Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:32]1([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:15])=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(COCC(=O)N(c1ccccc1)C1CCCCC1)Nc1ccc(Cl)cc1C(=O)O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
1.21 g (4.0 mmol) of (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i), 32 mg (0.44 mmol) of DMF, and 0.41 mL (4.8 mmol) of oxalyl chloride were added to 12 mL of THF, and stirring was conducted at 0° C. for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and dried. 0.84 g (4.8 mmol) of N-cyclohexylaniline and 8.4 mL of DMA were added to this residue and stirred at room temperature overnight. After completion of the reaction, an aqueous sodium bicarbonate solution was added, extraction was carried out using ethyl acetate, and washing was conducted with a saturated sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography, thereby giving 1.77 g of 5-chloro-2-[((2-[cyclohexyl(phenyl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:52])([F:51])[C:40]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:41]=1[NH2:42]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([NH:42][C:41]2[CH:43]=[C:44]([C:47]([F:48])([F:49])[F:50])[CH:45]=[CH:46][C:40]=2[C:39]([F:38])([F:51])[F:52])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 43, step (a)) and 2,5-bis-trifluoromethyl-aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].Cl.[I:13]Cl>O>[I:13][C:9]1[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]([NH:2][CH3:1])=[CH:11][CH:10]=1
Reactant: ClI
Reactant: CNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Product: CNc1ccc(I)cc1C(=O)O
Reaction time: 2 h
Yield: 94626.9 %

Procedure:
In a 1 L beaker was placed 40 grams (0.267 mmol) of N-methylanthranilic acid dissolved in 300 mL water and 26.7 mL conc. HCl cooled to 20° C. A solution of ICL, prepared by dissolving 44 grams of ICl to a cooled (0° C.) solution of 167 mL water and 45 ml conc. HCl, was rapidly added to the stirred N-methylanthranilc acid solution. The reaction was allowed to stir for 2 hrs, filtered on a medium glass frit funnel, washing the solids with water. The green powder isolated was dried under vacuum to yield 70 grams (96%) of 5-iodo-N-methylanthranilic acid. 1H NMR (DMSO-d6) 7.61 (1H, bs, C6-H), 7.21 (1H, bd, 3JHH =8 Hz, C4-H), 6.19 (1H, d, 3JHH =8 Hz, C3-H), 2.43 (3H, s, NCH3); 13C NMR (DMSO-d6) 169.0, 151.4, 142.7, 139.6, 114.2, 112.7, 74.2, 29.6.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH2:11]([SH:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([S:13][CH2:11][CH3:12])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.0 g of 4-chloro-2-fluorobenzaldehyde, 2.05 ml of ethanethiol, 3.82 g of potassium carbonate and 6 ml of DMF was stirred at room temperature for 6 hours, and was allowed to stand overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.57 g of 4-chloro-2-ethylsulfanylbenzaldehyde. 4-Chloro-2-ethylsulfanylbenzaldehyde
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([CH2:17][O:18][CH3:19])[CH:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:17][O:18][CH3:19])[CH:8]=2)=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COCc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-(methoxymethyl)benzoate (Preparation 34, 0.140 g, 0.000374 mol) in tetrahydrofuran (3.00 mL) and water (3.00 mL) was added lithium hydroxide (0.050 g, 0.00209 mol) and the reaction stirred at room temperature under nitrogen for 2 hours. Then more lithium hydroxide (0.500 g, 0.0209 mol) was added and the reaction stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL) and washed with water (10.0 mL). The organic layer was separated, dried with sodium sulphate, filtered and concentrated in vacuo to yield title compound as a pale yellow foam (0.134 g, 0.000374 mol, 99% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58]([CH2:61]CO)=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58]([CH2:61][CH2:20][Br:24])=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84 %

