mixture is extracted with CH2Cl2. The extracts are combined dried over MgSO4 and concentrated in vacuo to give the title amine product, which is used as is in step 9, below.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[CH:6]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[CH:6]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Reaction time: 1 h
Yield: 121.1 %

Procedure:
To a stirring solution of the above benzofuran (5.00 g, 28.25 mmol) and benzoyl peroxide (0.68 g, 2.83 mmol) in carbon tetrachloride (200 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (4.04 g, 14.12 mmol). The mixture was irradiated with a 200 watt lamp while stirring for 1 hour, cooled and partitioned between dichloromethane/water. The organic phase was washed with water (2×100 mL) and brine (2×100 mL), dried (MgSO4), decolorized (charcoal), and concentrated in vacuo to afford 7.12 g of crude product. Recrystallization from ethyl acetate/hexane afforded 4.38 g (61%) of 2-bromomethyl-5-nitro-benzofuran as an off-white solid: 1H NMR (CDCl3): δ 8.49 (d, 1H), 8.25 (dd, 1H), 7.58 (d, 1H), 6.91 (s, 1H), 4.59 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1C=CC(O)=[CH:6][CH:5]=1.[NH2:14][C@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)C.N[C@H](C(O)=O)CC(C)C.NCC(O)=O>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:14]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCC(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Tyr.Arg.Arg.Ala.Ser.Leu.Gly SEQ ID NO: 7
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:19])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:1]/[N:2]=[C:3](\[NH2:19])/[CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)=[O:26])=[CH:23][CH:22]=1
Reactant: NC(CCCOc1ccc2c(c1)CCC(=O)N2)=NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N/C(CCCOc1ccc2c(c1)CCC(=O)N2)=N\OC(=O)c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 22.9 %

Procedure:
To a stirred solution of N′-hydroxy-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.100 g, 0.37 mmol) in dry toluene (2 mL) at room temperature, p-chlorobenzoyl chloride (0.066 g, 0.37 mmol) and potassium carbonate (0.061 g) were added. The reaction mixture was heated to 110° C. overnight in a sealed tube. Solids were filtered, then water was added to the filtrate and stirred for few minutes. The solid precipitate which formed was filtered and dried to yield (Z)—N′-((4-chlorobenzoyl)oxy)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.034 g; 22%). 1H NMR: 400 MHZ, DMSO-d6: δ 2.00 (t, J=6.80 Hz, 2H), 2.29 (t, J=7.60 Hz, 2H), 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=7.60 Hz, 2H), 3.97 (t, J=6.40 Hz, 2H), 6.60 (s, 2H), 6.76 (s, 2H), 6.82 (s, 1H), 7.58 (d, J=8.40 Hz, 2H), 8.13 (d, J=8.40 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Na].Cl.Cl[CH2:15][C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]>C(O)CC>[OH:10][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:15]=1[C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCOC(=N)CCl
Agent: Cl
Agent: [Na]
Solvent: CCCO
Product: CCCOC(=N)c1sc2ccccc2c1O
Yield: 26.3 %

Procedure:
16.8 g (0.1 mol) of methyl thiosalicylate are added dropwise to a solution of 4.6 g (0.2 mol) of sodium in 400 ml of anhydrous n-propanol. To this mixture 17.2 g (0.1 mol) of propyl chloroacetimidate hydrochloride are slowly added and the resultant mixture is heated under reflux for 6 hours. The reaction mixture is evaporated under vacuum and the residue distributed between water and dichloromethane. The organic phase is dried, evaporated, and the residue recrystallized from ethyl acetate/diisopropylether solution to yield 6.2 g of yellow crystals with an m.p. of 185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([N:25](C)[C:26](=O)C(F)(F)F)=[C:23]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([NH:25][CH3:26])=[C:23]([C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CN(C(=O)C(F)(F)F)c1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
A solution of the product from Step A (0.0703 mmol) in methanol (2 mL) and water (0.1 mL) was treated with potassium carbonate (0.049 g; 0.351 mmol) at room temperature. The reaction mixture was stirred a room temperature until the reaction was judged complete by TLC analysis. The reaction mixture was then partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 487.0 (M+1), 489.0 (M+3); Rt=5.03 min.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([NH:6][C:5]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:4]=1[C:1](=[O:3])[CH3:2])=[O:21]
Reactant: O=C(Cl)c1ccco1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Product: COc1cc(NC(=O)c2ccco2)c(C(C)=O)cc1OC
Yield: 99 %

Procedure:
2-Acetyl-4,5-dimethoxyaniline (300 mg) and 2-furoyl chloride (260 mg) were reacted in the same manner as in the preparation of compound 95 to obtain N-(2-furoyl)-2-acetyl-4,5-dimethoxyaniline (440 mg). The compound (380 mg) and potassium t-butoxide (740 mg) were reacted in the same manner as in the preparation of compound 95 to obtain 6,7-dimethoxy-2-(2-furyl)-4(1H)-quinolone (compound 94, 30 mg).
Reaction SMILES: [ClH:1].[C:2]([Cl:6])(=[O:5])[CH:3]=[CH2:4]>>[Cl:1][CH2:4][CH2:3][C:2]([Cl:6])=[O:5].[C:2]([Cl:6])(=[O:5])[CH:3]=[CH2:4]
Reactant: Cl
Agent: C=CC(=O)Cl
Product: O=C(Cl)CCCl

