Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1
Reactant: N#CCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: [Ni]
Solvent: CO
Product: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogenation flask charged with a solution of N-((1-(cyanomethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (2.80 g, 7.13 mmol) in methanol (20 mL) and Raney nickel (˜1 g, rinsed with methanol). The flask was shaken at room temperature under hydrogen (40 psi) overnight. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated to give sticky foam which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH:10][CH:11]([CH3:24])[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][C:2](=[CH:10][CH:11]([CH3:24])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=1)[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CC(C)=CC(C)C(OC)c1ccc(N(C)C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C=CC(C)=CC(C)Cc1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a stirred solution of ester compound 31 (99 mg, 0.299 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylsilane (41.9 mg, 0.36 mmol) followed by BF3.Et2O (51 mg, 0.36 mmol) dropwise via microsyringe, and the mixture was stirred at 0° C. for 30 min. The reaction was quenched with saturated NaHCO3 solution (3 mL), diluted with CH2Cl2 (20 mL), and washed with water, and the organic phase was dried and concentrated. Purification by flash silica gel chromatography (10% ethyl acetate in hexane) afforded the title compound 36 (87 mg, 97% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, J=15.6, 0.6 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 5.74 (d, J=15.6 Hz, 1H), 5.73 (br d, J=10.2 Hz, 1H), 4.20 (q, J=6.9 Hz, 2H), 2.90 (s, 6H), 2.73 (m, 1H), 2.53 (d, J=7.2 Hz, 2H), 1.61 (d, J=0.6 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 12.1, 14.3, 20.0, 35.5, 40.8, 42.2, 60.1, 112.7, 115.5, 128.1, 129.7, 131.6, 147.5, 149.0, 149.8, 167.5.
Reaction SMILES: [NH2:1][CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].CCN(CC)CC.[C:24](Cl)([CH3:26])=[O:25]>C(Cl)Cl>[C:24]([NH:1][CH:2]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4])(=[O:25])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(N)C(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(C)=O)C(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
To a solution of methyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate (35.5 g, 137 mmol) and Et3N (57.2 mL, 411 mmol) in DCM (120 mL) at 0° C. was added AcCl (12.9 g, 164 mmol) dropwise. The reaction mixture was stirred at 0° C. for 40 min and then quenched with water (500 mL). The resulting mixture was extracted with DCM (300 mL×2) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether/EtOAc (300 mL, 100:1) to methyl 2-acetamido-3-(4-methoxyphenyl)-3-oxopropanoate (22.0 g, 61% yield) as a colorless solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.C[Si]([N:31]=[C:32]=[O:33])(C)C.C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:32]([NH2:31])=[O:33])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), (trimethyl)silyl isocyanate (78 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and THF, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (39.5 mg).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC1C=C(C=CC=1COC(=O)C1C=CC=CC=1)CBr)(=O)C1C=CC=CC=1.[C:47]([O:55][CH2:56][C:57]1[CH:58]=[C:59]([CH:79]=[CH:80][C:81]=1[CH2:82][O:83][C:84](=[O:91])[C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[CH2:60][O:61]C1C=C(C2C=CC=C(CC(OC)=O)C=2)C=CC=1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:47]([O:55][CH2:56][C:57]1[CH:58]=[C:59]([CH:79]=[CH:80][C:81]=1[CH2:82][O:83][C:84](=[O:91])[C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)[CH2:60][O:61][C:10]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:9]1)(=[O:54])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COC(=O)Cc1cccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)c1
Reactant: COC(=O)Cc1cccc(-c2cccc(O)c2)c1
Agent: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)CC1(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)C=CC=C(c2ccccc2)C1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 1 g (4.1 mmol) of methyl (3′-hydroxybiphenyl-3-yl)acetate with 2 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, 2.2 g (91%) of methyl {3′-[3,4-bis(benzoyloxymethyl)benzyloxy]-biphenyl-3-yl}acetate are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([S:18][C:19]2[CH:20]=[N:21][C:22]([NH:32][C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:64][C:65](=[NH:67])[CH3:66]>CN(C=O)C.CCOC(C)=O>[CH3:66][C:65]1[N:67]=[C:15]([CH:14]([S:18][C:19]2[CH:20]=[N:21][C:22]([NH:32][C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[O:16][N:64]=1
Reactant: CC(=N)NO
Reactant: Cc1csc(Nc2ncc(SC(C(=O)O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncc(SC(c3nc(C)no3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Placed 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetic acid (0.250 g, 0.449 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0638 g, 0.494 mmol) in DMF (10 mL) and added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate(V) (0.119 g, 0.449 mmol) and stirred for 30 minutes. Added N-hydroxyacetamidine (0.0366 g, 0.494 mmol) and heated to 110° C. for 4 days. The reaction was diluted with EtOAc and washed with water, dried, filtered and concentrated. The residue was purified by reverse phase chromatography to provide the title compound (0.122 g, 35.6%) Product was contaminated with ˜15% acid. Crude material was used in Step B.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CN(C=O)C>[C:4]([S:7][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CC(C)(C)S
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)SCc1ccc(C#N)cc1
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
Add sodium hydride (359 mg, 14.21 mmol) to a solution of 2-methyl-2-propanethiol (900 mg, 9.98 mmol) in anhydrous DMF (15 mL) under nitrogen. Stir the mixture for 15 min, add 4-bromomethyl-benzonitrile (2.348 g, 11.97 mmol) and stir the resulting mixture overnight at room temperature. Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc 92:8 to give the desired intermediate (1.42 g, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C(C)C)cc1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)C)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (Step 41.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.40 min (HPLC 1); tR: 1.02 min (LC-MS 2); ESI-MS: 443 [M+H]+ (LC-MS 2); Rf=0.06 (EtOAc).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1cccc(-c2cccnc2)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cccc(-c2cccnc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (1.3 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-3-(pyridin-3-yl)benzoate (0.35 g) in dioxane (3.5 mL) and methanol (3.5 mL), followed by stirring at room temperature for 1 hour. A 2 mol/L aqueous solution of sodium hydroxide (1.3 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 4.5 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.18 g of 2-(benzyloxy)-3-(pyridin-3-yl)benzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2ncnn2c1
Product: C(#Cc1cnc2ncnn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=221.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (example 32, step 1) and phenylacetylene.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Agent: Cl
Solvent: CO
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nc1
Yield: 49.1 %

