Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]2[O:16][CH:6]1[CH2:7][C:8]([C:18]1[N:26](C3CCCCO3)[C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=1)([OH:17])[CH2:9]2)=[O:4]>Cl.C1COCC1.CO>[CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]2[O:16][CH:6]1[CH2:7][C:8]([C:18]1[NH:26][C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=1)([OH:17])[CH2:9]2)=[O:4]
Reactant: CCCn1c(=O)c2c(nc(C3(O)CC4OC(C3)C(C(=O)OC)C4C(=O)OC)n2C2CCCCO2)n(CCC)c1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3(O)CC4OC(C3)C(C(=O)OC)C4C(=O)OC)nc2n(CCC)c1=O
Yield: 56.4 %

Procedure:
To a solution of 3-[2,6-dioxo-1,3-dipropyl-7-(tetrahydropyran-2-yl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-3-hydroxy-8-oxa-bicyclo[3.2.1]octane-6,7-dicarboxylic acid dimethyl ester (0.060 mmol, 0.030 g) in 1:1 THF/MeOH (6 ml) was added 1N HCl (3 drops). The reaction was stirred at room temperature 3d and then concentrated to dryness. The residue was purified by PLC on a 1 mm layer, eluting with 20% THF/CH2Cl2, providing the title compound (0.0162 g, 56%). 13C NMR (100 MHz, CDCl3): 11.53 (q), 11.50 (q), 21.72 (t), 21.75 (t), 41.74 (t), 43.82 (t), 45.85 (t), 51.02 (d), 52.64 (q), 70.37 (s), 77.12 (d), 107.53 (s), 149.12 (s), 151.17 (s), 156.32 (s), 159.98 (s), 173.36 (s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 74.6 g of methyl 4-hydroxyphenylacetate, 92.2 g of bromoacetone, 125 g of potassium carbonate and 750 ml of dimethylformamide was stirred at room temperature for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The resulting concentrate was mixed with water and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:8 by volume mixture of ethyl acetate and benzene as the eluent, to give the title compound having an Rf=0.43 (thin layer chromatography over silica gel, using a 1:7 by volume mixture of ethyl acetate and benzene as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[F:17][C:18]([F:28])([F:27])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:18]([F:17])([F:27])[F:28])[NH:11][C:12]3=[N:13][NH:14][CH:15]=[C:16]23)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccc(OC)cc1

Procedure:
The title compound was prepared from 4-methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:11](/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(N(CC)CC)C>O1CCCC1>[C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:14](=[O:15])/[CH:13]=[CH:12]/[C:11]1[C:2](=[O:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:26])=[O:25]
Reactant: O=C(Cl)/C=C/c1cc2ccccc2oc1=O
Reactant: Nc1ccccc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cc2ccccc2oc1=O)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(2-oxo-2H-chromen-3-yl)-acrylic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.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>[CH:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: C#CC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2CCCC2)cc1C
Temperature: 80 °C

