Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:16]1([NH2:39])[C:22](=[O:23])[N:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]1=[O:38])=O)C>>[CH:1]1([CH2:6][C:7]([NH:39][C@H:16]([C:22]([NH:39][CH:16]2[C:17](=[O:38])[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[N:21]([CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]2=[O:23])=[O:23])[CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white amorphous solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:2). Rf=0.29 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CCCC2=NCCN2)cc1)OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=C(Nc1ccc(CCCc2ncc[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 40.5 %

Procedure:
Compound 56 (274 mg, 0.81 mmol) was first dissolved in acetonitrile (10 mL), with potassium permanganate (192 mg, 1.22 mol) and alumina (567 mg, 0.3 mol) added into the solution in batch. After stirring the resulting mixture at room temperature for 40 min, CH3OH (1 mL) was added to reduce excess oxidant. The mixture was filtered and the solid material was washed with DCM:CH3OH=10:1. The filtrate was evaporated and the resulting crude material was purified with silica gel column chromatography (PE:EtOAc:TEA=3:1:0.2) to give compound 57 (110 mg, 41%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.32-7.43 (m, 6H), 7.28 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 6.90-9.95 (m, 2H), 6.70 (br s, 1H), 5.19 (s, 2H), 2.65 (t, 2H, J=7.4 Hz), 2.62 (d, 2H, J=7.4 Hz), 1.98-2.07 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C1(C)C=CC=CC=1.O.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:19]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: CN(C)c1nc(Cl)ccc1C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1nc(C2CC2)ccc1C=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
6-chloro-2-(dimethylamino)nicotinaldehyde (155 mg, 0.840 mmol), sodium carbonate (267 mg, 2.52 mmol), cyclopropylboronic acid (108 mg, 1.26 mmol) and palladium tetrakis(triphenylphosphine) (0) (48.5 mg, 0.0420 mmol) were diluted with toluene (2 mL) and water (200 μL). The reaction was purged with argon, sealed and heated to 90° C. After stirring for 4 hours, the reaction was cooled, loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield 6-cyclopropyl-2-(dimethylamino)nicotinaldehyde (100 mg, 0.526 mmol, 62.6% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=[N:4][NH:3]1.O.NN>CO>[NH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1ccn[nH]c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (255 mg, 1.00 mmol) in methanol (2 mL) was mixed with hydrazine monohydrate (250 mg, 5.00 mmol) at room temperature and stirred at 60° C. for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give a crude reaction product containing the desired product, which was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:31]#[C:30][C:32]1[CH:38]=[CH:37][CH:36]=[C:34]([NH2:35])[CH:33]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(I)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To the degassed mixture of dimethyl 5,5′-{N-[(6-amino-5-iodopridin-3-yl)carbonyl]sulfonimidoyl}dipentanoate (1.16 g, 2.15 mmol, 1.0 equiv.), 3-ethynylaniline (0.34 mL, 3.25 mmol, 1.5 equiv.), and triethylamine (1.2 mL, 8.61 mmol, 4.0 equiv.) in anhydrous DMF (7 mL) under nitrogen atmosphere was added CuI (81.5 mg, 0.42 mmol, 0.2 equiv.) and PdCl2(Ph3P)2 (150.6 mg, 0.21 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and lastly dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to neat EtOAc) to give the title compound as a white foam (1.0 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]2[C:11]([C:14]([F:26])([F:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:12][O:13][C:8]2=[CH:7][CH:6]=1>C(O)C>[F:25][C:14]([F:26])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:11]1[C:9]2=[N:10][C:5]([N:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=[C:8]2[O:13][N:12]=1
Reactant: CNC
Reactant: FC(F)(c1ccc2ncccc2c1)c1noc2ccc(Cl)nc12
Solvent: CCO
Product: CN(C)c1ccc2onc(C(F)(F)c3ccc4ncccc4c3)c2n1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a microwave vial was added dimethylamine (2.0 M in THF, 0.75 mL, 1.5 mmol) and, 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol) in ethanol (3 mL). The mixture was stirred at 140° under microwave irradiation for two hours then was concentrated and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a light yellow solid (87 mg, 85%). MS m/z=341.2 [M+1]+ Calc'd for C18H14F2N4O: 340.3.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:22][S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:7]=[N:6][CH:5]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:16]3[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:8]4[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=4)[C:3]([OH:31])=[O:2])=[N:20][CH:19]=[N:18][C:17]=3[S:21][CH:22]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cncc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cncc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotinic acid methyl ester (100 mg) in dioxane (10 mL) was added 0.80 M lithium hydroxide in water (2.0 mL). The reaction was stirred at ambient temperature for 16 hours, then acidified with 1M hydrochloric acid to pH 3, and the solvent removed under reduced pressure. The residue was dissolved in 20% methanol/dichloromethane (40 mL), filtered, and the filtrate was concentrated. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to give 90 mg (93%) of 5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotinic acid as a white solid. MS [M+H] 425.9, 1H NMR (CD3OD) δ (ppm) 8.91 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 7.60-7.45 (m, 3H), 7.10 (t, J=8.7 Hz, 2H), 4.67 (t, J=9.0 Hz, 2H), 3.94 (t, J=9.3 Hz, 2H), 2.22 (t, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:44](Cl)([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>N1C=CC=CC=1>[CH2:1]([O:19][CH2:20][CH:21]([O:43][S:44]([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
In 9 ml of pyridine was dissoved 5.0 g (8.52 mmole) of 3-O-octadecyl-1-O-tritylglycerol, and after 1.95 g (10.22 mmole) of tosyl chloride was added to the solution, the mixture was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of water and 50 ml of dichloromethane, and after shaking throroughly, the dichloromethane layer was separated out. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (50 g), with n-hexane.ethyl acetate (193:7) used as an eluent, to give 5.3 g (yield of 83.9%) of colorless needles.
Reaction SMILES: FC1C=CC(CN)=CC=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37]([NH:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=3)=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccc(Cl)c1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3-chlorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 46% yield: mp 178-179° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 9H), 6.10 (s, 1H), 4.51 (d, J=5.7 Hz, 2H), 4.44 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.43 (t, J=8.4 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.5, 157.3, 155.3, 153.4, 140.2, 135.5, 134.5, 130.0, 128.9, 128.3, 128.0, 127.8, 127.7, 125.8, 116.9, 47.9, 43.3, 42.0, 41.6, 17.2; MS (ES+) m/z 441.0 (M+1), 443.0 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]#[N:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:29]#[N:30])=[C:22]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:21]=1
Reactant: CCCCC(C(=O)OCC)n1ccc(I)cc1=O
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: CCCCC(C(=O)OCC)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (0.41 mmol) of ethyl 2-(4-iodo-2-oxopyridin-1(2H)-yl)hexanoate (racemate) and 97 mg (0.53 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 114 mg (purity 95%, 70% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26]C)=[O:25])=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])=[O:21])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To Methyl 2-(3-(4-(benzyloxy)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (150 mg) in THF (3 ml), 1 M aqueous solution of Lithium hydroxide monohydrate (0.735 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to obtain the title compound as white solid. Yield: 80 mg (55%); MS (ES+): m/z 395 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 12.91 (bs, 1H), 8.94 (d, 1H), 7.87 (d, 2H), 7.69 (s, 1H), 7.32-7.49 (m, 5H), 7.19 (d, 2H), 5.19 (s, 2H), 4.28 (m, 1H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([O-])=[O:24])=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH2:27][CH3:28])[C:3]1=[O:29].[Na+].Cl.[O:32]1[CH2:36][C@@H:35]([OH:37])[CH2:34][NH:33]1>>[OH:37][CH:35]1[CH2:36][O:32][N:33]([C:23]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:26][CH2:27][CH3:28])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:24])[CH2:34]1
Reactant: CCCn1c(=O)n(C)c(=O)c2c(C(=O)[O-])c(Cc3ccnc4ccccc34)sc21
Reactant: O[C@H]1CNOC1
Agent: Cl
Agent: [Na+]
Product: CCCn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3ccnc4ccccc34)sc21

