Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]([NH:8][C:9]([C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])[CH2:6][CH3:7].Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]([N:8]1[C:9](=[O:10])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][C:20]1=[O:21])[CH2:6][CH3:7]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@H](CC(=O)OC)NC(=O)c1ncccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Yield: 99 %

Procedure:
A solution of 1.6 g of (R)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester and 0.86 mL of trichloromethyl chloroformate in 25 mL of tetrahydrofuran is stirred at 90° C. for 3 h. The resulting mixture is diluted with saturated sodium bicarbonate solution and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica to give 1.75 g (99%) of (R)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.C(OCC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:13])=[O:8])[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.95 g (24.06 mmol) of 3-acetylbenzoic acid were initially charged in 100 ml of toluene and 75 ml of methanol. After dropwise addition of 4.12 g (36.09 mmol) of trimethylsilyldiazomethane 2M in diethyl ether at RT, an instant evolution of gas in the reaction solution was observed. Another 0.27 g (2.4 mmol) of trimethylsilyldiazomethane 2M in diethyl ether was added until the reaction solution remained yellow, and the mixture was stirred at RT for 10 min. The reaction solution was evaporated.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]1(=[O:46])[N:28]([CH2:29][C:30]([N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH3:33])=[O:31])[C:27](=[O:41])[C:26]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:25]12>CN(C=O)C>[C:27]1(=[O:41])[N:28]([CH2:29][C:30]([N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:36][CH:35]=2)[CH3:33])=[O:31])[C:24](=[O:46])[C:25]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:26]12
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-phthalimidomethylcarbonyl-N-methyl-amino)-aniline in DMF.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH2:36][C:35](=[CH:38][Sn](C)(C)C)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([N:32]1[CH2:37][CH2:36][C:35](=[CH:38][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N1CCC(=C[Sn](C)(C)C)CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Product: CC(C)(C)N1CCC(=Cc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 1-tert-butyl-4-[(trimethylstannyl)methylene]piperidine (INTERMEDIATE ABA3)by a procedure analogous to that described in EXAMPLE HHH1, Step A. Mass spectrum (ESI) 554 (M+1).
Reaction SMILES: C(Cl)(Cl)Cl.[N:5]1([CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:26].[OH2:32]>>[S:24]1[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13][CH:12]1[CH2:11][N:5]1[CH2:10][CH2:9][N:8]([CH2:26][C:25]([N:27]2[CH2:30][CH2:31][CH2:29][CH2:28]2)=[O:32])[CH2:7][CH2:6]1
Reactant: c1ccc2c(c1)nc1n2CCC(CN2CCNCC2)S1
Reactant: O
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCN(CC2CCn3c(nc4ccccc43)S2)CC1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To 20 ml of chloroform was dissolved 1.0 g of 3,4-dihydro-2-piperazinomethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, followed by the addition of 0.4 g of 1-chloroacetylpyrrolidine under ice-cooling conditions. Thereafter, 0.5 ml of triethylamine was added dropwise. The mixture was stirred at room temperature for 8 hours. After the completion of the reaction, the reaction mixture was added with water and then extracted with chloroform. The resultant chloroform layer was dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 0.57 g (Yield: 41%) of the intended product, m.p. 159°-162° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N12CCCN=C1CCCCC2.[CH:47]1(/[CH:52]=[CH:53]/[C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1>C(#N)C>[CH:47]1([CH:52]([N:25]2[CH:26]=[C:22]([C:20]3[NH:19][C:16]4=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][C:5]5[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:14]=[C:15]4[CH:21]=3)[CH:23]=[N:24]2)[CH2:53][C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: N#C/C=C/C1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C(CC#N)C5CCCC5)c4)cc3n2)cc(OC)c1
Reaction time: 16 h
Yield: 17.5 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 51.1 μmol) in acetonitrile (1.0 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.2 μL, 61.5 μmol) and (2E)-3-cyclopentylacrylonitrile (from Adesis, cat#9-245, 6.8 μL, 61.7 μmol) were added sequentially at room temperature. After 16 hours, the volatiles were removed and the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (4.2 mg) as its TFA salt. LCMS calculated for C27H31N6O2 (M+H)+: m/z=471.2. Found: 471.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(I)c1
Yield: 75.2 %

