Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:30])[C:11]([CH:28]=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4].CSC.C1COCC1>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:30])[C:11]([CH2:28][OH:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C=O)c(=O)n21
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(CO)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The formylated 2-pyridone 2 (100 mg, 0.239 mmol) was dissolved in tetrahydrofuran (3.30 mL) at 0° C. Then 2M BH3 DMS THF (0.131 mL, 0.262 mmol) was added dropwise during 15 min. The mixture was then stirred in room temperature during 1 h, quenched with methanol and concentrated twice from methanol. The residue was purified through flash column chromatography (CH2Cl2:MeOH, 9:1). Co-concentration from CH2Cl2 (×2) resulted in 4 as white foam (80.6 mg, yield: 80%). 1H-NMR (400 Mhz, CDCl3) δ 8.16 (d, J=8.23 Hz, 1H, ArH), 7.87 (d, J=7.96 Hz, 1H, ArH), 7.71 (d, J=8.14 Hz 1H, ArH), 7.64-7.48 (m, 2H, ArH) 7.30 (m, 1H, ArH) 6.83 (d, J=6.95 Hz, 1H, ArH), 5.68 (d, J=7.04 Hz, 1H, CHCO2Me), 4.72 (d, J=16.28 Hz, 1H, Nph-CH2), 4.61 (d, J=16.28 Hz, 1H, Nph-CH2) 4.58-4.36 (m, 2H, CH2OH) 3.84 (s, 3H, CH3) 3.76-3.62 (m, 2H, SCH2, OH) 3.60-3.50 (m, 1H, SCH2) 1.46-1.34 (m, 1H, CH-cyclopropyl) 0.65 (ss, 2H, CH2-cyklopropyl) 0.51 (ss, 2H, CH2-cyklopropyl) 13C-NMR (100 Mhz, CDCl3) δ 168.61, 161.87, 152.08, 146.62, 134.11, 133.76, 131.77, 128.94, 127.17, 126.37, 125.92, 125.66, 125.63, 124.26, 122.98, 114.93, 63.27, 58.78, 53.40, 31.77, 31.58, 11.81, 7.53, 7.20.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:7])(C)(C)C.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:32][N:19]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:12][C:8]=1[C:6]([OH:5])=[O:7]
Reactant: CI
Reactant: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)sc2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(C)c2nc(-c3ccccc3)sc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
4-(4-methyl-benzoylamino)-2-phenyl-thiazole-5-carboxylic acid t-butyl ester (50 mg) was dissolved in anhydrous DMF (5 mL). NaH (16 mg, 60% dispersion oil) was added. The mixture was stirred for 10 min., followed by adding iodomethane (25 μL). Stirring was continued for overnight and poured into water. The aqueous solution was extracted with methylene chloride, washed with water, brine and dried over MgSO4. Solvent was removed under reduced pressure. The residue was purified on silica gel using hexane:EtOAc 95:5. 9:1 and 85:5 as eluent. It yielded 25 mg of desired product.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][N:6]1[CH:10]=[N:9][C:8]([C:11](=[O:13])[CH3:12])=[N:7]1>C1COCC1>[CH3:5][N:6]1[CH:10]=[N:9][C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])=[N:7]1
Reactant: CC(=O)c1ncn(C)n1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncn(C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in THF, 4.32 mL, 2.16 mmol) at 0° C. was added 1-(1-methyl-1,2,4-triazol-3-yl)ethanone (180 mg, 1.44 mmol) in THF (5 mL) slowly. The reaction mixture was allowed to warm to RT and stirred for a further 1.5 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography eluting with 2-10% methanol in DCM afforded the title compound: 1H NMR (500 MHz, CDCl3) delta 1.93 (3H, s), 2.62 (1H, s), 3.53 (1H, s), 3.93 (3H, s), 8.01 (1H, s); LC-MS: m/z=+152.0 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH3:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18]>>[CH2:13]([CH:14]1[CH:15]([CH2:16][CH2:17][CH3:18])[N:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH2:12][CH3:11]
Reactant: CCC/C=C/CCC
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Product: CCCC1C(CCC)N1c1ccc(C)cc1

