Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[CH2:39][CH2:40][CH2:41][NH2:42]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:41][CH2:40][CH2:39][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]4[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC1CCCCN1CCCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN3CCCCC3C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(2-methylpiperidin-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.32 (m, 3H) 1.38-1.55 (m, 2H) 1.56-1.74 (m, 2H) 1.74-2.06 (m, 4H) 2.40-2.47 (m, 3H) 2.91-3.16 (m, 2H) 3.16-3.34 (m, 2H) 3.35-3.69 (m, 3H) 7.63-7.70 (m, 1H) 7.72-7.86 (m, 2H) 8.20 (br. s., 1H) 8.42 (d, J=7.33 Hz, 2H) 8.85-9.00 (m, 2H) 9.03-9.38 (m, 1H) 12.63-13.81 (m, 1H). MS m/z [M+H]+ 459.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].S([O-])([O-])(=O)=O.CS[C:15]([NH2:27])=[NH+:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH3:26].CS[C:30]([NH2:42])=[NH+:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41]>>[CH3:41][C:40]1[NH:39][CH:38]=[N:37][C:36]=1[CH2:35][S:34][CH2:33][CH2:32][N:31]=[C:30]([NH2:42])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:15]([NH2:27])=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH3:26]
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Reactant: NCCCCCN
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,5-diaminopentane (0.43 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.52 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (1.8 g) m.p. 115°-120°.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25]CC1C=CC(OC)=CC=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (25.5 g, 33 mmol) in CH2Cl2 (400 mL) at room temperature, was added trifluoroacetic acid (40 mL). After 1 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5%MeOH in CH2Cl2), to give 19.8 g of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O.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.C(OCC)(=O)C>[N+:17]([C:14]1[S:13][C:12]([C:2]#[C:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-ethynylbenzonitrile (0.5 g), 2-bromo-5-nitrothiophene (0.9 g) and bis(triphenylphosphine)palladium dichloride (83 mg) in anhydrous dimethylformamide (4 ml) was added triethylamine (2.2 ml). The reaction mixture was stirred at room temperature for 3 days then ethyl acetate (200 ml) and saturated sodium chloride (200 ml) were added. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude solid was triturated with 1:1 dichloromethane/hexane followed by diethyl ether to give 4-[(5-nitro-2-thienyl)ethynyl]benzonitrile as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1Br.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (12.5 g, 35.3 mmol) in THF (175 mL) at room temperature was added 4-bromophenol (6.49 g, 37.1 mmol) and Cs2CO3 (34.5 g, 106 mmol). The resulting suspension was warmed to 50° C. and the reaction turned faintly yellowish green after a few minutes and then subsequently faintly pink, the mixture remained a suspension. After 4 h at 50° C. the mixture was cooled to room temperature, diluted with water (175 mL), and stirred for 15 min. The solution was transferred to a separator funnel and the phases were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were then washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (14.7 g, 33.0 mmol, 93% yield) as a faintly pink solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm==3.83 (s, 3H), 6.92-7.03 (m, 3H), 7.25-7.35 (m, 2H), 7.39-7.50 (m, 2H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1)=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NNC(=O)[C@H]2CC[C@H]3CN2C(=O)N3OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)NNC(=O)[C@H]2CC[C@H]3CN2C(=O)N3O)C1
Yield: 88.2 %

Procedure:
To a solution of tert-butyl 3-[(2-{[(2R,5S)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 260 (0.35 g, 0.74 mml) in methanol (25 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[(2-{[(2R,5S)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 261 (0.25 g, 88%) as a white foam.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl>CO>[CH2:1]([S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:18])([CH3:19])[CH2:11][NH:12]2)=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc2c(c1)N(C(C)=O)CC2(C)C
Agent: Cl
Solvent: CO
Product: CCS(=O)(=O)c1ccc2c(c1)NCC2(C)C
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
1-(6-Ethanesulfonyl-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (130 mg, 0.46 mmol) was dissolved in MeOH (7 mL) and 5 M hydrochloric acid (920 μL, 4.6 mmol) was added. The solution was stirred at 90° C. for 1.5 h then solvent was removed in vacuo. The residue was quenched with saturated aqueous NaHCO3 and the product extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (60 mg), used without further purification. MS: [M+H]+=240.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[Cl:23]C1C=C(B(O)O)C=CC=1Cl>>[Cl:23][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
