Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C@@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10](O)=[O:11])(C)(C)C.CCN=C=NCCCN(C)C.[ClH:33].[CH2:34]([N:38]1[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=2)=[O:45])[N:40]=[C:39]1[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:33].[NH2:13][C@@H:9]([C:10]([O:63][CH2:62][CH2:61][NH:60][C:58]([C:39]1[N:38]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([F:55])([F:56])[F:57])=[CH:51][CH:52]=2)=[O:45])[N:40]=1)=[O:59])=[O:11])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCO
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCOC(=O)[C@H](N)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
91 mg (0.3 mmol) of (2R)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid are dissolved in 1 ml of DMF and, after addition of 58 mg (0.3 mmol) of EDCI×HCl and 37 mg (0.30 mmol) of DMAP, stirred at room temperature for 10 minutes. Then 70 mg (0.15 mmol) of 1-butyl-N-(2-hydroxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxamide (Example 81) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC. The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[C:21]([Cl:57])[CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Cl:57][C:21]1[CH:20]=[C:19]([OH:18])[CH:56]=[CH:55][C:22]=1[O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3Cl)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3Cl)cc2)CC1
Yield: 39.1 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}-2-chlorophenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-octyl-1-piperidinecarboxamide(0.185 g, 0.23 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.053 g, 0.09 mmol).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8].[OH-].[K+]>CO.O>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][C:3]([OH:16])=[O:2]
Reactant: CCCC(CC(=O)OC)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(CC(=O)O)c1ccccc1C

Procedure:
32 g of 3-o-tolyl-hexanoic acid methyl ester obtained from step (b) in 200 ml methanol are boiled under reflux with 9.8 g KOH in 20 ml H2O for 2 hours. Isolation of the acid product yields 3-o-tolyl-hexanoic acid as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][CH2:53][C:54]6[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:42][CH:43]=1
Reactant: NCCc1cccnc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3F)cn2)cc1
Yield: 185.3 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 3-(2-aminoethyl)pyridine (27.7 μl, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-(2-pyridin-3-yl-ethyl)-benzamide as a yellow solid (171 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-306) as a yellow powder (49.8 mg, 78%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(O)CO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CC(O)CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (4R)-4-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexane-1,2-diol, 191a, (0.140 g, 0.257 mmol) in THF (10 mL) was added sodium methoxide (0.055 g of 25% w/w solution, 0.257 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH/CH2Cl2) followed by preparative HPLC to afford 10 mg pure desired product: 1H NMR (400 MHz, d6-DMSO) δ 8.61 (dd, J=9.9, 2.6 Hz, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=4.1 Hz, 1H), 4.66 (d, J=10.4 Hz, 1H), 4.43 (s, 1H), 4.29 (d, J=4.1 Hz, 1H), 4.04 (s, 1H), 3.35 (s, 1H), 3.26 (d, J=6.1 Hz, 2H), 1.69 (t, J=12.3 Hz, 1H), 1.59-1.45 (m, 1H), 0.96 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.76 minutes (M+H) 392.46.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)([O-])O.[Na+].O>ClCCl>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Reaction time: 3 h

Procedure:
To 8-amino-2-naphthol (100 mg) were added phenyl chloroformate (87 μl), saturated aqueous sodium hydrogen carbonate (0.5 ml), dichloromethane (1 ml) and water (0.5 ml), and the mixture was stirred for 3 hrs. The reaction mixture was diluted with dichloromethane. After washing with 1N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Diethyl ether and hexane were added to the residue, and the precipitate was collected by filtration to give the title compound (160 mg). NMR data of Example 109: 1H-NMR (300 MHz, DMSO-d6) δ3.49 (2H, m), 4.06 (2H, s), 6.79 (4H, m), 7.10 (2H, m), 7.30 (2H, m), 7.75 (2H, m), 8.34 (1H, s), 9.69 (1H, s).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: C#CCNC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-methyl propargylamine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (15.6 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 8 h to give (Z)-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 41%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[C:13]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(=O)c1cccc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCC(=O)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 57.9 %

Procedure:
A mixture containing 2-bromomethyl naphthalene (3.0 g, 13.5 mmol), 3-hexanoylphenol (2.6 g, 13.5 mmol), powdered potassium carbonate (19.0 g, 135 mmol) and potassium iodide (0.1 g) in dry acetone (100 ml) was refluxed for two days. Most of the solvent was removed after filtering off the solid residue. The oil was purified by chromatography on silica gel using a 5% ethylacetate in hexane solution as eluent to leave the desined product as a clear, colorless liquid (2.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][Br:26])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester I-4a (2.8 g, 7.46 mmol), N-bromosuccinimide (1.6 g, 8.95 mmol), AIBN (245 mg, 1.49 mmol) in CCl4 (60 ml) was heated under reflux for 17 hours. The reaction was cooled to room temperature, filtered to remove any solids, and concentrated under vacuum. The crude residue was purified via silica gel chromatography (Flash 40) using a solvent gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the desired product (I-4b) as an amorphous solid (2.2 g, 64%): +APCI MS (M+1) 455.0.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12.[C-]#N.[Na+].[CH3:29][NH:30]CCNC>C1(C)C=CC=CC=1.[Cu]I>[F:19][C:18]([F:21])([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:5]([C:4]([C:22]([F:24])([F:23])[F:25])=[N:3][C:2]=3[C:29]#[N:30])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1nc(C(F)(F)F)n2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 130 °C