Procedure:
A solution of the compound (298 mg, 0.57 mmol) obtained in Example 51-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (114 mg, 49%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[C:4]([NH2:12])[CH:3]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[NH:11][C:18](=[O:19])[NH:12][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Yield: 83.5 %

Procedure:
A stirred solution of 4-chloro-5-nitro-1,2-phenylenediamine (2.0 g, 10.66 mmol) and CDI (2.59 g, 16 mmol) in anhydrous THF (50 mL) was heated to 85° C. for 4 h. The reaction was allowed to cool and the solvents were removed under reduced pressure. The resulting residue was washed with 2M aqueous hydrochloric acid and recrystallised from methanol to afford 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one as a brown solid (1.9 g, 84%), which was taken through to the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
Activated molecular sieves (8.9 g) 4 Å were placed in an oven dried round bottom flask and cooled to room temperature under nitrogen. Ethyl 6-chloro-1H-indole-2-carboxylate (from AsymChem, 0.500 g, 2.24 mmol), (3-fluorophenyl)boronic acid (0.938 g, 6.71 mmol), copper acetate (0.40 g, 3.3 mmol), methylene chloride (80 mL) was added to the flask, followed by pyridine (0.723 mL, 8.94 mmol). The reaction mixture was stirred at room temperature for 2 days, and then filtered through Celite. The filtrate was concentrated under reduced pressure. The resultant residue was purified by chromatography on silica gel (eluting with 0 to 50% EtOAc in hexane) to give the desired product (0.60 g). LCMS calculated for C17H14ClFNO2(M+H)+: m/z=318.1. Found: 318.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12](C)([C:18](OCC)=O)[C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 82.3 %