In analogy to 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (WO 2008/040651) by substituting 4-chlorophenylboronic acid with 3,4-dichlorophenylboronic acid the title compound was obtained as white solid. MS (EI): 365.9 and 364.1 (M−H).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:23])[CH3:22])[O:19][CH:20]=2)[CH:14]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([C:21](=[O:23])[CH3:22])[O:19][CH:20]=2)[CH:14]=1
Reactant: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {1-[2-(1-hydroxy-ethyl)-oxazol-4-ylmethyl]-1H-pyrazol-4-yl}-carbamic acid 2-chloro-benzyl ester (211 mg, 0.56 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (270 mg, 2.80 mmol) and the reaction mixture was stirred at 55° C. for 3 h before being filtered through Celite. Purification of the residue by FC (2:1 to 1:2 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (EA)=0.60. LC-MS-conditions 02: tR=0.94 min; [M+H]+=375.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:27]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: Nc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 29.1 %

Procedure:
To a solution of 6.0 g (15.15 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 100 ml of methylene chloride was added 1.70 ml (18.18 mmole) of sulfuryl chloride at 0° C. The resulting mixture was stirred at RT for 5 days under a nitrogen atmosphere. The mixture was quenched with water, then partitioned between methylene chloride and aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography using 20% ethyl acetate in hexane to give 1.9 g (31.62% yield) of the desired product, mp 172.5° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=[O:19])=O)C.[BH4-].[Na+]>C1COCC1.CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH:7]([OH:19])[CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred solution of 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10 g) in a mixture of THF (100 mL) and MeOH (50 mL) was added NaBH4 in 10 lots over 1 h period. At the end of 1 h, TLC analysis (eluant: EtOAC) showed complete consumption of starting material. Removed solvent under reduced pressure, to the residue was added saturated NH4Cl solution (200 mL) and stirred for 1 h at rt. The aqueous layer was extracted with DCM (4×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated the filtrate. The product was purified by silica gel column chromatography (Eluant 8:2 EtOAc/Hexanes) to give 3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, cis/trans mixture). The cis/trans mixture (5 g) was separated on ISCO (Combiflash instrument) on a silica gel column (300 g) by eluting with ethyl acetate in hexanes to get (±)-trans-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, HRf) and (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, LRf).
Reaction SMILES: [NH2:1][C:2](=[O:106])[CH2:3][NH:4][C:5](=[O:105])[C@@H:6]([NH:13][C:14](=[O:104])[C@@H:15]([N:17]([CH3:103])[C:18]([C@H:20]([CH2:92][C:93]([O:95]CC1C=CC=CC=1)=[O:94])[NH:21][C:22](=[O:91])[C@H:23]([CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[NH:24][C:25](=[O:83])[C@H:26]([CH:80]([CH3:82])[CH3:81])[NH:27][C:28](=[O:79])[C@H:29]([CH3:78])[NH:30][C:31](=[O:77])[C@H:32]([CH2:73][CH:74]([CH3:76])[CH3:75])[NH:33][C:34](=[O:72])[CH2:35][NH:36][C:37](=[O:71])[C@H:38]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[N:39]([CH3:63])[C:40](=[O:62])[C@H:41]([CH3:61])[NH:42][C:43](=[O:60])[C@H:44]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.[H][H]>CO.O[Pd].[C]>[NH2:1][C:2](=[O:106])[CH2:3][NH:4][C:5](=[O:105])[C@@H:6]([NH:13][C:14](=[O:104])[C@@H:15]([N:17]([CH3:103])[C:18]([C@H:20]([CH2:92][C:93]([OH:95])=[O:94])[NH:21][C:22](=[O:91])[C@H:23]([CH2:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)[NH:24][C:25](=[O:83])[C@H:26]([CH:80]([CH3:82])[CH3:81])[NH:27][C:28](=[O:79])[C@H:29]([CH3:78])[NH:30][C:31](=[O:77])[C@H:32]([CH2:73][CH:74]([CH3:75])[CH3:76])[NH:33][C:34](=[O:72])[CH2:35][NH:36][C:37](=[O:71])[C@H:38]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[N:39]([CH3:63])[C:40](=[O:62])[C@H:41]([CH3:61])[NH:42][C:43](=[O:60])[C@H:44]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Reactant: [H][H]
Agent: O[Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83 %

Procedure:
Hydroxypalladium/carbon (277 mg, 50% wet w/w) was added to a solution of benzyl (6S,9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-6,12,27-tribenzyl-18-isobutyl-24-isopropyl-2,2,9,11,21-pentamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oate synthesized according to a conventional method (Boc-Phe-Ala-MePhe-Gly-Leu-Ala-Val-Phe-Asp(OBn)-MeAla-Ser(OtBu)-Gly-NH2) (Compound SP-506) (831 mg, 0.563 mmol) in methanol (5 ml)-ethyl acetate (5 ml) under a nitrogen atmosphere, the atmosphere was replaced with hydrogen, and the mixture was then stirred at room temperature for 3.5 hours. The reaction solution was then filtered through celite, and the filtrate was concentrated under reduced pressure to afford the title compound (SP-505) (648 mg, 83%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc(Cl)cc4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (s, 1H), 12.95 (s, 1H), 8.99 (s, 1H), 8.28 (s, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.49 (tdd, J=7.1, 5.1, 1.7 Hz, 1H), 7.40-7.34 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Li+].C[Si]([N-:34][Si](C)(C)C)(C)C.Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([O:4][C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:34])=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)OC(=O)C=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)C=Cc1ccc(N)cc1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
