Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
4-(Diphenylmethoxy)-1-(ethoxycarbonyl)piperidine (4a) (11.45 g, 33.7 mmol) was dissolved in ethanol (72 mL). A cold solution of sodium hydroxide (8.2 g, 205 mmol) in water (12 mL) was added slowly and a small amount of heat was detected. The mixture was heated at reflux for 17 h and then cooled to room temperature. The mixture was subsequently diluted with water (100 mL) and ethyl acetate (100 mL) and stirred for 0.5 h to dissolve the resultant solid. The organic and aqueous layers were separated and the organic layer was washed with water (100 mL). The separate aqueous layers were extracted with ethyl acetate (100 mL) and the organic layers were combined, dried with Na2SO4, filtered and concentrated to yield 7.88 g (87.5%) of 5 as a viscous yellow oil. The structure was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=O.[F:23][C:24]([F:32])([F:31])[C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:22][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:27]([CH3:28])[C:26]=2[C:25](=[O:30])[C:24]([F:32])([F:31])[F:23])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(F)c(F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(F)c(F)c2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3,4-difluoro-phenyl)-methanone [example A12] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 36%; MS: m/z=435 (M).
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([NH:36][C:37]([NH:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: CC[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride monoethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 1.37 mL (12.6 mMol) phenyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.40 gm (70%) N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea. This material was dissolved in methanol and to it was added an equivalent of methanolic hydrogen chloride. The solution was then concentrated under reduced pressure and the residual oil crystallized from ethanol to give the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[N:13]=[C:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:48]=[CH:49][CH:50]=2)[C:22]([NH:24][C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:26]=2[O:44][CH2:45][CH2:46][NH2:47])=[O:23])[S:15][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[OH2:3].[C:8]([C:12]1[N:13]=[C:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:48]=[CH:49][CH:50]=2)[C:22]([NH:24][C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[CH:28]=[CH:27][C:26]=2[O:44][CH2:45][CH2:46][NH:47][C:1](=[O:3])[CH3:2])=[O:23])[S:15][CH:16]=1)([CH3:11])([CH3:9])[CH3:10].[C:8]([C:12]1[N:13]=[C:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:48]=[CH:49][CH:50]=2)[C:22]([NH:24][C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[CH:28]=[CH:27][C:26]=2[O:44][CH2:45][CH2:46][NH:47][C:1](=[O:3])[CH3:2])=[O:23])[S:15][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCCN)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCOc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Product: O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Under ice-cooling, acetic anhydride (30 μl, 0.3 mmol) was added to a mixture of 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-(2-aminoethoxy)benzanilide 1.4 hydrochloride.0.7 hydrate (170 mg, 0.24 mmol), dichloromethane (2 ml) and pyridine (32 μl, 0.4 mmol), and the resulting mixture was stirred at room temperature for 3 hours. Ice-water was added to the reaction solution and the mixture was stirred for 1 hour. The product formed was extracted with chloroform and the resulting organic layer was washed with 20% potassium hydrogensulfate aqueous solution, saturated sodium bicarbonate aqueous solution and distilled water in that order, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was crystallized from chloroform-ether to give 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-(2-acetylaminoethoxy)benzanilide hemihydrate (97 mg, 0.14 mmol, 58%) as white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([C:21]3[N:20]=[C:19]([C:11]4[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[C:9]([Cl:8])[CH:10]=4)[O:23][N:22]=3)[C:25]=2[CH3:34])[CH2:30]1)[CH3:47]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Reaction time: 0.58 h
Yield: 88.7 %