Procedure:
Methyl 4-bromo-2-methylbenzoate (1.0 g, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43 mg, 5 mol %), followed by PdCl2(PPh3)2 (157 mg, 5 mol %) and ethynylcyclopentane (0.75 mL, 5.3 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on sililca gel using EtOAc-hexane (0-100% gradient) as eluet to give the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:23]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=2[Cl:32])=[C:22]([F:33])[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:10]=2[CH:9]=1)=[O:7].N1C=NN=N1.C(N(C(C)C)[P:43]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(C)C.C([O:61]O)(C)(C)C>CN(C=O)C>[C:50]([O:49][P:43](=[O:61])([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[O:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:23]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=2[Cl:32])=[C:22]([F:33])[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:10]=2[CH:9]=1)=[O:7])([CH3:51])([CH3:52])[CH3:53]
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(NOCCO)c1cc2c(ncn2C[C@@H]2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OO
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
401.2 mg of (S)-6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-(tetrahydropyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide, 78.6 mg of tetrazole and 320 μL of di-tertbutyl diisopropyl-phosphoramidite were dissolved/suspended in 3 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was stirred for about 4 hrs after which time the reaction was cooled to 0° C. and 300 μL of 70% tert-butyl hydrogen peroxide were added. The cooling bath was then taken away and the reaction was slowly warmed up to room temperature and reacted for 2.5 hrs. The reaction was then quenched with 10 mL of saturated aqueous sodium thiosulfate. The resulting solution was partitioned between a solution of ethyl ether/ethyl acetate (10:1) and saturated aqueous NaHCO3. The organic layer was saved and successively washed with water (3×) and then with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was purified using silica gel chromatography eluting with 2:1 Ethyl acetate/dichloromethane to give 295.3 mg of phosphoric acid mono-(2-{[6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-(tetrahydropyran-2-ylmethyl)-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethyl) ester di-tert-butyl ester which was then dissolved in a solution of 5 mL of TFA and 3 mL of dichloromethane under an atmosphere of dry N2. The reaction was stirred at room temperature for about 2 hours after which time it was concentrated under vacuum. The resulting residue was taken up in methanol and re-concentrated (2×). The resulting residue was stirred in methanol for about 1 hour. The white solid was collected via suction filtration, washed with methanol followed by ethyl ether and then air-dried to give 188.6 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (brs, 1H), 8.35 (s, 1H), 7.95 (brs, 1H), 7.79 (s, 1H), 7.61 (d, 1H), 7.26 (dd, 1H), 6.40 (dd, 1H), 4.37 (m, 1H), 4.26 (m, 1H), 4.03 (brs, 4H), 3.85 (m, 1H), 3.70 (m, 1H), 3.27 (m, 1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.46 (m, 3H), 1.22 (m, 1H); 19F NMR (376 MHz, DMSO-d6) −132.9 (s, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)COC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CC(C)COC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid isobutyl ester was prepared from [(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using isobutyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 504.2 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[CH:20]=[O:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:18]2[CH:17]=[CH:16][C:15]([Br:14])=[CH:22][C:19]=2[CH:20]=[O:21])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 120 °C
Yield: 37.1 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 5-bromo-2-fluorobenzaldehyde (1.06 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.70 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH2:20]([Mg]Cl)[CH:21]=[CH2:22].Cl>C1(C)C=CC=CC=1>[C:10]([N:6]1[C:7]([CH2:22][CH:21]=[CH2:20])=[CH:8][C:3](=[O:2])[CH2:4][CH2:5]1)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[Mg]Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: C=CCC1=CC(=O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxypyridine (50 mL, 0.492 mol) in toluene (1 L) is added benzyl chloroformate (70.3 mL, 0.492 mol) at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes then cooled to −75° C. and allyl magnesium chloride (295.5 mL, 0.591 mol) is added. The solution is held at −75° C. for 4 hours and allowed to warm to 0° C. at which point a solution of 20% HCl is added to quench the reaction. The organic layer is isolated and purified over silica gel to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19]Cl)([O:17]Cl)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1>CCOCC>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH:14]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[P:15]([OH:19])([O:17][S:43][C:40]1[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=1)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4]
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCOC(=O)CN(C(=O)C(F)(F)F)C(N1CCOCC1)P(=O)(O)OSc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 9.6 %

Procedure:
A solution of n-butyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (14.3 g, 0.04 mole) in 250 ml. of ether was added slowly to a solution of morpholine (3.5 ml, 0.04 mole) and triethylamine (5.6 ml, 0.04 mole) in 100 ml. of ether. After three hours, the solution was filtered and the filtrate was added slowly to a cooled (0° C.) solution of p-chlorothiophenol (5.7 g, 0.04 mole) and triethylamine (5.6 ml, 0.04 mole) in 100 ml. of ether. After 16 hours at 25° C., the solution was filtered and the filtrate was concentrated in vacuo and the residual semi-solid was crystallized from ethyl acetate/cyclohexane (1/10). Recrystallization from hexane yielded butyl N-trifluoroacetyl-N-(morpholino(p-chlorothiophenoxy)phosphonomethyl)glycinate (2.1 g) as a white solid, m.p. 79.5°-81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[C:38]2[CH:37]=[N:36][C:35](S(C)=O)=[N:34][C:33]=2[N:32]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])[CH:45]=[CH:46][CH:47]=2)[C:31](=[O:53])[CH:30]=1>C(O)(C)(C)C.O1CCOCC1>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]3[N:36]=[CH:37][C:38]4[C:29]([CH3:28])=[CH:30][C:31](=[O:53])[N:32]([C:42]5[CH:43]=[C:44]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])[CH:45]=[CH:46][CH:47]=5)[C:33]=4[N:34]=3)=[C:3]([O:17][CH3:18])[CH:4]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(C)=O)CC5)cc4OC)nc32)c1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
A suspension of 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (20b; 351 mg, 1.40 mmol), diisopropylethylamine (0.41 mL, 2.34 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 288 mg, 0.78 mmol) in tert-butanol (2 mL) and dioxane (1 mL) in a sealed glass tube was heated in an oil bath at 110° C. for 72 h. It was concentrated under reduced pressure. The brown residue was stirred in 5 mL of ether for 10 min. The liquid was decanted; the remaining solid was loaded on a silica gel column and eluted with 2-10% MeOH in DCM followed by 5% 2 M NH3 in MeOH in DCM to give the title compound (20) (150 mg, 34% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.81 (1H, s), 8.12 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.42-7.61 (2H, m), 7.28 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=7.8 Hz), 6.56 (1H, m), 6.44 (1H, m), 6.33 (1H, s), 6.24 (1H, m), 6.04 (1H, br. s.), 5.75 (1H, m), 3.78 (3H, s), 3.56 (4H, m), 3.04 (2H, m), 2.97 (2H, m), 2.46 (3H, s), 2.03 (3H, s). m/z (ESI, +ve ion) 554.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.CCOCC>O1CCCC1>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:3][C:2](=[NH:4])[NH2:1])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: NC(N)=S
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CSC(=N)N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.8 %

