Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15](OC)=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1>C(OCC)(=O)C>[CH2:37]([O:36][N:31]1[C:32]([CH3:35])([CH3:34])[CH2:33][CH:28]([NH:27][C:15](=[O:16])[CH2:14][CH2:13][C:12]2[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]([OH:22])=[C:10]([N:2]3[N:3]=[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1]3)[CH:11]=2)[CH2:29][C:30]1([CH3:45])[CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Reactant: COC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)CCc2cc(-n3nc4ccccc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C
Yield: 14.6 %

Procedure:
A mixture of 4.0 g (11.3 mmol) of methyl 3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate and 8.0 g (28.1 mmol) of 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine is heated at 190°-200° C. for 2 hours. The reaction mixture is dissolved in ethyl acetate (300 ml). The organic solution is washed with 1N hydrochloric acid (2 ×100 ml) and saturated sodium bicarbonate solution (200 ml), then dried over magnesium sulfate and evaporated to obtain a solid. Purification by flash chromatography on silica gel (3:1 heptane: ethyl acetate) following by recrystallization from methanol affords 1.0 g (15% yield) of the title compound, a white solid, mp 153°-9° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:23]=[CH:22][C:13]([O:14][CH2:15][CH:16]3[O:20][C:19]([NH2:21])=[N:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:3]1.CC1(C)CC(C)(C)CC(C2C=CC(O)=CC=2)C1.C([C@@H]1OC1)Cl.C([O:49][C:50](=O)[C:51]#[C:52][CH2:53][F:54])C>C(Cl)(Cl)Cl>[F:54][CH2:53][C:52]1[N:18]2[CH2:17][C@@H:16]([CH2:15][O:14][C:13]3[CH:12]=[CH:11][C:10]([CH:4]4[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:24])([CH3:1])[CH2:3]4)=[CH:23][CH:22]=3)[O:20][C:19]2=[N:21][C:50](=[O:49])[CH:51]=1
Reactant: CC1(C)CC(c2ccc(OCC3CN=C(N)O3)cc2)CC(C)(C)C1
Reactant: CCOC(=O)C#CCF
Agent: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1
Agent: ClC[C@H]1CO1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(c2ccc(OC[C@@H]3Cn4c(CF)cc(=O)nc4O3)cc2)CC(C)(C)C1

Procedure:
The title compound was prepared from 5-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (prepared from 4-(3,3,5,5-tetramethyl-cyclohexyl)-phenol and (R)-epichlorohydrin according to the procedures employed in Step 1 through 2 of Example 1) and 4-fluoro-but-2-ynoic acid ethyl ester (see Example 105) according to the procedures described in Example 95. [α]D25 −21.40 (c 0.5, CHCl3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11].C1C2C(=CC=CC=2)C=CC=1S([N:34]=[N+:35]=[N-])(=O)=O>C1(C)C=CC=CC=1>[N+:34](=[C:12]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:9][CH2:8][CH3:7])=[O:11])=[N-:35]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=[N+]=[N-])P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
A suspension of potassium t-butoxide (4.42 g, 39.4 mmol) in toluene (200 ml) was stirred at 0° under Ar for 10 minutes. A solution of ethyl diethoxyphosphoryl acetate (6.53 ml, 32.9 mmol) in toluene (20 ml) was added in 20 minutes keeping the temperature below 5°. Another solution of 2-naphthalenesulfonyl azide (7.67 g, 32.9 mmol) was added dropwise below 5°, and the reaction mixture was warmed to RT and stirred overnight. The resulting suspension was filtered and the filtrate washed with toluene. The pooled organic phase was concentrated and the brown oily residue distilled producing pure title compound (6.12 g, 24.5 mmol, yield 74.3%) as a yellow oil, b.p.=70-73°/0.02 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7]1[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:6]=1[C:5]2=[O:23].I[CH2:25][CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]1[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:6]1=[C:5]2[O:23][CH2:25][CH2:26][CH3:27]
Reactant: CCCI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Product: CCCOc1c2cc(F)c(F)cc2nc2c1c(C)nn2-c1ccccn1
Yield: 27 %

Procedure:
Following the procedure described in Example 2-16, from 6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one and 1-iodopropane was prepared the title compound (27% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][N:11]([C:24]([C:26]3([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:32][C:26]1([C:24]([N:11]2[CH2:10][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[CH2:14][CH:13]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:12]2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C2)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(N)CCOCC3)C2)cc1C