Procedure:
1.21 g (0.0063 mol) of 1-benzyl-4-hydroxypiperidine and 0.874 ml (0.0063 mol) of triethylamine were dissolved in 80 ml of toluene and treated with 1.6 g (0.006 mol) of 3-iodo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.9 g (76%) of 1-benzyl-piperidin-4-yl 3-iodo-benzoate were obtained as yellowish crystals; m.p. 101°-103°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]#[N:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>ClCCl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]#[N:33])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1C#N
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (810 mg) and 37% formalin (0.53 mL) in the same manner as in the synthesis of Example 1 was dissolved in dichloromethane (15 mL), and triethylamine (1.90 mL) and 3-chloro-5-cyano-4-methoxybenzoyl chloride (993 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (580 mg) as a yellow oily substance.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.C(Cl)Cl.Cl>CC(O)C>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(N[C@H](CO)c1ccc(Cl)c(Cl)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Reaction time: 2 h

Procedure:
To a solution of 69a (0.175 g, 0.301 mmol) and DCM (3 mL) was added 6M HCl (0.0110 g, 0.301 mmol) in IPA and the reaction was stirred for 2 h and then poured into satd. aq. Na2CO3 and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:30 to 500:45) to afford 0.030 g (21.3%) of I-43: MS m/z (APCI-pos) M+1=466.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CN(C)[CH:22]=[O:23].O>C(OCC)C>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:22]=[O:23])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.4 g of 2-bromobenzaldehyde diethyl acetal in 200 ml of dry diethyl ether at -65° C. was added 27.5 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred at this temperature for 30 min. then slowly warmed to -40° C. when 3.4 ml of dimethylformamide was added dropwise. The reaction was warmed to room temperature then 100 ml of water was added and the organic layer was separated. The aqueous layer was extracted with two 100 ml portions of ether and the combined organic extracts were dried over sodium sulfate and evaporated to give 8.5 g of 2-formylbenzaldehyde diethylacetal as an oil; ; 1H-NMR (200 MHz, CDCl3) d 5.06 (CHOEt).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[K+].C(O)C.Cl>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(NCCc2cccs2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 29.7 g. of crude ethyl 4-[2-(2-thienyl)-ethylamino]benzoate, 20 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The solution is diluted with 100 ml. of water and adjusted to pH 6 with concentrated hydrochloric acid. The mixture is cooled, filtered and the solid washed with ethanol-water (1:1) to give a solid. The solid is heated with 200 ml. of ethanol, filtered and the filtrate concentrated. Purification gives the product, m.p. 163°-165° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([CH2:31][CH2:32][CH2:33][CH3:34])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[CH:5]1[C:35]([O:37]C)=[O:36])(=[O:3])[CH3:2].[OH-].[Na+:40]>CO>[Na+:40].[Na+:40].[CH2:31]([C:11]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]2[CH:5]([C:35]([O-:37])=[O:36])[N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][C:7]=2[N:10]=1)[CH2:32][CH2:33][CH3:34].[CH2:31]([C:11]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]2[CH:5]([C:35]([O-:37])=[O:36])[N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][C:7]=2[N:10]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)[O-])N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in Example 4 (142 mg), 1N aqueous sodium hydroxide solution (0.60 ml) and methanol (5 ml) is stirred at room temperature overnight, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by column chromatography of nonionic adsorbing resin (tradename; NP-20, manufactured by Mitsubishi Kasei Corporation, Japan), and lyophilized to give 2-n-butyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylic acid disodium salt (100 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@@H:10]([NH:49][C:50](OCC1C=CC=CC=1)=[O:51])[C:11]([N:13]([CH:23]([C:41]1[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=1)[C:24](=[O:40])[NH:25][C:26]1C=C[CH:29]=[CH:28][C:27]=1OCC1C=CC=CC=1)[C@@H:14](C(OC)=O)[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12].[C:60]([OH:63])(=O)[CH3:61]>C(O)C.[Pd]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C@H:10]1[NH:49][C:50](=[O:51])[C@@H:14]([C@@H:15]([CH3:16])[CH2:17][CH3:18])[N:13]([CH:23]([C:41]2[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[C:24]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:61][C:60]=2[OH:63])=[O:40])[C:11]1=[O:12]
Reactant: CC(=O)O
Reactant: CC[C@H](C)[C@H](C(=O)OC)N(C(=O)[C@H](NC(=O)OCc1ccccc1)C1Cc2ccccc2C1)C(C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(C)nc1C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C

