Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[C:38](O)=[O:39]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[CH:37][C:28]=4[O:27][CH3:26])=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)ccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methoxynaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:6]([O:8][C:13](=[O:14])[NH:12][C:4]=12)=[O:7]
Reactant: O=C(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 3-methoxyanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.33 g (98%) of the 3-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 53%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].C1([NH2:36])CCCCC1.C1(C)C=CC=CC=1>C(OC(=O)C)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH:13]1([C:8]([NH2:36])=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:12]1
Reactant: NC1CCCCC1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 5 g (0.012 mol) of lovastatin, 6 ml (0.052 mol) of cyclohexylamine and 50 ml of toluene was refluxed for 6 hours. The reaction mixture was cooled to room temperature and 20 ml of ethylacetate was added. The mixture was washed with 2N HCl (2×30 ml) and water (2×20 ml). The organic layer was dried with sodium sulfate, filtered and evaporated to a volume of 15 ml. 50 ml of hexane was added and the precipitate was filtered to give 5.5 g of lovastatin cyclohexanamide as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.[F:14][C:15]([F:19])([F:18])[CH:16]=O.C(=O)CC>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=CC(F)(F)F
Solvent: CCC=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NCC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H).
Reaction SMILES: CN1CCCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:19][CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[O:32])[CH:28]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]1[OH:44]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][NH:33][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]([OH:44])[CH:20]3[NH:19][S:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)(=[O:17])=[O:16])=[CH:36][CH:37]=1
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C(N)C1O
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: Cc1cccc(S(=O)(=O)NC2c3cc(CC(=O)NCc4ccc(Cl)cc4)ccc3OC(C)(C)C2O)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
15 mg PS-methylpiperidine and a solution of 6.0 mg 3-methylbenzenesulfonyl chloride in 0.5 ml dichloromethane were added in succession in a sample well of a sample plate for automatic parallel synthesis to a solution of 9 mg of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-4-chlorobenzyl acetamide obtained above in 0.5 ml dichloromethane. The sample plate was shaken for 40 hours at room temperature, and then 20 mg AMPS was added to the well. The plate was shaken for a further 16 hours at room temperature before the liquid reaction phase was separated from the resin, and the resin was washed twice with 1 ml portions of dichloromethane. The solvent of the combined organic phases was evaporated at reduced pressure, and the title compound was obtained in a purity of 95% (determination by HPLC-MS), [M+H]+ 529.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45](=O)[CH2:46]Br)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:49][C:50]([NH2:52])=[S:51].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45]1[N:49]=[C:50]([NH2:52])[S:51][CH:46]=1)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)C(=O)CBr)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