Procedure:
Triphenylphosphine (0.13 g) and carbon tetrabromide (0.16 g) were added to a methylene chloride (3.4 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate (0.17 g), followed by stirring at room temperature for 50 minutes. The reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] and then purified by silica gel column chromatography [eluent: 100-85% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethyl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=3[F:26])=[C:14]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:13]=2)[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([CH:40]=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C=O)C.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].O>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:14]1[N:13]=[C:12]([CH2:11][O:10][C:6]2[N:5]=[CH:4][N:3]=[C:2](/[CH:40]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:7]=2[O:8][CH3:9])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[F:26]
Reactant: CCOC(=O)C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3OC)nc2CC(C)(C)C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To a solution of 4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidine (1.20 g) in DMF (10 mL) were added ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.22 g), tris(dibenzylideneacetone)dipalladium (310 mg), cesium carbonate (1.30 g) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (257 mg), and the mixture was stirred at 90° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.09 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1)([O-])=O.[BH4-].[Na+].C(OCC)(=O)C>CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH3:18])([CH:13]([O:14][CH3:15])[O:16][CH3:17])[C@@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Reaction time: 1 h
Yield: 61.1 %

Procedure:
(2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.2 mmol) prepared in example 109 was dissolved in methanol (2 ml), thereto Cu(OAc)2 aqueous solution (0.38 ml, 0.4 M aqueous solution, 0.15 mmol) was added. To the solution sodium borohydride (NaBH4, 113 mg, 3.0 mmol) was slowly added at the room temperature for 30 min. The reaction mixture was stirred for 1 hour, thereto ethyl acetate (5 ml) was added. The reaction mixture was filtered to remove the black precipitation. NaHCO3 aqueous solution (5 ml) was added to the resulting filtrate. The filtrate was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine solution, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:3), to give desired compound (58 mg, yield: 62%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[C:36]([CH2:37][NH2:38])=[N:35][N:34]=[N:33]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:38][CH2:37][C:36]3[NH:35][N:34]=[N:33][N:32]=3)=[O:28])=[CH:30][CH:31]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1nnn[nH]1
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(N(Cc2ccc(C(=O)NCc3nnn[nH]3)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 5 Step A (0.06 mmol, 25 mg) 1H-tetraazol-5-ylmethylamine (0.09 mmol, 12 mg), HOBt (0.15 mmol, 23 mg) and EDC (0.18 mmol, 35 mg) in 0.5 mL of DMF was added DIEA (0.3 mmol, 52 μL). The reaction was allowed to proceed overnight at ambient temperature. The mixture was partitioned between EtOAc/brine. The organic phase was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 517 (M+H). HPLC A: 1.94 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=[CH:2][CH:3]=1
Reactant: Cc1ccncc1-c1cc(Cl)nn2ccnc12
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccncc1-c1ccnn2ccnc12
Temperature: 70 °C

Procedure:
To a suspension of 6-chloro-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine (800 mg, 3.27 mmol) in ethanol (80 mL) were added ammonium formate (825 mg, 13.08 mmol) and palladium hydroxide on carbon (459 mg, 0.327 mmol) (20% wet) under nitrogen. The suspension was heated to 70° C. in a sealed pressure bottle for 2 h and cooled to room temperature. The reaction mixture was passed through a pad of CELITE® and washed with MeOH. The filtrate was concentrated and the residue was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.53-8.67 (2H, m), 8.43 (1H, d, J=4.53 Hz), 8.09 (1H, d, J=1.26 Hz), 7.81 (1H, d, J=1.01 Hz), 7.31 (1H, d, J=5.04 Hz), 6.99 (1H, d, J=4.53 Hz), 2.33 (3H, s); LC/MS: Rt=0.21 min. LC/MS (Condition A): 211.18.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=2)=[N:30][CH:31]=1.[C:40](O)(=[O:43])[CH:41]=[CH2:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)(=[O:43])[CH:41]=[CH2:42]
Reactant: O=Cc1ccc(-c2ncc(OCCCCCCCCO)cn2)cc1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1cnc(-c2ccc(C=O)cc2)nc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
4.2 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 5.5 g of 4-(5-[8-hydroxyoctyloxy]pyrimidin-2-yl)benzaldehyde, 1.2 g of acrylic acid and 0.2 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and the filtrate was concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 4.8 g of 4-(5-[8-acryloyloxyoctyloxy]pyrimidin-2-yl)benzaldehyde.
Reaction SMILES: O1CCCC1.[CH:6]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH:6]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(OC3CCCCC3)cc2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclohexyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Manufacturing Example 79-1-4 and 3-ethynyl-pyridin-2-ylamine (42 mg, 0.357 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (195 μL, 1.4 mmol), which was stirred for 4 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (37 mg, 19%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:34]=3)[C:29]([OH:31])=[O:30])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>ClCCl>[CH:19]1[C:20]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@H:28]([C:29]([O:31][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:30])[CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH:34]=3)=[O:26])[C:22]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 48 h