Procedure:
25 g (about 0.7 mol) of gaseous hydrogen chloride are introduced into 45 g (0.5 mol) of acrylic acid chloride at 50° C for a period of 6 hours. The batch is allowed to stand over night. Thereafter it is distilled at about 20 torrs. 3 g (4.7% of the theory) of β-chloropropionic acid chloride and 39 g (87% of the theory) of acrylic acid chloride are obtained, the latter being condensed in a recipient cooled with dry ice.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH:28]([N:41]1[C:49]2[C:44](=[CH:45][C:46](Cl)=[CH:47][CH:48]=2)[C:43]([CH2:51][CH2:52][O:53][C:54]2[CH:62]=[CH:61][C:57]([C:58]([OH:60])=[O:59])=[CH:56][CH:55]=2)=[C:42]1[CH2:63][CH2:64][NH:65][S:66]([CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)(=[O:68])=[O:67])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:28]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[CH:47][CH:48]=2)[C:43]([CH2:51][CH2:52][O:53][C:54]2[CH:62]=[CH:61][C:57]([C:58]([OH:60])=[O:59])=[CH:56][CH:55]=2)=[C:42]1[CH2:63][CH2:64][NH:65][S:66]([CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)(=[O:68])=[O:67])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(N4CCOCC4)cc23)cc1
Yield: 7.8 %

Procedure:
Step 1—A flask was charged with tris(dibenzylideneacetone)dipalladium(0) (0.01 eq.), 2-(di-t-butylphosphino)biphenyl (0.04 eq.), sodium t-butoxide (2.4 eq.) and the acid from Example 1 step 8 (1.0 eq.). 1.5 ml toluene (1.0 M) was added to the flask followed by morpholine (1.2 eq.) The reaction was heated to reflux for five hours. The reaction mixture was partitioned between 5% hydrochloric acid and dietheyl ether. The organic layer was washed with distilled water, followed by brine, dried over sodium sulfate and concentrated. The product was purified by preparatory LC-MS to afford 7.8% of the desired product. HRMS calc for [C43H43N3O6S+H] 730.2945 found 730.2945.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][C:12](=[CH2:15])[CH2:13]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:13][C:12]([CH3:15])=[CH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: C=C(C)CCl
Product: C=C(C)COC1CCN(C(C)=O)CC1