To a solution of benzhydryl 7-(2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (2.5 g) in tetrahydrofuran (25 ml) was added a solution of thiourea (0.78 g) and sodium acetate (0.34 g) in water (10 ml), followed by stirring at 35° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-benzyloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[S:9]1[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.O>CS(C)=O>[S:9]1[C:13]2[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: CCOC(=O)/C=C/c1cccc2nnsc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a suspension of 60% sodium hydride (1.34 g, 30.7 mmol) in dimethyl sulfoxide (20 mL) was added a solution of trimethylsulfoxonium iodide (6.76 g, 30.7 mmol) in dimethyl sulfoxide (50 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(1,2,3-benzothiadiazol-7-yl)acrylate (6.00 g, 25.6 mmol) in dimethyl sulfoxide (130 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.00 g, yield 47%).
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][CH:25]=[C:24]([O:28][CH3:29])[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.[N:30]1[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[N:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[CH:4][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][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][N:32]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccncn1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccncn2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and pyrimidine-4-carboxylic acid (9 mg, 0.07 mmol). Yield 12 mg (34%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:7])=[O:5])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN1CCOCC1>CN(C=O)C>[CH2:39]([NH:47][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C@@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:7])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)O
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
N[1-(R)-Ethoxycarbonylethyl]-L-leucine (1.39 g, 6 mM), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.16 g, 6 mM), 1-hydroxybenzotriazole (0.93 g, 6 mM) and phenethylamine (0.7 g, 6 mM) were dissolved in DMF (50 ml) at -6°. N-Methyl-morpholine (0.62 g, 6.2 mM) was added and the reaction mixture allowed to warm to room temperature. After 12 h the solvent was removed in vacuo. The residue in EtOAc (150 ml) was washed with H2O (2×100 ml), dried and evaporated in vacuo to yield an oil which was purified by chromatography on SiO2 in EtOAc to give N[1-(R)-ethoxycarbonylethyl]-L-leucine N-phenethylamide as an oil (1.84 g). For analysis, a portion of this material was dissolved in MeOH, treated with anhydrous HCl in Et2O and evaporated in vacuo to yield the corresponding hydrochloride as a foam; (Found: C,60.28; H,8.54; N,7.35; C19H30N2O3.HCl.0.4H2O (requires C,60.35; H,8.48; N,7.41%); [α]D20 =+9.4° (c=0.2, MeOH); νmax (Nujol) 3400 (br), 3100 (br), 2510 (br), 2400 (br), 1740, 1670 and 1550 cm-1 ; δ(CDCl3) 0.92 and 0.95 (6H, each d, each J=7 Hz, (CH3)2CH), 1.27 (3H, t, J=6.5 Hz, CH3CH2), 1.28 (3H,d,J=7 Hz, CH3CH), 1.3-1.7 (3H,m,CH2CH), 2.85 (2H,t,J=6 Hz,CH2CH2C6H5), 3.21 (1H,dd,J=10 Hz and 4 Hz, α--CH), 3.27 (3H,q,J=6.5 Hz, CH3CH), 3.54 (2H,q,J=7 Hz, NHCH2CH2), 4.16 and 4.18 (2H, each q, each J=6.5 Hz, OCH2CH3) and 7.25 (6H,m,C6H5 and NHCO).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][C@@H:31]([O:55][Si:56]([CH2:61][CH3:62])([CH2:59][CH3:60])[CH2:57][CH3:58])[CH2:32][S:33][C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][C@@H:31]([O:55][Si:56]([CH2:59][CH3:60])([CH2:61][CH3:62])[CH2:57][CH3:58])[CH2:32][S:33][C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:39][C:38]=12)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC[C@@H](CN=[N+]=[N-])O[Si](CC)(CC)CC)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 48.8 %

