Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:19]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: C[Si](C)(C)c1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1ccc([Si](C)(C)C)cc1
Yield: 83.5 %

Procedure:
8.32 g (0.05 mole) of p-trimethylsilylphenol was dissolved in 25 ml toluene. 6.1 g (0.06 mole) triethyl amine and 0.05 g hydroquinone was added. The solution was warmed. 5.43 g (0.06 mole) of acryloyl chloride was added over a 15 minute period. After 11/2 hours, the solution was washed two times with 5 percent sodium carbonate in water and separated. After washing with brine and separating, the organic phase was dried over magnesium sulfate, filtered, and the solvent removed in a rotary evaporator under reduced pressure. Vacuum distillation yielded 9.2 g of pure p-trimethylsilylphenyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1F)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of 5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-ylamine (75 mg, 0.31 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (103 mg, 0.36 mmol), DMAP (20 mg, 0.16 mmol) in anhydrous pyridine (1 mL) was stirred at room temperature for 2 days. The reaction product was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1 H), 7.96 (s, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 7.15-7.13 (m, 3 H), 7.00-6.96 (m, 1 H). MS m/z: 481.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:7]=2)=[CH:9]1
Reactant: Clc1cc(-c2ccsc2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 57.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070 g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.064 g, 0.36 mmol) to afford the title compound (0.065 g, 57%) as an orange-brown oil. MW=378.49. APCI MS m/z 379 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([C:11]#[N:12])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(Br)cn2ccnc12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Yield: 59.7 %

Procedure:
Prepared from 6-bromo-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23 step 2) (1.6 g, 7 mmol) and commercially available 4-trifluoromethylphenylboronic acid (1.505 g, 36 mmol) as described in example C.20 step 2. Obtained the title compound as a white solid (1.2 g, 46%). MS (ISP) 288.0 [(M+H)+].
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.CC1(C)O[C:16](=O)[CH2:15][C:14](=O)O1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][C:3]3[N:4]4[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]4=[N:1][CH:2]=3)[CH2:30][CH:29]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1cn2c(n1)CCCCC2
Reactant: Clc1ccc(C2=CCNCC2)cc1
Product: Clc1ccc(C2=CCN(CCCc3cnc4n3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 91 using 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine, 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-(4chlorophenyl)-1,2,3,6-tetrahydropyridine, 3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][C:2]1[N:3]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate (4.125 g), 1-(bromomethyl)naphthalene (5 g) and K2CO3 (6.2 g) was stirred at 80° C. for 3 h. When TLC showed no starting material remaining, the mixture was cooled to room temperature and then poured into water (500 mL). It was extracted with EtOAc (500 mL×3) and the combined organic layers were washed with brine (500 mL×3) and then concentrated in-vacuo. The residue was purified by silica gel chromatography eluted with MeOH:DCM=1:100 to afford the desired product as a yellow solid (4.6 g, 74%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.42 (s, 3H), 3.04 (t, 4H, J=4.8 Hz), 3.68 (t, 4H, J=4.8 Hz), 3.90 (s, 3H,), 6.02 (s, 1H), 6.28 (d, 1H, J=7.5 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=7.5 Hz), 7.39 (d, 1H, J=2.4), 7.60-7.71 (m, 2H), 7.84 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.24 (d, 1H, J=7.5 Hz); LC-MS: m/e=416 [M+1]+.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3cccc(C(F)(F)F)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 3-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 446.4. HPLC (Condition A), Rt: 4.31 min (HPLC purity: 73.9%).
Reaction SMILES: Br[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:12][OH:13]>>[C:9]([NH:8][CH:2]([NH:12][OH:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(Br)NC(C)=O
Reactant: NO
Product: CCOC(=O)C(NO)NC(C)=O

