Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]1[C:38]([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]5[C:38]([OH:40])=[O:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: O=C(O)[C@H]1COCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCOC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-3-(R)-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Morpholine-3-(R)-carboxylic acid following general procedure C.
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[C:20](N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)C.C(Cl)C(=C)C>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2](=[CH2:20])[CH3:3]
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Agent: C=C(C)CCl
Product: C=C(C)CON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Yield: 84 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and methallylchloride in 84% yield as colorless oil.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([O:21][C:22]([C:24]1[C:25]([NH2:29])=[N:26][NH:27][CH:28]=1)=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]([C:24]1[C:25]([NH:29][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:26][NH:27][CH:28]=1)=[O:23])[CH3:20]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]nc1NC=C1C(=O)Nc2ccccc21

Procedure:
The named compound is prepared by substituting 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2001 gms. of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[K].[K].C(C1C=CC(S(NC(=O)C(C2C=CC3OCOC=3C=2)OC2C=CC(C(O)=O)=CC=2CCC)(=O)=O)=CC=1)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:91]([NH2:95])([NH2:94])(=[O:93])=[O:92].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH:94][S:91](=[O:93])(=[O:92])[NH2:95])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: NS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)NS(N)(=O)=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 158 mg (0.293 mmol) of N-(4-iso-propylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acid form of the product of Example 58) and 71 mg (0.440 mmol) of 1,1'-carbonyldiimidazole in 1 mL of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 mmol) of sulfamide and 110 μL (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600E HPLC system with a 4.6×250 mm 5 μM Zorbax-RX C8 at 40° C. and eluting isocratically 1.5 mL/min using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector. After 2.0 hour of additional refluxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diluted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 5500 HPLC by applying the compound in a 4.5 mL total volume (2.5 mL methanol and 2 mL water) onto two in series 21.2×250 mm Zorbax ODS C18 columns and eluting at 15 mL/min with 60% acetonitrile and 40% water both with 0.1% TFA. The column effluent was monitored 254 nM with a Kratos Spectroflow 783 UV detector. Combination and evaporation of the purified fractions afforded 50 mg (28%) of the title compound. The mixed fractions were combined and subjected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65% water and 35% acetonitrile both with 0.1% TFA to 65% acetonitrile and 35% water both with 0.1% TFA, holding all other conditions from the previous chromatography. The purified fractions were combined and concentrated to afford 57 mg (31%) of the title compound, which was combined with the previously purified material to provide a total of 107 mg (59%) of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:24]Cl>CO>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:24])=[O:4]
Reactant: COc1cccc(CC(C)NC(=O)C(F)(F)F)c1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CC(C)NC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
A solution of N-trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine (4.29 g, 15.7 mmol) in methanol (100 mL) was cooled to −78 C. and treated with CaCO3 (3.17 g, 31.4 mmol), followed by a solution of ICl (6.37 g, 39.3 mmol) in methanol (50 mL). The reaction was allowed to warm to 20 C. while stirring overnight. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 6.72 g of a white solid powder. MS calculated for C12H13F3INO2+H: 388, observed: 388.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:27]([C:29]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:27][C:29]2([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31]2)[CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCO)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 83.4 %

Procedure:
2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 71c), (1-formylcyclopropyl)-carbamic acid, 1,1-dimethylethyl ester (0.260 g), sodium triacetoxyborohydride (0.600 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate), to afford the subtitled compound (0.302 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:18]=1.C[Si]([C:36]#[N:37])(C)C>II.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:19]2[CH:18]=[CH:17][C:22]([NH:23][CH:12]([C:11]3[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[C:36]#[N:37])=[CH:21][CH:20]=2)=[CH:26][CH:27]=1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: II
Solvent: CO
Product: N#CC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(OCc2ccccc2)c1
Yield: 67.3 %

Procedure:
Reference to α-amino nitrile synthesis: Synlett, 2005, 8, 1325. A methanol solution (50 mL) of 3-benzyloxybenzaldehyde (5 g, 23.6 mmol), 4-amino-4-chlorodiphenyl ether (5.7 g, 25.9 mmol), iodine (120 mg, 0.47 mmol) and trimethylsilylcyanide (3.8 mL, 28.3 mmol) is stirred at room temperature for 18 h. The precipitate that formed is collected and rinsed with ethyl acetate/hexane (1:4) to obtain ˜7 g (67%) of 2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(benzyloxy)phenyl)acetonitrile as a light brown solid.
Reaction SMILES: [N:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][N:12]=3)[C:7](=O)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)C>[CH:4]1[C:5]2[C:6]3[C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[N:12][C:13]=4[C:14]=2[N:1]=[CH:2][CH:3]=1)=[N:24][C:17]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:23]=3
Reactant: Nc1ccccc1N
Reactant: O=C1C(=O)c2cccnc2-c2ncccc21
Solvent: CCO
Product: c1ccc2nc3c4cccnc4c4ncccc4c3nc2c1
Reaction time: 0.08 h