The mixture of 12 (1.53 g, 5.68 mmol), Pd2(dba)3 (260 mg, 5% mmol), P(t-Bu)3 (0.23 mL, 1 M in toluene, 4% mmol) in dry toluene (30 mL) was stirred under N2 protection for 15 min. Then a solution of LHMDS in toluene (6.2 mL, 1 M in toluene, 6.2 mmol) was added dropwise. After stirred at ambient temperature overnight, the resultant dark color suspension was added 1 N hydrochloric acid (8 mL) slowly. The resulting mixture was stirred at ambient temperature for 2 hours. Then the suspension was filtered through celite and the filtrate was diluted with dichloromethane (70 mL). The organic layer was washed with saturated NaHCO3 aqueous solution, brine, and dried over Na2SO4. After filtered and concentrated, the crude product was purified by silica gel column using hexane and ethyl acetate (2:1) as eluent to give 1.03 g light yellow solid, in 90% yield. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J=15.9 Hz, 1H), 7.35 (d, J=8.48 Hz, 2H), 6.65 (d, J=8.56 Hz, 2H), 6.22 (d, J=15.9 Hz, 1H), 5.12 (seq, J=6.24 Hz, 1H), 3.91 (brs, 2H), 1.30 (d, J=6.24 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 167.20, 148.56, 144.55, 129.80, 124.88, 114.84, 114.35, 67.32, 22.00. mp 78-80° C. IR v (Diamond, cm−1): 3417, 3335, 1673, 1592, 1513, 1264, 1168, 1104, 980, 823. MS (ESI) m/z found 206.2 (M+H)+.
Reaction SMILES: O[C:2]1([C:22]2[C:23]([OH:31])=[CH:24][C:25]3[O:29][CH2:28][CH2:27][C:26]=3[CH:30]=2)[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[N:4]([CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][O:17]2)[C:3]1=[O:21].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(O)(C3C=CC(OC)=CC=3O)C2=O)C=CC=CC=1>>[OH:31][C:23]1[C:22]([CH:2]2[C:10]3[CH:9]=[C:8]4[O:11][CH2:12][CH2:13][O:14][C:7]4=[CH:6][C:5]=3[N:4]([CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[C:3]2=[O:21])=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: O=C1N(C[C@H]2CCCO2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3
Agent: COc1ccc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C[C@H]1CCCO1)OCCO3

Procedure:
Following the procedure as described in PREPARATION 12B, and making non-critical variations using 8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one, 8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained (76%): 1H NMR (300 MHz, CDCl3) δ9.27-9.07 (m, 1H), 6.90-6.81 (m, 1H), 6.74 (s, 1H), 6.72-6.68 (m, 1H), 6.53 (s, 1H), 4.99-4.89 (m, 1H), 4.62-4.45 (m, 2H), 4.38-4.08 (m, 5H), 3.94-3.57 (m, 4H), 3.18-2.89 (m, 2H), 2.06-1.93 (m, 1H), 1.93-1.78 (m, 2H), 1.72-1.55 (m, 1H); MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].[CH2:22](I)[CH2:23][CH3:24]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[N:8]([CH2:22][CH2:23][CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1C
Yield: 34.2 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 1-propyl iodide (0.07 mL, 0.7 mmol) to give the title compound (0.056 g) as a white solid.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:20](=[O:21])[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:22][CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=3)[N:9]=[C:8]1[C:26](OCC)=[O:27])([O:3][CH2:4][CH3:5])=[O:2].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][NH2:40]>C(Cl)(Cl)Cl>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:26]([C:8]1[N:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:20](=[O:21])[C:19]2[C:10]([N:9]=1)=[N:11][C:12]1[C:17]([CH:18]=2)=[CH:16][C:15]([O:22][CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=1)=[O:27]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)nc2nc3cc(OC)c(OC)cc3cc2c1=O
Reactant: NCCOc1ccccn1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCCOc2ccccn2)nc2nc3cc(OC)c(OC)cc3cc2c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 3-carbethoxymethyl-7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (0.415 g., 1mM) and 2-(2-pyridyloxy)ethylamine (0.276 g., 2 mM) in chloroform (10 ml.) is refluxed for 24 hours. It is then cooled to room temperature and concentrated in vacuo. The residue, an oil, is crystallized by addition of ether until precipitation is complete. Yield = 0.41 g. (81%) of product; m.p. 170°-180° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[O:3]1.[N:12]([O-:14])=[O:13].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[C:4]=2[O:3]1
Reactant: Cc1ccc2c(c1)C[C@@H](C)O2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c([N+](=O)[O-])c1)O[C@H](C)C2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-2,5-dimethyl-2,3-dihydrobenzofuran (3d) (2.0 g, 13 mmol) in TFA (40 mL) was cooled to 0° C., NaNO2 (1.7 g, 23 mmol) was added thereto. It was stirred at ambient temperature for 12 h. The mixture was concentrated, poured into water (50 mL), extracted with EtOAc (150 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (3e).