Procedure:
33 mg (0.06 mmol) of tert-butyl [4-({3-(3,4-dimethylphenyl)-5-[(phenylcarbonyl)amino]piperidin-1-yl}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate were dissolved in 4 ml of dioxane, 1 ml of concentrated hydrochloric acid was added and the mixture was immediately concentrated on a rotary evaporator. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 15 mg (57% of theory)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Yield: 27.3 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.34 mmol), 4-aminobenzamide (93 mg, 0.68 mmol) and trimethylsilyl chloride (TMSCl) (0.100 mL, 0.79 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (50 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.49 g, 2.9 mmol) and sodium methoxide (0.16 g, 2 9 mmol) were added. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.48 g, 2.1 mmol, yield: 79%) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([N:6]=[C:12]=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 3,5-dimethoxyaniline (8.4 g) in toluene (100 ml) was dropwise added to a toluene solution containing 20 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give (3,5-dimethoxy)phenyl isocyanate (9.8 g). The thus obtained crude substance was added to a methanol solution (50 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give methyl N-(3,5-dimethoxyphenyl)carbamate (10.2 g) in a yield of 88% (calculated from the starting 3,5-dimethoxyaniline). M.P., 64.5°-65° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O1CCOCC1.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]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Yield: 85.8 %

Procedure:
A mixture of 2-chloronicotinonitrile (2.49 g, 18.02 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (from Example 2, step d) (6.14 g, 23.43 mmol) and potassium fluoride (3.46 g, 59.47 mmol) in tetrahydrofuran (120 ml), was degassed with nitrogen for 30 min then treated with tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.360 mmol), followed by tri-tert-butylphosphine (3.6 ml of a 0.2 M solution in 1,4-dioxane, 0.721 mmol). The mixture was degassed again before heating at 50° C. for 18 h. The mixture was cooled to ambient temperature then partitioned between ethyl acetate and water. The organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2) to afford 3.759 g (86%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 8.97 (1H, dd, J 5, 2 Hz), 8.56 (1H, dd, J 6, 3 Hz), 8.40-8.45 (1H, m), 8.15 (1H, dd, J 8, 2 Hz), 7.55 (1H, dd, J 8, 5 Hz), 7.43 (1H, dd, J 9, 9 Hz); MS (ES+) m/z 244 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH2:8][CH:9]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:10]#N)[CH:7]=1>C1COCC1.CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:19][CH2:10][CH:9]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:8]2
Reactant: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(C)nc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CC(c1ccc(C)nc1)CN2
Temperature: 40 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of 3-(5-methyl-2-nitrophenyl)-2-(6-methylpyridin-3-yl)propanenitrile (0.3 g, 0.00106 mol), 10% palladium carbon (0.180 g) in THF (1 mL) and MeOH (6 mL) was stirred under atmospheric hydrogen pressure at 40° C. for 24 h. After completion of reaction (monitored by TLC), catalyst was removed by filtration through Celite, and the filtrate concentrated under reduced pressure. The product was purified by column chromatography (25% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (0.075 g, 30% yield).
Reaction SMILES: CN(C1C=CC(N=NC2C=CC(N=C=S)=CC=2)=CC=1)C.[CH:21]1[C:26](N=C=S)=[CH:25][C:24]2[C:30]3([O:50][C:51](=[O:52])[C:23]=2[CH:22]=1)[C:43]1[C:38](=[C:39]([I:46])[C:40]([O-:45])=[C:41]([I:44])[CH:42]=1)[O:37][C:36]1[C:31]3=[CH:32][C:33]([I:49])=[C:34]([O-:48])[C:35]=1[I:47].[Na+].[Na+]>C([O-])(O)=O.[Na+].CN(C)C=O>[CH:21]1[CH:26]=[CH:25][C:24]2[C:30]3([C:31]4[CH:32]=[C:33]([I:49])[C:34]([OH:48])=[C:35]([I:47])[C:36]=4[O:37][C:38]4[C:39]([I:46])=[C:40]([OH:45])[C:41]([I:44])=[CH:42][C:43]3=4)[O:50][C:51](=[O:52])[C:23]=2[CH:22]=1
Reactant: O=C1OC2(c3cc(N=C=S)ccc31)c1cc(I)c([O-])c(I)c1Oc1c2cc(I)c([O-])c1I
Agent: CN(C)c1ccc(N=Nc2ccc(N=C=S)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(c3ccccc31)c1cc(I)c(O)c(I)c1Oc1c2cc(I)c(O)c1I
Reaction time: 8 h