Procedure:
1.0 g of 1,10-phenanthroline-5,6-dione in the Fourteen Preferred Embodiment was dissolved into 200 g of ethanol to prepare a solution. 1.0 g of o-phenylene diamine was dissolved into 100 ml of ethanol to prepare a solution. The latter solution was added into the former solution, and the mixed solution was current-circulated for 5 minutes. Then, the mixed solution was vacuum-concentrated to precipitate a crystal. The precipitated crystal was recrystallized by water-ethanol to obtain dipyrido (3,2-a:2',3'-c) phenazine. The melting point of dipyrido (3,2-a:2',3'-c) phenazine as the condensed polycyclic compound was 257° C. according to the DSC measurement.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1([N:18](C)N)C=CC=CC=1>>[OH:1][C:2]1[C:11]([NH2:18])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: CN(N)c1ccccc1
Product: Nc1c(O)ccc2cccnc12
Temperature: 130 °C
Yield: 30.8 %

Procedure:
7-Hydroxyquinoline (1.1 g, 7.5 mmol) and 1-phenyl-1-methylhydrazine (0.92 g, 7.5 mmol) were combined and heated at 130° C. under nitrogen for 16 h. After cooling the solvent was partially evaporated, the crude product was purified by column chromatography with heptane/EtOAc (1:1) as the eluent to give the title compound (370 mg, 31%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.NC1C=CC(Cl)=CC=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].N1C=CC=CC=1>ClCCl.CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][CH:15]=[O:16])=[N:19][CH:20]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=CNc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{2-{[tert-butyl)amino]sulfonyl}phenyl}benzoic acid (167 mg, 0.5 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.09 ml, 1 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). The compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.17 g, 0.6 mmol) and pyridine (0.122 ml, 1.5 mmol) were added to the solution. The mixture was stirred at r.t. overnight. The solvent was evaporated to give (2-{[4-(2-{[tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide. MS found for C29H26Cl2N4O4S M+=597, (M+2)+=599. Step 2: The mixture of the compound of (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide example 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t. for 5 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].COC(Cl)[Cl:22]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][C:14]([Cl:22])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(Cl)Cl
Reactant: O=C(O)COC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: O=C(Cl)COC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of p-nitrobenzyloxycarbonyloxyacetic acid (300 mg) and 1,1-dichlorodimethyl ether (1 ml) in ethyl acetate (7.5 ml) was refluxed for 5 hours. The reaction mixture was evaporated to give p-nitrobenzyloxycarbonyloxyacetyl chloride, which was then added to a solution of 2-hydroxymethyl-penem-3-carboxylic acid p-nitrobenzyl ester (168 mg) and triethylamine (0.1 ml) in dichlormethane (10 ml) with ice-cooling, followed by stirring for 1 hour. The reaction mixture was treated by the procedure similar to that described in Example 53 to give 2-p-nitrobenzyloxycarbonyloxyacetoxymethyl-penem-3-carboxylic acid p-nitrobenzyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[C:7]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].CC1C=CC(S([O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[C:48]([F:49])=[CH:47][C:46]([F:50])=[C:45]([F:51])[C:44]=2[F:52])(=O)=O)=CC=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([C:8]#[C:7][C:6]2[CH:10]=[CH:2][C:3]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]3[C:48]([F:49])=[CH:47][C:46]([F:50])=[C:45]([F:51])[C:44]=3[F:52])=[CH:4][CH:5]=2)=[C:10]2[C:6]=1[C:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([CH3:11])[N:9]2[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2c(F)cc(F)c(F)c2F)cc1
Reactant: COC(=O)CCCc1c(C)[nH]c2c(Br)ccc(F)c12
Product: COC(=O)CCCc1c(C)n(CCCC(=O)OC)c2c(C#Cc3ccc(OCCCCc4c(F)cc(F)c(F)c4F)cc3)ccc(F)c12

Procedure:
By the same procedure as in Example 2→Example 3→Example 4→Example 8 using methyl 4-(7-bromo-4-fluoro-2-methyl-1H-indol-3-yl)butanoate instead of the compound prepared in Example 1; using methyl 4-bromobutyrate instead of ethyl 4-bromobutyrate; and using 4-(2,3,4,6-tetrafluorophenyl)butyl 4-methylbenzene sulfonate instead of the compound prepared in Example 7, the title compound having the following physical properties was obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][N:15]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC([CH2:23][C:24]([OH:26])=O)(C(O)=O)O>O1CCCC1.ICI.C[Li]>[O:26]1[CH2:24][CH:23]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[CH:9]=[CH:10][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccnc(Oc2ccccc2)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: ICI
Product: c1ccc(Oc2ccc(C3CO3)cc2)nc1
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxyisonicotinaldehyde (378 mg) in tetrahydrofuran (4 ml), 0.228 ml of diiodomethane and 3.8 ml of methyllithium (1.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:44])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:35])[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH3:22])=[C:17]([CH2:36][O:37]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:44])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:35])[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH3:22])=[C:17]([CH2:36][OH:37])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:45][CH:46]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1ccc2ccccc2n1
Yield: 98.5 %

