Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[C:12](=[O:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1
Reactant: CCCc1ccc(C(=O)Nc2ccc3sc(C)nc3c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(C(=O)N(C)c2ccc3sc(C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-methylbenzothiazol-5-yl)-4-propylbenzamide (130 mg, 0.4 mmol) in DMF (5 mL) was added sodium hydride (17 mg, 0.44 mmol), followed by methyl iodide (85 mg, 059 mmol). The mixture was stirred at rt overnight, partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give a residue that wad purified with flash chromatography (ethyl acetate-hexane gradient elution). A thick syrup (41 mg, 26% was obtained. 1H NMR (400 MHz, CDCl3): δ 7.61-7.79 (3H, m, ArH), 7.22-7.26 (2H, m, ArH), 6.92-7.02 (2H, m, ArH), 3.54 (3H, s, CH3) 2.81 (3H, s, CH3), 2.45 (2H, t J=7.4 Hz, CH2) 1.52 (2H, m, CH2), 0.83 (3H, t, .J=7.4 Hz, CH3); FAB-MS 325 (MH+); FAB-HRMS calcd for C19H21N2OS (MH+) 325.1375, found 325.1992.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].N1C=CC=CC=1.O>C(#N)C>[C:16]([CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:7]=2)[NH:11][CH:10]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.21 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) and pyridine (0.24 ml) in dry acetonitrile (10 ml) at 0°-2° under nitrogen. When the addition was complete the solution was stirred at 0° for 30 minutes, poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were dried (MgSO4), filtered and evaporated under reduced pressure to a brown solid (0.5 g) which was crystallised from an ethanol-cyclohexane mixture to give the title compound (0.43 g) as off-white needles, m.p. 171.5°-175°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([OH:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cc(O)cc2oc(-c3ccccc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc(O)cc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
A mixture of 6-hydroxy-2-phenylbenzoxazole-4-carboxylic acid (104 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-hydroxy-2-phenylbenzoxazole-4-carboxamide (29 mg, 30%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.22 (br s, 1H), 9.29 (d, J=7.4 Hz, 1H), 8.17-8.13 (m, 2H), 7.67-7.63 (m, 3H), 7.46 (d, J=2.3 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 4.09-4.06 (m, 1H), 3.30-3.27 (m, 1H), 2.90-2.86 (m, 2H), 2.77-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.99-1.94 (m, 2H), 1.69-1.63 (m, 3H); MS (ESI+) m/z 364 (M+H); HPLC>99% (AUC), tR=11.90 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (4.5 g, 27 mmol) and 4-bromo-benzaldehyde (5.0 g, 27 mmol) in ethanol (150 mL) was prepared. The reaction mixture was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(4-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.3 g, 70%) as a white solid: LC/MS m/e calcd for C16H14BrNO2 M+: 332.2, observed: 332.2, 334.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C(OCC)(=O)C.C1COCC1>[O:42]=[C:33]1[C:34]2[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](=[O:37])[N:32]1[O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: NC(=O)c1ccc(CO)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(CON2C(=O)c3ccccc3C2=O)nc1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg of triphenylphosphine, 503 mg of N-hydroxyphthalimide, and 4.7 ml of THF was added dropwise 0.53 ml of diisopropyl azodicarboxylate, followed by stirring overnight. After concentration, the solid thus produced was suspended in water, and ethyl acetate was added thereto. After stirring for 30 minutes, the solid was collected by filtration to obtain 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3)CC2)c(OC)nc1C
Yield: 86 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C(OC(N1C=C(C2N(C(OC(C)(C)C)=O)C3C=C(NC4C=CC(C(=O)N(C)C)=CC=4)N=CC=3C=2)C=N1)=O)(C)(C)C>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[CH:15]=[C:14]([NH:41][C:40]4[CH:39]=[CH:38][C:37]([CH2:36][N:33]5[CH2:32][CH2:31][O:30][CH2:35][CH2:34]5)=[CH:43][CH:42]=4)[N:13]=[CH:12][C:11]=3[CH:10]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(CN5CCOCC5)cc4)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from compound (17) and 4-(morpholinomethyl)aniline using the method described for compound (49). 1H-NMR (500 MHz, CDCl3) 1.51 (s, 9H), 1.69 (s, 9H), 2.47 (br t, J=4.2 Hz, 4H), 3.49 (s, 2H), 3.72 (t, J=4.7 Hz, 4H), 6.58 (d, J=0.5 Hz, 1H), 6.66 (s, 1H), 7.31 (br s, 4H), 7.61 (s, 1H), 7.82 (d, J=0.5 Hz, 1H), 8.22 (d, J=0.5 Hz, 1H), 8.45 (d, J=0.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.CO.[OH-].[Ba+2:36].[OH-]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:36]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 20 h