Procedure:
The crude methyl N-[(2R)-2-(2,3-dihydro-1H-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-alloisoleucinate (intermediate 1) (7.46 g) was dissolved in ethanol (150 mL) and acetic acid (10 mL) and the mixture was hydrogenated at 1 atmosphere of H2 over 10% palladium on carbon (Degussa type) (1.8 g wetted with water 1:1 w:w) for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water with saturated aqueous sodium hydrogen carbonate added until the aqueous phase was basic (pH 8). The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate:water 3:1 (100 mL) then with saturated brine before being dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The crude product was purified on a Redisep silica column (120 g) eluted with 0-10% methanol in ethyl acetate to give the title compound as a pair of diastereomers (2.94 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10](=[O:15])[CH:9]=[CH:8]2.C(O[CH2:20][C:21](=[CH2:27])[CH2:22][Si](C)(C)C)(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C:10](=[O:15])[CH:9]3[CH2:22][C:21](=[CH2:20])[CH2:27][CH:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc2oc(=O)ccc2c1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C=C1CC2C(=O)Oc3ccc(OCOC)cc3C2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxymethoxy coumarin 17a (21 g, 0.102 mol) and Pd(OAc)2 (2.75 g, 0.012 mol) in 500 mL THF add 2-(acetoxymethyl)allyl-trimethylsilane (26 mL, 0.122 mol) followed by triisopropyl phosphite (18.1 mL, 0.073 mol). After stirring at 60° C. overnight, cool the solution to RT, concentrate under reduced pressure, and dilute with EtOAc. Wash the solution with saturated aqueous sodium bicarbonate and brine. Dry over Na2SO4, and then concentrate to an oil. Purify the material by silica gel chromatography (Biotage 40M+65M columns, 10 to 30% EtOAc/Hex over 60 min at 50 mL/min followed by 30 to 50% EtOAc/Hex over 60 min at 50 mL/min) to give 18.3 g (0.070 mol, 69%) of cyclopentanoid 18 and 3.8 g (18.3 mmol, 18%) of recovered starting material. HRMS(ES+) calc for C15H17O4: 261.1127, found: 261.1122 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(N)=O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C#N
Temperature: -35 °C
Yield: 84.8 %

Procedure:
In a dry three-necked flask, 286 mL of pyridine, (S)-[2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (13.5 g, 49.8 mmol) and imidazole (7.11 g, 104.6 mmol) were added successively under nitrogen atmosphere. Then the reaction system was cooled to −35° C. followed by dropwise addition of phosphorus oxychloride (19 mL, 204.2 mmol) with stirring. The reaction mixture was stirred for 1 hour at the same temperature. After warmed up to room temperature, the reaction mixture was stirred for another 30 minutes. The mixture was evaporated to remove pyridine and the resulting mixture was diluted with ethyl acetate followed by addition of water. The mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (S)-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1c (10.7 g, yield 84.9%) as a white powder.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4].[CH2:24]=[O:25]>C(O)(=O)C>[CH2:1]([N:5]1[C:9]([CH2:24][OH:25])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(-c2ccc(OC)cc2)nc1-c1ccccc1
Reactant: C=O
Solvent: CC(=O)O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 150 ml sealed flask is added 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole (10.72, 35 mmol) followed by the addition of 24 ml of acetic acid and 24 ml of 37% formaldehyde, the resulting mixture is stirred at 70° C. for 8 h, then cooled to room temperature. The organic solvents is evaporated, the residue is diluted 100 ml of water and basified with sodium hydroxide solution, the mixture is extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over Na2SO4 Concentration and purification through silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 1:1) affords 10.0 of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol as white solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, dd, J=8.7 Hz), 7.354˜7.51(2H, m), 7.44˜7.38 (3H, m), 6.87 (2H, d, J=8.7 Hz), 4.59 (2H, s), 3.95 (2H, t, J=7.5 Hz), 3.784 (3H, s), 1.60 (2H, m), 1.16 (2H, m), 0.77 (3H, t, J=7.2 Hz); MS (+VE) m/z 337(M+1).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclohexyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 94 mg, 65%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O)=[CH:11][CH:10]=1)#[N:8].C[N:23](C=O)C>ClCCCl>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:23])=[CH:11][CH:10]=1)#[N:8]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: N#Cc1ccc(CCCCCN)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (43.0 mL, 0.492 mol) was added dropwise to a suspension of 5-(p-cyanophenyl)pentanoic acid in 100 mL of dry 1,2-dichloroethane at 23° C. under a nitrogen atmosphere. After 5 min, 50 mL of DMF was added. After 30 min, the reaction was concentrated in vacuo. The residue was dissolved in anhydrous THF (150 mL) under a nitrogen atmosphere. Azidotrimethylsilane (14.6 mL, 0.110 mL) was added dropwise at 23° C. After 5 min, the reaction was warmed to achieve reflux for 1 hour. The reaction was cooled to 10° C. and concentrated HCl (20 mL) was added over 1 min. The cooling bath was removed and stirring was continued for 15 min. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was basified with 1N NaOH (250 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was diluted with ethyl acetate:methanol (150 mL:5 mL) and treated with anhydrous HCl in dioxane (6.9N) at 0° C. The resultant precipitate was filtered, washed with ethyl acetate then ether. The solid was dried (atmospheric pressure; 55° C.) to afford 14.3 g: m.p. 155°-160° C.