Procedure:
p-Tolyl azide (0.113 g, 0.852 mmol), trans-4-octene (3.705 g, 33.0 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0118 g, 0.0085 mmol) were used in the General Catalytic Reaction described above yielding 0.055 g, 30%. 1H NMR (CDCl3, 499.74 MHz): δ 7.02 (d, J=7.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 2.28 (s, 3H), 2.03 (t, J=5.5 Hz, 2H), 1.62 (m, 2H), 1.53 (m, 4H), 1.10 (m, 2H), 0.96 (t, J=7.0 Hz, 6H) 13C NMR (CDCl3, 125.66 MHz): δ 148.10, 130.91, 129.36, 120.95, 44.99, 33.29, 21.11, 20.80, 14.18. GC/MS (m/z): 217.2. DART HR MS (m/z): [M+H]+218.1901 (found). C5H24N, 218.1909 (calcd).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=2)=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[Cl:41].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:23])=[N:20][CH:21]=3)=[CH:6][CH:7]=2)[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(Br)cc2)cn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1
Temperature: 25 °C

Procedure:
tert-butyl 3-(5-(2-(((4-bromophenyl)amino)methyl)phenyl)picolinamido)propanoate (80 mg, 0.16 mmol), (3,4-dichlorophenyl)boronic acid (34 mg, 0.18 mmol), Pd(dppf)Cl2 (13 mg, 0.02 mmol), and K2CO3 (43 mg, 0.31 mmol) were dissolved in 1,4-dioxane (1.2 mL) and water (0.3 mL) and heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[CH:6]1)[CH3:2].[CH3:24][Mg]Cl>CCOCC>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:24])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: C[Mg]Cl
Reactant: CCOCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Solvent: CCOCC
Product: CCOCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The compound was also obtained, for example, by Grignard synthesis from 7-ethoxymethyl-3-methyl-1-(5-oxohexyl)xanthine with methylmagnesium chloride in anhydrous ether analogously to Example 9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[N:20]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=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]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:3]([F:28])[CH:4]=2)(=[O:10])=[O:9])=[C:13]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[N:20]2)[CH:14]=1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1-n1nnc2ncccc21)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1ccc(Cl)cc1-n1nnc2ncccc21)c1ccc(N2CCOCC2)c(F)c1
Yield: 44.2 %

Procedure:
4-Bromo-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-benzensulfonamide (synthesized according to general procedure G, 180 mg, 0.37 mmol) was dissolved in 3 ml of anhydrous dimethylformamide under an atmosphere of nitrogen. To this mixture was added morpholine (161 mg, 1.85 mmol), 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) (34 mg, 0.055 mmol), potassium phosphate tribasic monohydrate (511 mg, 2.22 mmol), and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and the resultant mixture was heated at 80° C. overnight. The following day, the reaction mixture was partitioned with a saturated solution of sodium bicarbonate and dichloromethane and the aqueous layer was extracted three times with dichloromethane. The combined organics were subsequently dried over magnesium sulfate, concentrated in vacuo, and purified by reverse phase HPLC, followed by silica gel chromatography employing ethyl acetate:hexanes (1:1), to afford 80 mg of the desired product as a white powder: MS (ES) M+H expected 489.1, found 489.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:41])[C@H:15]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:30][C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[NH:29])[NH:16]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:43]>O1CCOCC1>[ClH:43].[CH2:1]([N:30]([C:28](=[NH:29])[NH:27][CH2:26][CH2:25][CH2:24][C@H:15]([NH2:16])[C:14](=[O:41])[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:42])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:31](=[O:32])[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(NCCC[C@H](N)C(=O)NCCNC(=O)OCc1ccccc1)N(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 334 mg (0.417 mmol) of benzyl (2-{[N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithyl]amino}ethyl)carbamate (Example 102A) and 17 ml of a 4M solution of hydrogen chloride in dioxane is stirred at RT for 4 h. The reaction solution is concentrated, coevaporated with dichloromethane several times, and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: COC(=O)[C@H](CC1C=CC(OCC=C)=CC=1)[NH2:5].[CH3:18][O:19][C@@:20]([C:30]([F:33])([F:32])[F:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](O)=[O:22].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:18][O:19][C@@:20]([C:30]([F:33])([F:32])[F:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:5])=[O:22]
Reactant: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Reactant: C=CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CO[C@](C(N)=O)(c1ccccc1)C(F)(F)F