Procedure:
A solution of compound (26a) (10.8 g, 32.6 mmol) in acetic acid (36 mL), and concentrated sulfuric acid (10 mL), and water (26 mL) were treated in the same manner as in (b) in Production Example 1 to give 6.2 g (82%) of compound (27a) as yellow solid.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>CO.[Pd]>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:18]=[CH:19][CH:20]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CCCC(c1cccc(C=CC(=O)O)c1)n1ccnc1
Agent: [Pd]
Solvent: CO
Product: CCCC(c1cccc(CCC(=O)O)c1)n1ccnc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
1.08 g of 3-[1-(1-imidazolyl)-butyl]-cinnamic acid (example 42) is dissolved in 20 ml of methanol and mixed with 100 mg of palladium on carbon (10%) and hydrogenated at normal pressure. After 2 hours, the reaction mixture does not take up any more hydrogen. Then the catalyst is filtered off on kieselguhr and the filtrate is concentrated by evaporation in a vacuum. 1.05 g of 3-[3-[1-(1-imidazolyl)-butyl]-phenyl]propionic acid is obtained
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH3:6])[CH3:2].[Br-:10]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]([Br:10])[CH3:6])[CH3:2]
Reactant: CCOC(CC)OCC
Reactant: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(OCC)C(C)Br
Temperature: 25 °C

Procedure:
13.22 g of propion-aldehyde-diethyl-acetal are dissolved in 15 ml of carbon tetrachloride; at -10° C. 20 ml of the carbon tetrachloride solution of 17.58 g of bromide are dropped to it under stirring. After its warming to room temperature it is distilled in vacuo.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:16](O)[CH2:17][CH2:18]O.[OH-].[K+]>>[O:12]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:15])[O:14][CH2:18][CH2:17][CH2:16]1
Reactant: OCCCO
Reactant: O=C(O)CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: O=C1CCCCCCCCCC(=O)OCCCO1
Reaction time: 4.5 h

Procedure:
100 g of a polyester of undecanedioic acid and 1,3-propanediol, having a degree of polymerization of 29 and an acid number of 7 mg KOH/g, is mixed with 3 g of one of the catalysts listed in Table 2 (derived from French Pat. No. 796,410) in a distillation flask of a conventional vacuum distillation apparatus. The mixture is thermolyzed for 4-5 hours under vacuum (pressure: less than 0.5 mbar) at 270° C. The yields of crude 1,5-dioxacyclohexadecane-6,16-dione, based on the amount of polyester employed, are listed in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][N:20]1[C:26](=[O:27])[CH:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[C:22]2[CH:36]=[CH:37][CH:38]=[CH:39][C:21]1=2>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][N:20]2[C:26](=[O:27])[CH:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[C:22]3[CH:36]=[CH:37][CH:38]=[CH:39][C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)CC1C(=O)N(N)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CC(C)CC1C(=O)N(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-F), the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 99:1 CHCl3/MeOH.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
An oven-dried 300 mL round-bottomed flask was charged with 2-methylphenol (15.0 g, 139 mmol), finely powdered K2CO3 (38.3 g, 277 mmol), and anhydrous DMF (60 mL) and the resulting solution was cooled to 0° C. Next, ethyl bromoacetate (18.5 mL, 167 mmol) was added dropwise at 0° C., and the reaction was stirred vigorously at room temperature for 1 h. The reaction mixture was cooled using an ice-water bath, water (180 mL) was added and the product was extracted twice with AcOEt (200 mL and 100 mL). The combined organics were sequentially washed with 2×100 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a slightly yellow oil which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 5% AcOEt/hexane-10% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to provide compound 10.1 as a colorless oil (29.3 g). 1H NMR (300 MHz) (CDCl3) δ 7.26-7.13 (2H, m); 6.90 (1H, t, J=7.3 Hz); 6.71 (1H, d, J=8.0 Hz); 4.63 (2H, s); 4.27 (2H, q, J=6.9 Hz); 2.30 (3H, s); 1.30 (3H, t, J=6.9 Hz).