Procedure:
1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (50.0 mg, 0.118 mmol), NaCN (7.0 mg, 0.142 mmol, 1.2 equiv.), CuI (2.2 mg, 0.0118 mmol, 0.1 equiv.) and KI (3.9 mg, 0.0236 mmol, 0.2 equiv.) were successively placed in a 5 mL Samith vial. To the vial was added a solution of N,N′-dimethylethylenediamine (10.4 mg, 0.118 mmol, 1.0 equiv.) in toluene (5 mL). The suspension was heated by the microwave reactor (Biotage, Personal Chemistry) at 130° C. for 60 min. The suspension was filtered through Celite (3 g) using EtOAc (70 mL). The solvent was removed from the filtrate under a reduced pressure to give a crude mixture. The crude mixture was purified by a preparative TLC (SiO2=1 plate, EtOAc/hexane=1:7 Rf=0.1) to give 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carbonitrile as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:35])[CH2:33][CH3:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and propanoyl chloride (14 mg, 150 μmol). Yield 17 mg (72%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(=O)([O-])O.[Na+]>C1COCC1.C1COCC1.O>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:4][OH:3])=[N:7][N:8]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: OCc1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Ethyl6-benzyloxy-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (182 mg) which can be prepared according to the method described in Reference example 21, etc. was dissolved in dehydrated THF (4.78 mL; manufactured by Kanto Chemical Co., Inc.). After the replacement with nitrogen, LiAlH4 (54 mg) was added at 0° C., and the mixture was stirred for 1 hour while warming to room temperature. After cooling to 0° C., THF/water=1/1(5 mL), rochelle salt (manufactured by Kanto Chemical Co., Inc.), and saturated aqueous solution of sodium hydrogen carbonate were added, and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, hexane was added to the residue and the solvent was evaporated under reduced pressure to give the title compound (155 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: COc1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(CCOc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C19H22O6 [M−H]−: 345.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:38](=[O:40])[CH3:39])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 10.6 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and acetic anhydride (20 uL, 0.2 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification, to yield 3.2 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 491.2 (100).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Li]CCCC>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:3]#[CH:2])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C=C(Br)Br)cc1OC
Agent: [Li]CCCC
Product: C#Cc1ccc(OC)c(OC)c1
Yield: 84.5 %

Procedure:
According to the General Procedure E, 2,2-dibromo-1-(3,4-dimethoxyphenyl)ethene (4.00 g, 12.40 mmol) and n-BuLi (17.11 ml, 27.28 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=1:1, Rf=0.51) the title compound (1.70 g, 10.48 mmol, 85%) as a colorless solid, m.p. 71-72° C.;
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:45]=[C:46]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[CH:47]=2)[O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[Na]>>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:45]=[C:46]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[CH:47]=2)[O:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCOc1cc(CCCOC)cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: [Na]
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2 but using instead ethyl 4-[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phenoxy]-butanoate (Example 15) as the starting material. The sodium salt of the title compound was a foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][C@@H:12]2[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]2[CH2:10]1.[C:20]([O:24][C:25]([N:27]([CH3:36])[C@H:28]([C:33](O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:36][N:27]([C@@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:33](=[O:34])[NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:18])[F:19])[CH2:13]2)[CH2:16][CH2:15]1)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 4 mL vial was added (3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Step 2 (21.6 mg, 0.080 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-leucine (21.56 mg, 0.088 mmol), and 1-hydroxybenzotriazole hydrate (13.46 mg, 0.088 mmol) in dichloromethane (1 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.088 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was diluted with 1 mL of dichloromethane and quenched with 2 mL of water. The aqueous layer was extracted with more dichloromethane (2×2 mL), the solvent was removed in vacuo, and the crude material was applied to a 24 g silica gel cartridge and purified with 1-50% ethyl acetate/hexanes to give tert-butyl methyl((S)-4-methyl-1-oxo-1-((3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=6.8, 1H), 7.69-7.62 (m, 1H), 7.45 (t, J=7.4, 1H), 7.26 (d, J=8.2, 1H), 7.11 (t, J=7.6, 1H), 5.17 (s, 1H), 4.46 (s, 1H), 3.45 (d, J=8.8, 1H), 3.08 (d, J=24.1, 4H), 2.98-2.87 (m, 2H), 2.63 (s, 2H), 2.09 (s, 1H), 1.86 (ddd, J=23.7, 16.2, 10.4, 3H), 1.70-1.51 (m, 3H), 1.48 (s, 9H), 0.90 (d, J=6.5, 3H), 0.86 (d, J=6.5, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[N:10]1([C:15]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:1][CH:2]([CH2:3][C:4](=[O:5])[N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C:15](=[O:16])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22]1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1COCCO1
Product: CC(CC(=O)O)CC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Reaction time: 8 h
Yield: 110.7 %

Procedure:
1.6 g of 3-methylglutaric anhydride and then 2.62 g of pyrrolidinocarbonylmethyl-piperazine are added to 10 cm3 of dioxane. After stirring for 8 hours, an additional 320 mg of 3-methylglutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is then evaporated under reduced pressure and then the resulting oil is dried at 45° C. (90 Pa) to give 4.5 g of (3RS)-3-methyl-5-oxo-5-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]pentanoic acid in the form of an orange-colored oil which is used as it is.