Procedure:
Raltegravir (10 gm), methanol (60 ml), acetonitrile (40 ml) and barium hydroxide (4.2 gm) were added at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 20 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir barium.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2ccccc2)cc1
Yield: 78.4 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (142.2 mg, 1.0 mmol), acetophenone (302.1 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.0 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 16.7 h. 2-(4′-Methoxyphenyl)-1-phenyl-1-ethanone (177.3 mg) was obtained with a yield of 79% as solid. m.p.: 94.1-94.4° C. (n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.07-8.00 (m, 2H, ArH), 7.60-7.51 (m, 1H, ArH), 7.51-7.42 (m, 2H, ArH), 7.25-7.17 (m, 2H, ArH), 6.92-6.86 (m, 2H, ArH), 4.24 (s, 2H, CH2), 3.78 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 197.8, 158.3, 136.4, 132.9, 130.3, 128.45, 128.41, 126.3, 113.9, 55.0, 44.4; IR (KBr) v (cm−1) 3056, 2998, 2954, 2934, 2905, 2835, 1691, 1612, 1596, 1579, 1514, 1463, 1447, 1411, 1335, 1301, 1245, 1218, 1204, 1178, 1107, 1035; MS (70 eV, EI) m/z (%): 227 (M++1, 3.58), 226 (M+, 21.25), 121 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: COc1ccc(C)cc1C(O)=S
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:12][C:10](=[O:11])[C@H:9]([NH2:8])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CO
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)CC(C)C
Temperature: 25 °C

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-4-methyl-pentanoic acid (2 g, 8.7 mmol) in methanol (20 mL) is added thionyl chloride (2.59 g, 21.7 mmol). The reaction mixture is refluxed for 2 h. The reaction mixture is cooled to room temperature and concentrated in vacuo. The crude product is carried on without any further purification. 1H NMR (400 MHz, MeOD): δ 1.00 (q, 6H, J=3 Hz), 1.7-1.9 (m, 3H, J=7.7 Hz), 3.85 (s, 3H), 4.0 (t, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C1C=CC=CC=1.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.C1([Pd-3](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([Pd-3](c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Yield: 66.9 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (110 mg) and tetrakis(triphenylpalladium(0) (54 mg) in 30 ml benzene, were added 2 M aqueous sodium carbonate (0.22 ml) and 4-methyl-benzeneboronic acid (60 mg). The reaction solution was stirred at reflux for 24 hours. Then the solvent was evaporated off under reduced pressure. The resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate=2:1) to give 76 mg of 2,2-dimethyl-4-(4-methylphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 167-168° C. NMR: δ1.57 (s, 6H), 2.38 (s, 3H), 3.07 (s, 3H), 7.17 (m, 4H), 7.89 (m, 4H). IR (cm−1): 1707, 1660, 1531, 1289, 1230. MS (EI): 356 (m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[C:13](=[O:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11]3[CH2:32][CH2:33][C:34](=[O:35])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[C:13](=[O:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:11]3[CH2:32][CH2:33][C:34](=[O:35])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)propanoate (intermediate 27, 125 mg, 0.26 mmol) in 1,4-dioxane (3 mL) is treated with aqueous lithium hydroxide (2.0 M, 390 μL, 0.78 mmol), and the mixture is stirred at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The aqueous phase is acidified with 1M aqueous hydrogen chloride and extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. Yield: 91 mg; ESI mass spectrum: [M+H]+=470; Retention time HPLC: 0.85 min (Z018_S04).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[Cl:15][CH2:16][C:17](=O)[CH2:18]Cl>C(#N)CC>[Cl:15][CH2:16][C:17]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][CH:8]=2)[O:11][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: CCC#N
Product: ClCCCOc1ccc(-c2nc(CCl)co2)cc1
Yield: 83 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzamide ax54 (1.9 g, 8.9 mmol, 1 eq), 1,3-dichloro-propan-2-one (1.13 g, 8.9 mmol, 1 eq) in propionitrile (45 ml) is stirred at reflux for 48 h. The solvent is then removed under vacuum and filtered over silicagel with dichloromethane. The dichloromethane is evaporated under vacuum to give 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole ax57 (2.1 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13](C(OCC)=O)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCc2[nH]c3c(Br)ccc(Br)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 95 °C
Yield: 95.7 %