Procedure:
O-Allyltyrosine methyl ester (20 mg, 0.084 mmol) was added to a stirred solution of (S)-(-)-methoxy(trifluoromethyl)phenyl-acetic acid (28.0 mg, 0.120 mmol) and DCC (40 mg, 0.20 mmol) in CH2Cl2 (0.50 mL). After 3 h the reaction mixture was diluted with CH2Cl2 (10.0 mL), filtered, and washed with 0.5M aq NaOH. Drying and solvent removal afforded the crude (S)-(-)-methoxy-(trifluoromethyl)phenyl-acetamide as a waxy oil containing DCC and N,N-dicyclohexylurea: Rf 0.55 (50% ether/hexane); 1H NMR (CDCl3) δ3.05 (1H, dd, J=6.4, 14.4 Hz), 3.13 (1H, dd, J=5.4, 14.4 Hz), 3.24 (3H, s), 3.74 (3H, s), 4.52 (2H, d, J=5.2 Hz), 4.87 (1H, ddd, J=5.4, 6.0, 6.4 Hz), 5.29 (1H, d, J=10.4 Hz), 5.41 (1H, d, J=17.6 Hz), 6.06 (1H, m), 6.83 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz), 7.28 (1H, d, J=6.0 Hz), 7.39 (3H, m), 7.52 (2H, m); 13C NMR (CDCl3) δ28.9, 37.0, 52.5, 53.4, 53.7, 55.0, 69.0, 77.9, 115.2, 117.8, 127.8, 128.1, 128.7, 129.8, 130.4, 133.4, 158.0, 166.2, 171.9,; IR (film) 3411, 3140, 2953, 2851, 1745, 1696, 1511, 1244, 1233, 1224, 1178 cm-1 ; HRMS (M+1) calcd for C23H25F3NO5 452.1685, found 452.1685.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[N:25]=[C:26]([NH:30][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cccc(NS(=O)(=O)c3ccccc3F)n2)c2c(N)ncnc21
Temperature: 40 °C
Yield: 38.8 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (72 mg, 0.37 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone (100 mg 0.34 mmol) in pyridine (2 mL). The resulting solution was heated to 40° C. in a sealed tube for 12 h. The reaction mixture was concentrated in vacuo and the residue was triturated with MeOH and filtered to provide a crude yellow solid. Purification by flash column chromatography (hexanes/ethyl acetate 5:5-1:9) afforded the title compound as a yellow solid (60 mg, 40%). MS: 455.1 (MH+); HPLC Rf: 4.67 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[C:6]([O:16][CH3:17])(=[O:15])/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([O:13]C)=O>C1COCC1>[CH:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:13])[CH:7]1[C:6]([O:16][CH3:17])=[O:15])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/CCC(=O)OC
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CCC1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
An isopropylmagnesium bromide (58 mL, 58 mmol) solution (15% in THF, M) was treated with Cu(I)I (0.28 g, 1.5 mmol) and cooled to 0° C. A solution of (E)-dimethyl hex-2-enedioate (5.0 g, 29 mmol; See Example 80, Step 1) was added dropwise, and the solution was stirred at 0° C. for an additional 30 minutes and then at room temperature. The product was poured into saturated NHCl4 (250 mL) with rapid stirring. The mixture was extracted into DCM. The combined organics were back extracted with H2O, and dried with MgSO4, filtered, and concentrated under reduced pressure to yield methyl 2-isopropyl-5-oxocyclopentanecarboxylate (5.4 g, 100%), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.76-3.73 (m, 3H), 2.94-2.91 (m, 1H), 2.48-2.16 (m, 2H), 1.87-1.84 (m, 2H), 1.68-1.43 (m, 2H), 0.97-0.84 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:24][CH:23]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Reaction time: 48 h

Procedure:
2-Chloronicotinoyl chloride (9.15 g, 0.052 mol) was added to a stirred solution of 4-phenoxyaniline (10.00 g, 0.054 mol) and DIEA (10.00 ml, 0.057 mol) in CH2Cl2 (100 ml) at RT. The mixture stirred for 48 h before removal of solvent under reduced pressure. The resulting residue was dissolved EtOAc and washed several times with saturated NaHCO3 aqueous solution and brine, respectively. The organic layer was dried over Na2SO4 and evaporated to leave a solid. This material was re-crystallized from EtOAc/Hexane mixture, followed by filtration and rinsing with Et2O to leave the desired compound as a white solid. MS m/z: 325 (M+1); 323 (M−1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O>[I:22][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: [I-]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1I
Temperature: 90 °C
Yield: 81.2 %