Procedure:
The procedure of Example 1a) was repeated, except that 582 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.11 g of 7-((2R)-3-azido-2-triethylsilyloxypropyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 560 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC=CC=1[Mg]Br.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>C1COCC1>[OH:39][C:32]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)=[C:31]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccccc1Br
Agent: COc1ccccc1[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Reaction time: 0.25 h

Procedure:
To dry magnesium turnings (81 mg, 3.4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2 O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[CH2:15][C:16]([O:18]CC1CC1)=[O:17].O>CO>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH:7]=[CH:6][C:5]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(Cc1ccc(OCC2CC2)cc1Br)OCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(OCC2CC2)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
1M Aqueous sodium hydroxide solution (30 mL) was added to a solution of cyclopropylmethyl [2-bromo-4-(cyclopropylmethoxy)phenyl]acetate (6 g) in methanol (50 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, water was added thereto, and the mixture was washed with diisopropyl ether. The aqueous layer was acidified with 1M hydrochloric acid, and extracted 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 to give the title compound (4.48 g).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9](O)=[O:10].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9]([N:3]([O:4][CH3:5])[CH3:2])=[O:10]
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Yield: 73 %

Procedure:
N,O-dimethlyhydroxylamine hydrochloride (3.28 g, 33 mmol) and 2-amino-3,6-dichlorobenzoic acid (4.76 g, 22 mmol) were dissolved in DMF (110 ml). At r.t. under nitrogen and stirring, first N-methyl morpholine (10 g, 99 mmol) and then HBTU (12.5 g, 33 mmol) were added, and the reaction was stirred at r.t. overnight. The reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was treated with heptane and little diethyl ether to yield 4 g of the product. The mother liquor was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to give another batch of the title compound as an off-white solid (5.52 g, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11](=O)(OCC)[O:12]CC.C([O-])([O-])=O.[K+].[K+]>>[C:5]1([C@@H:2]2[CH2:3][O:4][C:11](=[O:12])[NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCOC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N[C@H](c2ccccc2)CO1

Procedure:
7.54 g (55 mmol) of (2R)-(-)-2-amino-2-phenylethanol are dissolved in 8 ml (61 mmol) of diethyl carbonate, 770 mg (5.5 mmol) of K2CO3 are added, and ethanol is removed by distillation via a column. The crude product is recrystallized from ether/petroleum ether.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][C:10](=[O:28])/[CH:11]=[CH:12]/[C:13]1[CH:27]=[CH:26][C:16]2[NH:17][C:18]([C:20]3([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:15]=2[CH:14]=1.[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]([NH:25][C:20]4([C:18]5[NH:17][C:16]6[CH:26]=[CH:27][C:13](/[CH:12]=[CH:11]/[C:10]([O:9][CH3:8])=[O:28])=[CH:14][C:15]=6[N:19]=5)[CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)/C=C/c1ccc2[nH]c(C3([NH3+])CCCC3)nc2c1
Reactant: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2[nH]c(C3(NC(=O)c4ccc5c(C6CCCCC6)c(-c6ccccc6)n(CC(=O)N(C)C)c5c4)CCCC3)nc2c1
Reaction time: 8 h

Procedure:
To a solution of 1-{5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-benzimidazol-2-yl}cyclopentanaminium trifluoroacetate (from Step 4, 1 eq), 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Example 1, Step 6, 1 eq) in DMF (0.02 M), HATU (1 eq) and DIPEA (5 eq) were added. The reaction mixture was left at RT with stirring overnight. The resulting mixture was partitioned between EtOAc and hydrochloric acid. The combined EtOAc layers were washed with saturated aqueous NaCl solution, separated, dried over Na2SO4, filtered and evaporated in vacuo to afford methyl (2E)-3-(2-{1-[({3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}-1H-benzimidazol-5-yl)acrylate, which was used without further purification. MS (ES+) m/z 672 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Cl
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(C=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
6-Bromoindole-3-carboxaldehyde, 23 (5.0 g, 22.3 mmol) is dissolved in methylene chloride (40 mL), then cooled to 0° C. and tert-butylchloroformate (3.40 g, 25.0 mmol) and triethyl amine (2.50 g, 25.0 mmol) are added over 5 minutes. The reaction is maintained at reflux, under inert atmosphere for 3 hours. The reaction is cooled, filtered and the solvent removed in vacuo. The residue composed primarily of compound 24 is used in the Example 18 without purification. (See, e.g., G. Wille and W. Steglich, Synthesis, 2001, 759-762 for a related procedure.)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)[CH2:12][CH:14]1[O:16][CH2:15]1
Reactant: CNc1ccc(CC#N)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CC1CO1)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of 4-methylaminobenzylcyanide (3.05 g, 20.9 mmol), epichlorohydrine (2.4 ml, 2.87 g, 31 mmol), ethanol (25 ml) and water (20 ml) was heated under reflux for 3 hours. After cooling the mixture was diluted with ethanol (10 ml) followed by addition of aqueous 10N NaOH (6 ml). The obtained clear solution was stirred at room temperature for one hour and the ethanol was distilled off. The residue was diluted with 100 ml of water and extracted with ether (3×50 ml). The organic extracts were washed with brine until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to give 2.21 g of the oily title compound, yield: 52.2%.