Procedure:
A suspension of ethyl 6,9-dibromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (2.70 g, 6.72 mmol) in ethanol (25 mL) was treated with a solution of potassium hydroxide (15.07 g, 269 mmol) in water (15 mL) and ethanol (50 mL). The dark brown mixture was bubbled with nitrogen with sonication for 1 min. The mixture was then heated under nitrogen to 90-100° C. for 44 h, then at reflux for 23 h more. The solution was cooled to room temperature and concentrated under vacuum. The residual aqueous sludge was diluted with water (about 100 mL), stirred and intermittently sonicated for 1 h, and the precipitate was collected by filtration, washed thoroughly with water and dried under vacuum to provide the desired product as a light reddish-brown powder (2.123 g, 96% yield). LCMS (M+H+) m/z 329, 331, 333).
Reaction SMILES: Br[C@:2]1([C@H:10]([CH3:12])[OH:11])[O:7][C:5](=[O:6])[C:4]([OH:8])=[C:3]1[O-:9].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>N1C=CC=CC=1>[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[O:6]=[C:5]1[O:7][C@H:2]([C@H:10]([CH3:12])[OH:11])[C:3]([O-:9])=[C:4]1[OH:8]
Reactant: C[C@H](O)[C@@]1(Br)OC(=O)C(O)=C1[O-]
Agent: NCCCC[C@H](N)C(=O)O
Solvent: c1ccncc1
Product: C[C@H](O)[C@H]1OC(=O)C(O)=C1[O-]

Procedure:
6-Deoxybromo ascorbate (8 mmoles) is reacted with lysine (10 mmoles) in dry pyridine to give the desired product. The α-amino group of lysine is protected so that the ε-group is available for reaction. The reaction is carried out overnight. Pyridine is removed under reduce pressure, poured in ice, extracted with ether, washed with water, dried over sodium sulfate. Ether is removed and crystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:16]=1)(=[O:9])=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:16]=1)(=[O:8])=[O:9]
Reactant: COC(=O)C(C)Nc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NC(C)C(=O)O)c2)c(OC)c1

Procedure:
To a solution of methyl (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoate (0.1 mol) in ethanol (200 mL), was added sodium hydroxide (20% aqueous solution, 200 mL). The resulting mixture was heated at reflux for 2.5 h. The reaction was monitored by TLC. When the reaction was complete, the volatiles were removed under vacuum and the resulting residue was acidified to pH 4 by addition of acetic acid. A solid precipitate formed. The precipitate was separated by filtration. The filtered solid was recrystallized twice from acetone to provide the desired (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoic acid. m.p. 176-180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2Cl)c1
Temperature: 200 °C

Procedure:
N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)acrylamide (25 mg, 0.085 mmol), 4-morpholinoaniline (15.15 mg, 0.085 mmol) and Cs2CO3 (27.7 mg, 0.085 mmol) were dissolved in toluene (4.5 ml) in a sealable microwave compatible reaction tube, and then Pd2 dba3 (1.557 mg, 1.700 μmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (1.967 mg, 3.40 μmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (30 min, 200° C., 3 atm). The reaction was monitored by TLC. After completion of the reaction, solvent was removed in vacuo. The product was purified by flash column chromatography (5% CH3OH/CH2Cl2) to give the title compound. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 7.66 (m, 1H), 7.56 (s, 1H), 7.45-7.39 (m, 1H), 7.20 (m, 2H), 6.93 (m, 1H), 6.70 (m, 2H), 6.46-6.34 (m, 2H), 5.78 (dd, 1H, J=2.0 & 9.6 Hz), 3.80 (m, 4H), 2.99 (m, 4H). ESI-MS: 436.07 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 80.2 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 27.9 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of N,N-dimethylaniline chloride was removed by filtration and the filtrate was subjected to distillation to recover toluene, whereby 19.8 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.