Procedure:
To a suspension of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (Example 10; 90 mg; 0.18 mmol) in DMF (3 ml) under nitrogen at room temperature was added caesium carbonate (177 mg; 0.54 mmol) followed by ethyl bromoacetate (0.026 ml; 0.23 mmol). After 35 min, the mixture was diluted with ethyl acetate and the precipitate removed. The solution was washed with water and the aqueous layer further extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (75 mg).
Reaction SMILES: [C:1]([NH:4][CH:5](Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C[NH2:13].O1[CH2:18][CH2:17]CC1>>[CH3:17][CH2:18][NH:13][CH:5]([NH:4][C:1]([CH3:2])=[O:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Br)NC(C)=O
Reactant: CN
Reactant: C1CCOC1
Product: CCNC(NC(C)=O)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A cold (-78° C.) solution of ethyl 2-acetamido-2-bromoacetate (2.10 g, 9.38 mmol) in dry tetrahydrofuran (80 mL) was added slowly into a cooled (-78° C.) tetrahydrofuran (20 mL) solution of methylamine (1.40 g, 31.04 mmol) over a period of 20 min. The reaction was stirred at -78° C. (1 h), and then at room temperature (1 h). The precipitated salt was filtered and the filtrate concentrated. The residue was purified by flash column chromatography on SiO2 using 3% methanol/chloroform as the eluent to yield the desired compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.C([Li])CCC.[C:26]1([P:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[Li+]>O1CCCC1.CCCCCC>[C:17]([C:4]1[CH:3]=[C:2]([P:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A stirred suspension of 20.0 g (56 mmol) of 4-bromo-2,6-di-tert-butylphenoxy(trimethyl)silane in 80 ml of dry tetrahydrofuran at -78° C. is admixed dropwise with 38 ml (56 mmol) of a 1.55M solution of n-butyllithium in hexane. The resulting homogeneous solution is stirred for 1 hour at -78° C. and then 12.36 g (56 mmol) of diphenylchlorophosphine is added dropwise. The reaction mixture is stirred for 24 hours at room temperature, and then the suspension of lithium chloride is removed by filtration. The solvent is removed in vacuo. The residue is dissolved in 250 ml of diethyl ether and extracted (3×250 ml) with water. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo to give 27.8 grams of a yellow liquid. The crude product is purified by preparative HPLC (silica gel, 99:1 heptane:ethyl acetate eluent) to give 10.7 grams (41%) of a white solid, m.p. 76°-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:37])([F:36])[F:35])[CH:12]=1.C1(N(C2CCCCC2)C)CCCCC1.O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:6]([O:5][C:1](=[O:4])[CH:2]=[CH:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:35])([F:36])[F:37])[CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(Br)cc3OC(F)(F)F)cc21
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(C=CC(=O)OC(C)(C)C)cc3OC(F)(F)F)cc21
Temperature: 80 °C

Procedure:
A sealed tube was charged with Pd[P(tBu)3]2 (4 mg, 0.0075 mmol), tert-butyl acrylate (0.03 mL, 0.18 mmol) and Compound 5B (68 mg, 0.15 mmol) in 1 mL of dry dioxane. To this was added dicyclohexyl methyl amine (0.04 mL, 0.18 mmol) and the tube was sealed and heated to 80° C. overnight. After the reaction was cooled, 3 mL of water was added and the solution was passed through a 5 mL solid phase extraction (SPE) column. The SPE was washed with dichloromethane and the collected eluant was stripped on the roto yap to give crude product Compound 5C which was further purified by flash chromatography (25% EtOAc/Hexane) to yield 45 mg (60%) of product. MS (electrospray): mass calculated for C28H32F3NO4, 503.23; m/z found 504.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-].[CH2:40]1COCC1>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:13][CH3:14])[C:3]([CH2:1][CH2:2][CH3:40])=[N:4][C:5]([OH:17])=[C:6]2[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: C1CCOC1
Reactant: COCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCOC)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (215 mg, 0.92 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 3-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride SLA 47064B (292 mg, 0.92 mmol) and a 2 N aq. LiOH solution (0.92 mL, 1.84 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 50:50:0.05) followed by a new purification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 66:34:0.05) gave 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol (mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 77 as a brown solid (61 mg, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (171 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661 (M, M+2)+.
Reaction SMILES: [CH:1](/OC1C=CC=CC=1C1(CNC(=O)CCC)CC1)=[CH:2]\[CH3:3].[OH:21][C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][C@H:29]2[CH2:31][NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:25]=[CH:26][CH:27]=1.[OH-].[K+].C(I)C=C>C(O)C.CCOCC>[CH2:3]([O:21][C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][C@H:29]2[CH2:31][NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:25]=[CH:26][CH:27]=1)[CH:2]=[CH2:1]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Reactant: C/C=C/Oc1ccccc1C1(CNC(=O)CCC)CC1
Agent: C=CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 34 %