Procedure:
Using ethyl 2-bromo-2-acetamidoacetate (2.10 g, 9.37 mmol) and anhydrous NH2OH (0.93 g, 28.00 mmol) gave an oily residue. The residue was purified by flash column chromatography on SiO2 gel (5% MeOH/CHCl3) to give the desired product. The product was recrystallized from EtOH to give a white flaky solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9]O)[C:4]=1[CH3:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:9][C:5]1[N:6]=[CH:7][N:8]=[C:3]([N:2]([CH3:12])[CH3:1])[C:4]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncnc1N(C)C
Solvent: ClCCl
Product: Cc1c(CCl)ncnc1N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6-(dimethylamino)-5-methylpyrimidin-4-yl)methanol (46) (40 g, 239 mmol) in DCM was added thionyl chloride (35 ml, 478 mmol). The reaction mixture was stirred for 4 h at RT. The solvent was removed under reduced pressure to afford 6-(Chloromethyl)-N,N,5-trimethylpyrimidin-4-amine (47) as a brown solid; Yield: 40 g (90.9%); NMR (400 MHz, DMSO-d6) δ=8.69 (s, 1H), 4.86 (s, 2H), 3.27 (s, 6H), 2.35 (s, 3H).
Reaction SMILES: [PH4+].[CH2:2]([CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH3:16])O)/[CH:3]=[C:4](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])\[CH3:5]>>[CH3:22][C:20]([CH3:21])=[CH:19][CH2:18][CH2:17]/[C:14](/[CH3:16])=[CH:13]/[CH2:12][CH2:10]/[C:9](/[CH3:11])=[CH:8]/[CH2:7][CH2:6]/[C:4](/[CH3:5])=[CH:3]/[CH:2]=[CH:12]/[CH:13]=[C:14](/[CH:17]=[CH:18]/[CH:19]=[C:20](/[CH2:22][CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])\[CH3:5])\[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CC=CC(C)(O)CCC=C(C)C
Agent: [PH4+]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=C/C(C)=C/C=C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
In the last stage, V undergoes Wittig condensation with the phosphonium salt VI, which is obtainable from geranyllinalool, to give phytofluene.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[CH:15]=[CH:16]3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 6).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:11]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: O=C(O)C1(c2cccc(Br)n2)CC1
Reactant: CN
Product: CNC(=O)C1(c2cccc(Br)n2)CC1
Yield: 70 %

Procedure:
The title compound was prepared from 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 70% of theory; LC (method 3): tR=2.27 min; Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>O.C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([CH2:10][C:11]([F:12])([F:13])[F:14])[CH2:3][C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: NC(C(=O)O)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
The crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (0.92 g, 3.56 mmol) and NaOH mixture was dissolved in water (10 ml). The mixture was cooled to 0° C. in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (0.852 g, 3.9 mmol) was dissolved in THF (10 mL) and added dropwise to the reaction mixture over 10 min. After 60 min, the reaction mixture was allowed to warm gradually to 25° C. and stirred for 16 h. THF was removed in vacuo and the mixture was acidified to pH<2 with 1N HCl. After 15 min, a precipitate began to crash out of the milky white mixture. After 60 min, the mixture was cooled in a refrigerator for 45 min and then filtered. The precipitate was washed with 1N HCl (10 mL) to provide a white solid which gummed out. It was dissolved in EtOAc (100 mL). The aqueous layer was washed with EtOAc (3×50 mL) and the organic layers were washed with saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline as a brown oil (1.3 g, 86.3%).
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)=[CH:4][C:5]([O-:7])=[O:6])#N.[K+].S(=O)(=O)(O)[OH:17]>C(O)=O>[CH3:14][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:17])[O:6][C:5](=[O:7])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(C(C#N)=CC(=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: [K+]
Solvent: O=CO
Product: Cc1cccc(C2=CC(=O)OC2=O)c1
Temperature: 25 °C

Procedure:
A suspension of potassium 3-cyano-3-(3-methylphenyl)-acrylate (0.69 g, 3 mmol), in 88% formic acid (14 ml) containing concentrated sulphuric acid (2 ml) was stirred at reflux and monitored by LC-MS until the starting material was consumed. The reaction mixture was cooled to room temperature and poured into ice/water. The resulting precipitate was recovered by filtration, washed with water (15 ml), heptane (15 ml) and air dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[H][H]>C(O)C.[Pd]>[C@@H:9]1([NH:8][C:6]2[CH:5]=[C:4]([CH3:18])[N:3]=[CH:2][N:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N[C@H]2CCc3ccccc32)ncn1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
2-Chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine (1.95 g, 7.5 mmol) was dissolved in ethanol (5 mL) and 10% Pd/C (0.140 g, 0.13 mmol) was added. The flask was filled with hydrogen and stirred overnight. At that time, TLC indicated complete conversion. Palladium was filtered off and the solvent was removed in vacuo. The residue was purified using chromatography on silica gel using gradient 50 to 100% ethyl acetate in hexane to afford the title compound (1.65 g, 93%). LC/MS: Rt=1.51 min, ES+ 226 (AA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[NH:20][CH2:19][C:18](=[O:21])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:22]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[NH:33]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[NH:20][CH2:19][C:18](=[O:21])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:22]=2)[CH:35]=[N:34]1
Reactant: O=C1CNC(c2cc3c(s2)-c2ccc(Br)cc2OCC3)=NN1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: O=C1CNC(c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)=NN1