Procedure:
Antibody (2 mg) was dissolved in 2 ml of 1% NaHCO3 pH 8.6, and a 20-ul aliquot of a solution of 1 mg/ml 4-dimethylaminoazobenzene-4'-isothiocyanate in dimethylformamide (DMF) added. The mixture was stirred overnight, then desalted on a Sephadex G-25 (coarse) column (1×30 cm). The ultraviolet-and visible spectrum of the conjugate was compared to that of DAB and antibody alone, to determine the degree of substitution. An erythrosin-antibody conjugate was prepared the same way, except the concentration of the erythrosin-isothiocyanate in DMF was 2.5 mg/ml.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20](O)=[O:21])[CH:8]=[N:7][C:6]=12.Cl.[F:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]([N:28]3[CH2:29][CH2:30][C:25]([F:24])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:27]3)=[O:21])[CH:8]=[N:7][C:6]=12
Reactant: Cc1ccc(C)c(Nc2c(C(=O)O)cnc3c(Br)cnn23)c1
Reactant: FC1(c2ccccc2)CCNCC1
Agent: Cl
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(Br)cnn23)c1
Yield: 62.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-bromo-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (231 mg, 0.64 mmol) obtained in step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (207 mg, 0.96 mmol), the title compound (208 mg, 62%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:32][C:33]([CH3:39])([CH3:38])[CH2:34]C(Cl)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:24])[CH2:32][C:33]([CH3:39])([CH3:38])[CH3:34])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Product: CC(C)(C)CC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (30 mg, 0.067 mmol) and 3,3-dimethylbutyryl chloride (14 μL, 0.1 mmol) following a procedure analogous to that in Example 41 as a white crystal (28 mg, yield 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 3-{4-[1-Hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (150 mg, 0.28 mmol) in dichlormethane (10 mL) is added TFA (160 mg, 1.4 mmol) dropwise, followed by the addition of triethylsilane (161 mg, 1.4 mmol). After 2 h, the reaction is quenched by 1N HCl, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to afford the titled compound (130 mg).
Reaction SMILES: N[C:2]1[C:3]([CH3:25])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([C@@H:21]4[CH2:23][C@@H:22]4[F:24])=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=[O:29].CCCCCON=O>>[F:24][C@H:22]1[CH2:23][C@H:21]1[C:19]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([OH:29])[C:3]=1[CH3:25])[CH:17]=2)=[O:20]
Reactant: Cc1c(N)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCCON=O
Product: Cc1c(O)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
To a solution of (1S,2S)—N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (46.2 mg; 0.137 mmol) in trifluoroacetic acid (1.0 mL; 13 mmol) at 0° C. was added N-amyl nitrite (29 μL; 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and then partitioned between dichloromethane and 2M aqueous sodium carbonate. The aqueous layer was neutralized to pH 7 with citric acid, and then extracted twice more with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) followed by preparatory reverse-phase HPLC to yield 8.4 mg (18%) of the title compound. LCMS (ESI): RT (min)=3.583, M+H=338.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.94 (broad s, 1H), 9.19 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 4.95 m, 1H), 2.27 (m, 1H), 2.12 (s, 3H), 1.70 (m, 1H), 1.20 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](Br)=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39](B(O)O)[CH:40]=1)([CH3:34])[CH3:33].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:10]1[CH:19]=[C:20]([C:39]2[CH:40]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:36]=[CH:37][C:38]=2[O:44][CH3:45])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCNC(=O)c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 91.7 %

Procedure:
The mixture of 2,4-bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (484 mg, 1 mmol) and 5-isopropyl-2-methoxy-phenylboronic acid (388 mg, 2 mmol) was heated in the mixture of toluene (5 ml), ethanol (5 ml) and saturated NaHCO3 (5 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (60 mg, 0.056 mmol) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (25 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 508 mg of 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid-(3-methoxypropyl)-amide (92% yield). M.p.: 142-144 C; 400 MHz 1H NMR (CDCl3) δ: 8.16 (s, 1H), 7.92 (t, J=5.6 Hz, 1H), 7.43-7.38 (m, 5H), 7.33-7.26 (m, 5H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.59 (s, 1H), 5.11 (s, 2H), 5.06 (s, 2H), 3.72 (s, 3H), 3.44 (q, J=5.6 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 2.87 (m, 1H), 1.69 (pent, J=6.4 Hz, 2H), 1.23 (d, J=6.8 Hz, 6H); LCMS: 554 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][CH2:47][NH:48][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NCCCC2CCN(C(=O)OC(C)(C)C)CC2)CCO3)cc1
Yield: 99 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propylamine (1333 mg, 5.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 ml) was added to the residue and the resulting mixture was washed successively with water (10×3 ml), a 10% aqueous solution of potassium hydrogensulfate (10 ml×3), an aqueous saturated solution of sodium bicarbonate (10 ml×3) and an aqueous saturated solution of sodium chloride (10 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 80g, ethyl acetate/hexane=1/3→1/1)]. The objective fractions were concentrated under reduced pressure to obtain N-[3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (2498 mg, 4.95 mmol, 99%).