Procedure:
Prepared as the method of example 1, part g) using the product of step f) and (S)-isoxazolidin-4-ol hydrochloride. δ 1H DMSO 0.84 (3H, td), 1.60 (2H, septet), 3.21 (3H, d), 3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d), 3.90 (1H, m), 4.61 (2H, dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m) 7.79 (1H, m), 8.05 (1H, d), 8.27 (1H, dd), 8.87 (1H, d). MS (APCI) 481.1 (M++H)
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])C(OC)=O>Cl>[N+:25]([C:10]1[CH:11]=[CH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:14][C:9]=1[CH2:4][C:3]([OH:28])=[O:2])([O-:27])=[O:26]
Reactant: COC(=O)C(C(=O)OC)c1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2-[2-nitro-5-(3-nitro-phenylamino)-phenyl]-malonic acid dimethyl ester (0.68 g, 1.7 mmol) in 6 N hydrochloric acid (20 ml) is heated at 110° C. for 10 hours. It is then cooled to room temperature and the mixture is extracted with ethyl acetate (100 ml×3). The organic layers are combined, dried, concentrated to give crude [2-nitro-5-(3-nitro-phenylamino)-phenyl]-acetic acid: LC-MS: 318.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CS[C:19](=[NH:21])[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:19]([NH2:21])[NH2:20]
Reactant: CSC(=N)N
Reactant: Cc1nc[nH]c1CSCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc[nH]c1CSCCN=C(N)N
Yield: 52 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-aminobenzoate (5 g, 33.1 mmol) and pyridine (5.3 g. 66 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (0.2 g, 1.6 mmol). The mixture was cooled to 0° C. and treated with 4-tert-butylbenzoyl chloride (6.5 g, 33.1 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane (100 mL) and washed twice with 1 M aqueous citric acid (100 mL). The organic layer was then washed sequentially with water (100 mL) and 5 N aqueous HCl. It was dried over MgSO4, filtered and concentrated in vacuo to give 10.68 g (quantitative) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:7]([C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)O)=[CH:4][S:5][CH:6]=1.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CCO.[OH-].[OH-].[Pd+2]>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:1][C:2]1[C:3]([CH2:7][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd+2]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: Cc1cscc1Cc1c[nH]cn1
Reaction time: 8 h