Procedure:
This compound was prepared similarly to Preparation 4(A), starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride, and was distilled and used directly in the next stage. It had a b.p. of 128° at 1 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH:35][CH2:36][C@H:37]1[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[O:35][CH2:36][C@@H:37]4[CH2:38][CH2:39][C:40](=[O:42])[NH:41]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC[C@@H]1CCC(=O)N1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5S)-5-(hydroxymethyl)tetrahydro-1H-2-pyrrolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give [(2S)-5-oxotetrahydro-1H-2-pyrrolyl]methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (10 mg, 0.02lmmol). 1H NMR (CDCl-d) δ 1.90(m, 1H), 2.06(m, 4H), 2.34(m, 1H), 2.41(m, 2H), 3.64(m, 2H), 3.94 (s, 3H), 4.04(m, 2H), 4.14(m, 2H), 4.98(m, 1H), 5.33(m, 3H), 6.10(s, 1H), 6.98(s, 1H), 7.04 (s, 1H), 7.09(m, 1H), 7.31(s, 1H), 8.11(bs, 1H), 8.32(s, 1H). LC/MS: MH+481.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.CC(OC([N:24](C(OC(C)(C)C)=O)[C:25]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[N:26]=1)=O)(C)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.Cl>CO.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:2]3[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([N:9]([CH3:16])[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=3)=[CH:31][CH:32]=2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CN(c1ccccc1)c1cc(Cl)nc(N)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CN(c1ccccc1)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a 5-mL microwave vial was added 6-chloro-N4-methyl-N4-phenyl-2,4-pyrimidinediamine (61 mg, 0.260 mmol), 1,1-dimethylethyl 3-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (218 mg, 0.390 mmol), K2CO3 (0.130 mL, 0.260 mmol), PdCl2(dppf).CH2Cl2 adduct (212 mg, 0.260 mmol) and 1,4-dioxane (3 mL). The vial was capped and stirred for 10 minutes at 150° C. in a microwave reactor. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (50 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organics were dried with Na2SO4, then filtered. The filtrate was concentrated, and dissolved in dioxane (10 mL) and CH3OH (1 mL), and HCl (0.5 mL, 2 mmol) in dioxane was added. The reaction was stirred overnight at 40° C. At this time, LCMS analysis indicated complete conversion to the desired product. The reaction mixture was concentrated, and the residue was dissolved in DMSO and purified by RP-HPLC (15-35% CH3CN in H2O; 0.1% TFA). The fractions containing the product were combined, concentrated to remove the CH3CN, basified (NaHCO3, pH paper) and extracted into EtOAc. The organic layer was dried and concentrated to afford the title compound as a yellow solid (19 mg). LC-MS (ES) m/z=332 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.46 (s, 3H), 5.38-5.52 (m, 2H), 5.94-6.15 (m, 1H), 6.25-7.00 (bs, 1H), 7.12-7.27 (m, 1H), 7.34-7.46 (m, 4H), 7.47-7.57 (m, 2H), 7.58-7.66 (m, 1H), 7.67-7.78 (m, 1H), 11.40-11.77 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][C:11](OCC)=[O:12])[C:6]=2[CH:16]=1.[BH4-].[Li+]>O1CCCC1.CO.C(Cl)Cl.O.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)Cc1nsc2ccc(N)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2snc(CCO)c2c1
Temperature: -8 °C
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 5-amino-1,2-benzisothiazole-3-acetate (3.14 g, 0.0133 mol) in tetrahydrofuran is cooled to -8° C., treated dropwise with a 2 M solution of lithium borohydride in tetrahydrofuran (5.00 mL, 0.0100 mol), stirred at room temperature for 3.5 hours, cooled to -5° C., treated with additional lithium borohydride solution (4.20 mL, 0.0084 mol), stirred at room temperature overnight, cooled to 0° C., quenched sequentially with water (5.00 mL) and 10% hydrochloric acid (10.0 mL), stirred at room temperature for one hour, neutralized with saturated sodium hydrogen carbonate solution (10.0 mL), and concentrated in vacuo to obtain a residue. The residue is diluted with a 5% methanol in methylene chloride solution. The resultant mixture is diluted with water, brine and methylene chloride. The phases are separated and the organic phase is concentrated in vacuo to obtain an orange gum. The gum is crystallized from methanol to give the title product as a tan solid which is identified by NMR spectral analysis.
Reaction SMILES: O=[C:2]1[CH:10]2[CH2:11][C:6]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[NH:3]1)[CH2:9]2.CO>C1COCC1>[C:6]12([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:12][CH:4]([NH:3][CH2:2]3)[CH2:5]1)[CH2:7]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)NC(=O)C(C3)C2
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CC3CNC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A 1.0 M solution of BH3-Me2S in THF (1 5 mmol) was added dropwise to a solution of amide 14B (0.125 mmol) in THF (5 mL). The reaction mixture was heated at reflux for 2 h and was allowed to cool to rt. MeOH (2 mL) was cautiously added and the reaction mixture was concentrated. The residue was triturated with DCM (3×10 mL) and the combined organic layers were dried (Na2SO4) and concentrated to provide amine 15A. The amine was used in the next step without further purification. Data: LC/MS (ESR) m/z 167 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[C:40]#[CH:41].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:41]#[C:40][C:31]3[CH:32]=[CH:33][C:34]([C:36]([F:37])([F:38])[F:39])=[CH:35][C:30]=3[Cl:29])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(C(F)(F)F)cc4Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 43.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.060 g, 0.117 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.037 g, 0.175 mmol), TBAF (0.073 g, 0.234 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66-0.69 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=6.0 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.62-7.64 (m, 2H), 7.73 (d, J=11.4 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.92-7.97 (m, 2H), 8.09 (s, 1H), 8.69 (m, 1H), 12.00 (br s, 1H); MS (m/z): 589.14 (M+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=2)[CH:23]=[C:24]([O:26][CH2:39][C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (0.400 g, 0.78 mmol) in acetonitrile (3 mL) at room temperature was added 1-bromomethyl-3,5-difluoro-benzene (0.243 g, 1.17 mmol) and Cs2CO3 (0.508 g, 1.56 mmol). The resulting white suspension was stirred for 1 h. The white solid was filtered off and the solvent was removed in vacuo to obtain relatively pure 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(N)=O)ccc2c1=O
Yield: 69.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.17 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.81 g, 69.8%) as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccncc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(-c3ccncc3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of tert-butyl 9-(pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (109 mg, 0.334 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give the desired product (19.0 mg, 19.0%) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][CH:15]1[O:12][C:8]2=[CH:7][C:6]3[CH2:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=3[CH:10]=[C:9]2[CH2:16]1
Reactant: CCN1C(=O)Cc2cc(O)ccc21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)Cc2cc3c(cc21)CC(C)O3
Yield: 45 %

Procedure:
A mixture of 17.7 g. (0.1 mole) of 1-ethyl-5-hydroxyoxindole, 8.66 ml. (0.1 mole) of allyl bromide and 13.8 g. (0.1 mole) of potassium carbonate in 500 ml. of acetone was heated at reflux for 3 hours. The reaction was cooled, filtered and concentrated. The residue was purified by chromatographing on 550 g. of silica gel using diethyl ether-hexane (1:1, v:v) as the eluent to give 9.8 g. (45% yield) of the desired compound.