Procedure:
(trans)-N-[[(2-Propen-1-yloxyphenyl)cyclopropyl]methyl]butanamide: To a rapidly stirred solution of (trans)-N-[[2-(3 hydroxyphenyl)cyclopropyl]methyl]butanamide (0.8 g, 3.4 mmol) and KOH (210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg, 3.7 mmol). After stirring for 18 h, the suspension was diluted with Et2O (100 mL), and washed with H2O, 2N NaOH, brine, dried (K2CO3), and concentrated to a give a crude residue. The resulting material was purified by chromatography (silica gel, 40% EtOAc/hexane) to afford 320 mg (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 0.70-0.94 (m, 5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H), 3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607, 1548, 1494 cm-1 ; MS m/e 273; Analysis calc'd for C17H23NO2 0.20(H2O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]2[CH2:24][N:23]([CH3:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20]2)[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].OC1C=CC(C(OC)=O)=C(Cl)C=1>CN(C)C=O.COCCOC>[Cl:7][C:8]1[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]2[CH2:24][N:23]([CH3:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20]2)[CH:14]=[CH:13][C:9]=1[C:10]([Cl:4])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C[C@@H](COc2ccc(C(=O)O)c(Cl)c2)Oc2ccccc21
Agent: COC(=O)c1ccc(O)cc1Cl
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CN1C[C@@H](COc2ccc(C(=O)Cl)c(Cl)c2)Oc2ccccc21

Procedure:
Under argon atmosphere, oxalylchloride (0.3 mL) and N,N-dimethylformamide (1 drop) were added to a solution (4.5 mL) of 2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoic acid (488 mg: the compound produced by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2-chlorobenzoate instead of the compound produced in Example 3.) in 1,2-dimethoxyethane, which was stirred for 1 hour at 40° C. The title compound was obtained by concentrating the reaction mixture.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:59]1([CH2:65][CH2:66]O)[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][CH2:65][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CCN2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), 2-morpholin-4-ylethanol (0.51 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.34 g, 100%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[CH3:17]O>>[ClH:3].[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([O:11][CH3:17])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1N
Product: COC(=O)c1ccc(OC)c(N)c1
Product: Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Thionyl chloride (8.7 mL) is added dropwise to methanol (90 mL) at −30° C. under argon gas atmosphere over a period of 15 minutes and a mixture is stirred at −20° C. for 30 minutes. To the mixture is added 3-amino-4-methoxybenzoic acid (5.0 g) and the solution is stirred at the same temperature for 15 minutes and at room temperature for 3 days. The reaction mixture is concentrated in vacuo and the resultant crystals are washed with methanol/ether to give methyl 3-amino-4-methoxybenzoate hydrochloride (6.25 g, yield; 96%) as colorless crystals. M.p. 213-215° C., MS (APCI) m/z: 182 [M+H]+
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH:25]1(N=C=NC2CCCCC2)CCCC[CH2:26]1>C(Cl)Cl.CN(C=O)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:24]([NH-:19])[C:23]1[CH:26]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: c1ccncc1
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [NH-]Cc1ccccc1

Procedure:
When 5 is stirred with Z-Val-OH and pyridine in methylene chloride (24 hours, 20° C.), the carbonyl band at 1,888 cm-1 disappears and the polymeric activated ester 6a forms. A resin which has an identical IR spectrum can also be obtained by reacting 4 with Z-Val-OH and dicyclohexylcarbodiimide (DCC) in DMF. The dicyclohexylurea is removed by eluting with methanol. In order to determine the content of activated aminoacid ester, the resin 6a was reacted with benzylamine. From the amount of Z-L-Val-benzylamide formed, the proportion of active groups introduced is 0.15 mmole of Z-Val/g of resin. If the resin is reacted with Val-OMe in methylene chloride for 130 minutes at 20° C., the Z-dipeptide ester is again formed in a yield of 0.15 mmole/g of resin.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:3].[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:19](O)C>>[NH2:3][C:2]1[N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[N:18][C:4]=1[C:5]([O:7][CH2:8][CH3:19])=[O:6]
Reactant: COC(=O)CC#N
Reactant: CCO
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Na]
Product: CCOC(=O)c1nnn(Cc2ccccc2)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 1.15 g (0.05 mol) of sodium in 80 mL of absolute ethanol was added 4.5 mL of methyl cyanoacetate and 6.5 g (0.05 mol) of benzyl azide. A white precipitate formed immediately, and the resulting mixture was stirred overnight. The yellowish creamy mixture was poured into 500 mL of ice water, and a crude yellow precipitate was collected by filtration. Recrystallization from ethanol afforded the title compound as a pale yellow solid (5.0 g, 42%). m.p. 153° C.