Procedure:
To a mixture of thiourea (3.8 g, 50.0 mmol) in tetrahydrofuran (30 mL) was added dropwise 4-methoxybenzyl chloride (8.0 g, 51.1 mmol) and the reaction mixture was stirred at room temperature for 2 h before heating to reflux for 4 h. After the reaction was stirred at room temperature for 18 h the product was isolated from ether to yield the title compound (11.46 g). Electrospray MSm /z 197 [M+H]+.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:19]#[N:20])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[C:19]([C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1)#[N:20]
Reactant: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1C#N)C(C)CNCC2
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A solution of N-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (10 mg, 0.032 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred 1 hour at 50 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 6.0 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.33 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H), 3.18-2.97 (m, 5H), 2.80 (m, 1H), 2.60 (m, 1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C13H16N2O+H: 217, observed: 217.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH3:12])[O:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([OH:25])CCC.CO>Cl.CCCCCC>[CH3:21][O:25][C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:13])[C:2]2[C:3]3[CH:11]=[C:10]([CH3:12])[O:9][C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[CH:16][CH:17]=1
Reactant: CNc1ccccc1
Reactant: Cc1nc(Cl)c2cc(C)oc2n1
Reactant: CCCCO
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(N(C)c2nc(C)nc3oc(C)cc23)cc1

Procedure:
To a 50 mL flask was added 5 (91 mg, 0.5 mmol), 6 (77 mg, 0.55 mmol) and 5 mL BuOH. To this solution was added 2 drops of concentrate HCl solution and the mixture was refluxed. TLC indicated the disappearance of starting material 5, the solvent was removed under reduced pressure. To the residue obtained was added silica gel and MeOH and the solvent removed to make a plug. This plug was separated by column chromatography to give 106 g (75%) of AGG1 as a white powder: TLC Rf0.36 (Hexane/EtOAC 3:1); mp 108-109° C.; 1H NMR (DMSO-d6) δ 2.14 (s, 3 H), 2.45 (s, 3 H), 3.43 (s, 3 H), 3.81 (s, 3 H), 4.55 (s, 1 H), 7.04 (d, 2 H, J=2.8 Hz), 7.25 (d, 2 H, J=28 Hz). Anal. (C16H17N3O2) m/z (ESI) 284.1387 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)=[O:16])[CH:14]=[CH:13][NH:12][CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].[OH2:32].[CH3:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:13][N:12]([C:33]([O:34][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:32])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)C1(c2ccc(Cl)c(Cl)c2)C=CNC=C1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)c(Cl)c2)(C(O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 140B (500 mg, 1.11 mmol) in dry MeOH (5 mL) was added NaBH4 (84 mg, 2.22 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour and water (10 mL) was added slowly. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=1/1) to give Example 140C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1C(C(O)=O)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:34]([C:35]([Cl:37])=[O:36])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)Cl)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
2-[(Benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) was dissolved in THF (6.0 ml), and oxalyl chloride (122 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][O:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccoc1
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: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4ccoc4)c3)n2)nc1
Yield: 32.4 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), 3-furylboronic acid (111.9 mg, 1.0 mmole) and Pd(PPh3)4 (57.8 mg, 0.05 mmole) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated overnight at 105° C. Standard work up afforded 47 mg (32%) of 3-(2-pyridyl)-5-[5-(3-furyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27]C1C=CC(NC(N)=S)=CC=1.BrCC(=O)C(OCC)=O>>[Cl:27][C:4]1[CH:5]=[CH:6][C:1]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)=[CH:2][CH:3]=1
Reactant: NC(=S)Nc1ccc(Cl)cc1
Reactant: COc1cc(C(=O)c2csc(Nc3ccccc3)n2)cc(OC)c1OC
Agent: CCOC(=O)C(=O)CBr
Product: COc1cc(C(=O)c2csc(Nc3ccc(Cl)cc3)n2)cc(OC)c1OC

Procedure:
(2-((4-Chlorophenyl)amino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5d) was prepared using the same method as used for 5a from 1-(4-chlorophenyl)thiourea and ethyl bromopyruvate. Melting point: 165-166° C. 1H NMR (500 MHz, CDCl3) δ 7.60 (s, br, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.38 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 3.89 (s, 6H). MS: 402.9 (M−1)−; 427.0 (M+Na)+.
Reaction SMILES: [I:1][CH:2]=[CH:3][CH2:4][CH:5]([O:10][Si](C)(C)C)[CH2:6][CH2:7][CH2:8][CH3:9]>C(O)(=O)C.O1CCCC1.O>[OH:10][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]/[CH:3]=[CH:2]/[I:1]
Reactant: CCCCC(CC=CI)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)C/C=C/I

Procedure:
A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.