Procedure:
A solution of (4-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol (2.5 g, 5.7 mmol) was combined with 1N HCl (6 mL) and Pd(OH)2 (1.25 g) in EtOH and hydrogenated (55 psi) at 50° C. for 48 hrs. The catalyst was removed by filtration through Dicalite, and the solvent was evaporated in vacuo. The residue was dissolved in water, washed twice with Et2 O, and then basified with Na2CO3 and extracted twice with EtOAc. The combined extracts were dried (K2CO3), filtered, and the solvent was evaporated. The residue was dissolved in 2-PrOH and combined with fumaric acid (0.57 g, 1 eq.). After standing overnight a white solid was collected and recrystallized from acetone to give the title compound m.p. 142°-144° C. 1H NMR (DMSO-d6) supported the assigned structure: δ2.15 (s, 3H), 3.75 (s, 2H), 6.6 (s, 2H), 6.75 (s, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.65 (s, 1H). Elemental analysis: Calc. for C9H10N2S.C4H4O4C, 53.05; H, 4.79; N, 9.52. Found C, 53.03; H, 4.73; N, 9.38.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([NH2:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C:34]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:33][C:32](=O)[O:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([NH:28][C:32](=[O:31])[CH2:33][C:34]([C:36]3[CH:43]=[CH:42][CH:41]=[C:38]([C:39]#[N:40])[CH:37]=3)=[O:35])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 92 %

Procedure:
Prepared from 4-(3-amino-4-tert.-butoxycarbonylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (Example G29) (544 mg, 1.4 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (336 mg, 1.5 mmol) according to the general procedure K. Obtained as an orange solid (722 mg).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[C:16]([C:18]1[C:19]([CH3:28])=[C:20]([O:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1)=[O:17].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:16]([C:18]3[C:19]([CH3:28])=[C:20]([O:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=3)=[O:17])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1C
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To aluminum trichloride (6.14 g, 0.046 mol) in methylene chloride (26 mL) under an atmosphere of nitrogen was added 5-Bromo-7-azaindole (67, 1.05 g, 5.31 mmol) dissolved in methylene dichloride (20.0 mL). The reaction was stirred at room temperature for 65.0 minutes, then acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (1.25 g, 5.88 mmol) in methylene dichloride (7.0 mL) was added. The reaction was stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 84 that was used directly in the next step.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:35][CH2:36][CH:37]=[CH2:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33][CH3:34])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1]/[C:2](/[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:10][C@@:9]([O:33][CH3:34])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:8]1)=[O:5]
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CCCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCCC)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1

Procedure:
Application of the method shown in Example 41, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl) 3-methylhepta-2,6-dienoate is substituted for (R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.