Procedure:
A solution of 174 mg of N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-quinolin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 2.5 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3% MeOH in CH2Cl2 provides 146 mg of the title compound as a white solid. Recrystallization from EtOAc-hexane affords white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].[CH2:46]([O:48][C:49]1[C:50](=O)[C:51](=[O:56])[C:52]=1[O:53]CC)[CH3:47]>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:50]2[C:51](=[O:56])[C:52](=[O:53])[C:49]=2[O:48][CH2:46][CH3:47])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNc2c(OCC)c(=O)c2=O)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reaction time: 6 h

Procedure:
To a solution of 100 mg of 4-((S)-3-Amino-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml DCM and 0.1 ml triethylamine, 32 mg 3,4-Diethoxy-cyclobut-3-ene-1,2-dione was added at RT. After stirring for 6 h, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25](O)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][CH2:24][C:25](=[O:26])[CH2:2][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reactant: CC(=O)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)CC(=O)c2ccncc2)CC1

Procedure:
Condensation of 4-acetylpyridine with 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1), employing the protocol described in Preparation 22, afforded the title compound: m/z (ES+)=263.2 [M-Boc+H]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Si:9]([O:16][CH2:17][C@@H:18]([N:20]1[C:24]2[N:25]=[CH:26][N:27]=[CH:28][C:23]=2[CH:22]=[CH:21]1)[CH3:19])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Si:9]([O:16][CH2:17][C@@H:18]([N:20]1[C:24]2[N:25]=[CH:26][N:27]=[CH:28][C:23]=2[C:22]([I:1])=[CH:21]1)[CH3:19])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2cncnc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
N-Iodosuccinimide (124 g, 553 mmol) was added to 7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidine (153.4 g, 526 mmol) (see Preparation 8) in acetonitrile (700 mL). The mixture was stirred at room temperature for 16 hours then saturated aqueous sodium thiosulfate (700 mL) was added. The mixture was extracted with EtOAc (800 mL) then the organic extract was dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow solid in 66% yield, 145 g. 1H NMR (400 MHz, CDCl3) δ: −0.90 (d, 6H) 0.80 (s, 9H) 1.58 (d, 3H) 3.84 (m, 2H) 5.07 (m, 1H) 7.48 (s, 1H) 8.73 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: [CH2:1](Br)[CH3:2].[C:4]([O:8][C:9](=[O:41])[N:10]([CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[C:28]2[C:33]([CH:34]=[C:35]3[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:7])([CH3:6])[CH3:5].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:4]([O:8][C:9](=[O:41])[N:10]([CH2:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]1[C:40]2[C:35]([CH:34]=[C:33]3[C:28]=1[CH:29]=[CH:30][CH:31]=[CH:32]3)=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:1][CH3:2])[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCNCc1c2ccccc2cc2ccccc12)C(=O)OC(C)(C)C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Ethylbromide (EtBr, 508 mg, 4.66 mmol) was dissolved in anhydrous acetonitrile and added to a stirring mixture of compound 10 (805 mg, 1.55 mmol) and anhydrous K2CO3 (644 mg, 4.66 mmol). The mixture was then stirred overnight at 75° C. under a N2 atmosphere. After the confirmation of the disappearance of the 10 by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 11 as a light yellow oil. Yield 80%; Rf=0.35 (3% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.43 (d, 2H), 8.25 (s, 1H), 7.86 (d, 2H), 7.43 (m, 2H), 7.37 (m, 2H), 4.34 (s, 2H), 2.78-2.92 (m, 4H), 2.64 (m, 4H), 2.36 (m, 2H), 1.21-1.48 (m, 23H), 1.16 (m, 2H); 13C NMR (CDCl3) δ 155.7, 131.1 (3C), 131.0, 128.7 (2C), 127.0 (2C), 125.2 (2C), 124.8 (2C), 124.5 (2C), 78.9, 78.4, 53.4, 50.6, 50.0, 47.9, 45.3, 43.5, 37.1, 28.3 (6C), 26.5, 11.7. HRMS (FAB) m/z calcd. for C33H47N3O4 (M+H)+ 550.3639, found 550.3619.