Procedure:
2-Methoxy-5-nitroaniline (10.0 g, 0.060 mol) was stirred in water (150 mL) and concentrated (conc.) sulfuric acid (12 mL, 0.22 mol). The solution was cooled below 5° C. with an ice-salt bath, and a solution of sodium nitrite (4.8 g, 0.070 mol) in water (40 mL) was added dropwise while maintaining the temperature below 5° C. A solution of potassium iodide (16.8 g, 0.101 mol) was added and the mixture was heated to 90° C. for 1 hour. Cooling to 0° C. gave dark red crystals which were filtered, washed with water, and dried. Purification by silica gel chromatography using ethyl acetate/hexanes gave the desired compound (13.6 g, 75%). 1H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.28 (d, 1H), 7.19 (d, 1H), 3.98 (s, 3H). LCMS for C7H7INO3 (M+H)+: m/z=280.1.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.O[C:28]1([C:49]2[C:57]([OH:58])=[CH:56][C:52]3[O:53][CH2:54][O:55][C:51]=3[CH:50]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][C:38]2[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=2[C:40]([O:42][CH3:43])=[O:41])[C:29]1=[O:48]>>[OH:58][C:57]1[C:49]([CH:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][C:38]3[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=3[C:40]([O:42][CH3:43])=[O:41])[C:29]2=[O:48])=[CH:50][C:51]2[O:55][CH2:54][O:53][C:52]=2[CH:56]=1
Reactant: COC(=O)c1ccccc1CN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: COC(=O)c1ccccc1CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with methyl 2-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate, the title compound was obtained (100%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.94 (dd, 1H), 7.50-7.34 (m, 2H), 7.26 (d, 1H), 7.08 (t, 1H), 7.00-6.86 (m, 2H), 6.76 (s, 1H), 6.64 (d, 1H), 6.38 (s, 1H), 5.93-5.86 (m, 2H), 5.34-5.12 (m, 2H), 4.83 (s, 1H), 3.87 (s, 3H); MS (ES+) m/z 418.2 (M+1).
Reaction SMILES: [Na].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8].[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:7]2[NH:9][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:8]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2cccc(Cl)c2)=N1

Procedure:
To a stirred solution of 56.4 g. of sodium metal in one liter of absolute ethanol there is added 156 g. of m-chlorobenzamidine hydrochloride followed by the dropwise addition of 144 g. of diethyl malonate over a fifteen minutes period. The reaction mixture is heated under reflux for three hours. The solution is filtered and the filter cake dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid separates which is removed by filtration. After washing this material several times with water the product (123 g., m.p. 254°-256°C.) is recrystallized from aqueous N,N-dimethylformamide to yield 2-(3-chlorophenyl)-4,6-(1H,5H)-pyrimidinedione, m.p. 256°-257°C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:11][C@H:10]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 99 %

Procedure:
Following method 2, tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1M solution) was reduced yielding tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (>99%). LCMS (m/z): 423.2 (MH+); LC Rt=3.78 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:13](=[O:20])[NH:14]3)=[CH:6][CH:5]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37]>C([O-])(O)=O.[Na+].C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH:19][C:36](=[O:37])[CH2:35][C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:13](=[O:20])[NH:14]3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2c(N)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2c(NC(=O)Cc3cccs3)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 90.1 %

Procedure:
Using Method M above, (Z)-4-[5-amino-2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (310 mg, 0.8 mmol) (from Example 46 supra) was acylated with 2-thiopheneacetyl chloride (260 mg, 1.6 mmol) (Aldrich) in saturated aqueous NaHCO3 (1.6 mL) and THF (15 mL) at room temperature for 3 h to yield (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid methyl ester (yield 370 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1.[CH3:27][C:28]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:29]2[C:28]([CH3:27])=[CH:33][N:32]=[C:31]([NH:34][C:35](=[O:37])[CH3:36])[CH:30]=2)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)c(C)cn1
Yield: 80.6 %

Procedure:
A mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (0.39 g, 0.78 mmol), N-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (0.36 g, 1.32 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and cesium carbonate (1.64 g, 5.04 mmol) in dioxane (13 mL) and water (1.8 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.33 g, 81%). LCMS (AA): m/z=525.1 (M+H).