Procedure:
tert-Butyl 2-bromoacetate (2.09 ml, 14.2 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)propanoic acid (Fmoc-Trp(Boc)-OH) (Compound SP613) (5.0 g, 9.50 mmol) and diisopropylethylamine (DIPEA) (4.98 ml, 28.5 mmol) in dichloromethane (DCM) (9.5 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 48 hours. An aqueous ammonium chloride solution was added to the reaction solution, the mixture was extracted with dichloromethane (DCM) twice, and the organic layer was washed with brine twice. The organic layer was dried over sodium sulfate, and then filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel chromatography (hexane/ethyl acetate) to afford (S)-tert-butyl 3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert-butoxy)-2-oxoethoxy)-3-oxopropyl)-1H-indole-1-carboxylate (Fmoc-Trp(Boc)-HoGly-OtBu) (Compound SP614) as a mixture (5.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]3=[CH:20][CH:21]=[N:22][N:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:20]1[CH:21]=[N:22][N:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]=12
Reactant: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1nccc1N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1ncc(Br)c1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
The product from Example 6 (0.52 g, 1.56 mmol) in dichloromethane was treated with N-bromosuccinimide (0.28 mg, 1.56 mmol) and allowed to stir at ambient temperature overnight. The mixture was filtered and the filter cake washed with CH2Cl2 to provide the title compound (0.54 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CC(C)CN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield a white solid (25%). LCMS: m/z=523.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.54 (m, 2H), 7.28 (m, 2H), 7.09 (d, 1H, J=7.3 Hz), 6.32 (s, 2H), 5.87 (s, 1H), 5.81 (s, 1H), 4.33 (m, 1H), 3.08 (s, 1H), 2.90 (s, 1H), 2.51 (d, 1H, J=8.1 Hz), 2.36 (m, 4H), 2.03 (m, 3H), 1.63 (d, 1H, J=8.6 Hz), 1.27 (m, 1H), 1.00 (d, 6H, J=6.6 Hz).
Reaction SMILES: I[C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[C@H:4]([CH3:11])[CH2:3]1.[SnH](CCCC)(CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C.C1C=CC=CC=1>[Ni].N1C=CC=CC=1>[CH3:11][C@@H:4]1[CH2:3][CH2:2][C@@H:8]2[CH2:9][C@H:5]1[C:6](=[O:10])[O:7]2
Reactant: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2
Agent: [Ni]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2

Procedure:
reacting said (1R,2R,4S,5S)-4-iodo-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (8) with n-Bu3SnH and catalytic AIBN in refluxing benzene, or with Raney Nickel in the presence of pyridine under 50 psi H2, to produce (1R,2R,5R)-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (9),
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH3:17].[Li+].[OH-]>C1COCC1.CO>[CH2:14]([O:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:18])=[O:2])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1cc(F)ccc1C=CC(=O)O
Yield: 101.5 %

Procedure:
3-(2-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (121 mg) was reacted with 1N LiOH (5 ml) in THF and CH3OH for 2 hrs as described above to yield title compound (116 mg).