Procedure:
Following the procedure in Example 44 for 134, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 212. MS: (ESI+) 366.2
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[SH:18])[CH2:3]1.[N:20]#[C:21]Cl>O1CCCC1>[CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:21]#[N:20])[CH2:3]1
Reactant: CC1CC(NC(=O)c2ccccc2S)CC(C)(C)C1
Reactant: N#CCl
Solvent: C1CCOC1
Product: CC1CC(NC(=O)c2ccccc2SC#N)CC(C)(C)C1
Temperature: -15 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
49.9 g (0.18 mol) of 2-mercaptobenzoic acid N-(3,5,5-trimethyl-cyclohexyl)-amide are initially introduced into 200 ml of tetrahydrofuran. The solution is cooled to -15° C. and 33.3 g (0.54 mol) of cyanogen chloride, dissolved in 50 ml of tetrahydrofuran, are added dropwise in the course of 30 minutes such that the internal temperature does not exceed -5° C. When the dropwise addition has ended, the mixture is allowed to come to room temperature in the course of 1 hour and stirring is then continued at this temperature for a further 2 hours. Excess cyanogen chloride and some of the solvent are distilled off under reduced pressure. The solution is poured into water, with vigorous stirring, and the solid which has precipitated is filtered off with suction and dried in a desiccator. 47 g (86.5% of theory) of 2-thiocyanato-benzoic acid N-(3,5,5-trimethylcyclohexyl)-amide are obtained as a colorless powder of melting point 117° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][NH:13][C:14]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]3[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:17]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])=[O:15])[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[Cl:45][C:39]1[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:38]=1[CH:17]1[CH:16]([C:14]([NH:13][O:12][CH2:11][C:8]2[N:7]=[C:6]([CH2:5][OH:4])[O:10][N:9]=2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: CC(=O)OCc1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2noc(CO)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][C:20]([O:23][C:24]([NH:26][C@H:27]([C:34](O)=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:20]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:34](=[O:35])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:22])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: Cc1ccc(CCNc2ccc(C)c(C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)c2ccc(C)c(C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a 0° C. solution of 35 mg (0.15 mmol) (3,4-dimethyl-phenyl)-[2-(5-methyl-pyridin-2-yl)-ethyl]-amine and 40.4 mg (0.16 mmol) Boc-L-alpha-phenylglycine in 540 uL dichloromethane under argon, was added 31.4 mg (0.16 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 3 hours then at ambient temperature overnight. The solution was washed once with a sat. NaHCO3 solution (3 mL) and once with water (3 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.052 g (75%) of the title compound as an oil. MS (m/e): 474.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][C:25](=O)[CH2:24][CH2:23]2>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][CH:25]2[CH2:24][CH2:23][C:22]3[C:27](=[C:28]([F:30])[CH:29]=[C:20]([F:19])[CH:21]=3)[CH2:26]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.9, 14.1, 14.2, 19.5, 19.6, 28.2, 28.6, 28.7, 28.9, 29.6, 29.9, 36.5, 36.6, 51.9, 52.3, 60.1, 60.6, 62.9, 100.7, 100.9, 101.2, 104.2, 110.5, 110.6, 110.8, 118.2, 118.5, 132.4, 137.9, 138.0, 139.6, 139.9, 159.8, 162.1, 162.2, 172.2, 172.4; MS 419.2 m/z (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[CH3:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Temperature: 70 °C
Yield: 51.7 %

Procedure:
Sodium hydroxide (43 mg) was added to a solution of ethyl 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D111) (310 mg) in iPrOH (10 mL) and water (10 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E85) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.24 (3H, s), 2.61 (2H, t), 2.96 (2H, t), 5.40 (1H, m), 7.34 (1H, d), 7.70 (2H, d), 8.11 (1H, t), 8.28 (1H, dd), 8.82 (1H, dd), 11.20 (1H, s), 12.11 (1H, br s). MS (ES): C22H22N4O4 requires 406; found 407.2 (M+H+).