Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:60][CH2:59][N:51]2[C:52]3[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=3[CH:58]=[C:50]2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1)(=[O:30])[CH3:29]
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
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: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, tert-butyl 6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate 120a (300 mg, 0.689 mmol), 114a (352 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.0345 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), 1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 174a.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[Br:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH2:29])[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH:29][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[CH:18][CH:17]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Cl)cc(OCc2ccc(Br)cc2)c1
Product: CCCc1ccc2c(Nc3cc(Cl)cc(OCc4ccc(Br)cc4)c3)ccnc2n1

Procedure:
The product from Example 2g (100 mg, 0.39 mmol) was reacted with the product from Example 196b (120 mg, 0.39 mmol) for 22 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the title compound (1990 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J=7.4 Hz, 3H), 1.83 (sextet, J=7.4 Hz, 2H), 2.97 (t, J=7.4 Hz, 2H), 5.18 (s, 2H), 6.91 (d, J=6.7 Hz, 1H), 7.05-7.17 (m, 3H), 7.43 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 8.51 (d, J=6.7 Hz, 1H), 9.05 (d, J=8.5 Hz, 1H); MS (ESI+) m/z 482, 484, 486 (M+H)+, (ESI−) m/z 480, 482, 484 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])#[N:2].CO>[Pt](=O)=O.C(Cl)(Cl)Cl>[NH2:2][CH2:1][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CC#N)cc2s1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Reaction time: 48 h
Yield: 121.5 %

Procedure:
A suspension of 1-(6-(2-cyanoacetyl)-2-benzothiazolyl)-3-ethylurea (0.56 g, 1.94 mmol) and platinum (IV) oxide (0.176 g, 0.78 mmol, 0.40 eq) in 50 mL of 2/3 mixture of MeOH and chloroform was purged and bubbled with hydrogen gas. It was stirred under hydrogen gas for about 2 days. The mixture was filtered and concentrated to give 0.689 g (quantitative yield) desired compound. LC/MS 292.9 (M+1); LC retention time 1.80 min. HPLC purification gave corresponding acetic acid salt. LC/MS 292.9 (M+1); LC retention time 1.80 min. In a similar reaction, compound as an acetate salt form was obtained after HPLC purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](O)=[O:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C1C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][OH:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A stirred solution of 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]benzimidazole (1.50 g) in benzene (30 ml) was added dropwise to sodium dihydro-bis(2-methoxyethoxy)aluminate (70% toluene solution). The mixture was stirred for one hour at room temperature, and then heated for 10 minutes under reflux. The reaction mixture was cooled and poured into 2N--HCl, followed by extraction with dichloromethane. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by silica gel (80 g) column chromatography to give the title compound (0.67 g, 46%) as an oil, which was crystallized from ethyl acetate--ether to afford pale yellow prisms, m.p. 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:23](=N)(OCC)[CH3:24]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:23]([CH3:24])=[N:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]1
Yield: 89.8 %

Procedure:
A solution of 2.99 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 1.85 parts of ethyl ethanimidate hydrochloride and 40 parts of methanol was stirred for 16 hours at room temperature. The solvent was evaporated and the residue was dissolved in a dilute hydrochloric acid solution. The whole was alkalized with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonia (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo, yielding 2.9 parts (89.8%) of 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-methyl-1H-benzimidazole; mp. 117.1° C. (compound 122).
Reaction SMILES: O.O[PH2]=O.[P].[CH2:6]([O:9][C:10](=[O:27])[C:11]([O:14][C:15](=[O:26])[C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=1[Cl:25])([CH3:13])[CH3:12])[CH:7]=[CH2:8]>[Pt].C1(C)C=CC=CC=1>[CH2:6]([O:9][C:10](=[O:27])[C:11]([O:14][C:15](=[O:26])[C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[Cl:25])([CH3:13])[CH3:12])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pt]
Agent: O=[PH2]O
Agent: [P]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
5.9 kg of 5% Pt/C catalyst 5% (H2O content: 62.8%) are placed in a 60-liter steel vessel together with 12 liters of water, and 470 g of 50% H3PO2 solution (≡5% phosphorus based on the catalyst) are added. The catalyst slurry is stirred for 10 minutes at room temperature, then 360 g of vanadylacetylacetonate VO(acac)2 as is (0.2 mol %) are added and the mixture is stirred for a further 5 minutes. 550 kg of a solution of 2-(chloro-5-nitro-benzoyl-oxy)-2-methyl-propionic acid allyl ester (content: 40%, 0.67 kmol) in toluene are placed in an autoclave having a stirrer and the catalyst suspension is added, rinsing the steel vessel with 15 kg of water. Hydrogenation is then carried out for 2 hours at a temperature of 100° C. and a hydrogen pressure of 5 bar. After cooling and rendering the autoclave inert using nitrogen, the catalyst is filtered off at 50° C. and washed with 50 kg of toluene. After working up by distillation, 196 kg of 2-(chloro-5-amino-benzoyloxy)-2-methyl-propionic acid allyl ester (yield 98% of theory) are obtained. The over-hydrogenated propyl ester content is <0.05%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=O.[NH2:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[N:15][C:16]1[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COCOc1ccc(OC)cc1C=O
Reactant: Cc1cccc(O)c1N
Solvent: c1ccccc1
Product: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) (2.77 g, 16.5 mmol) and 2-amino-m-cresol (2.03 g, 16.5 mmol) in benzene (70 mL) was refluxed for 15 h using an additional funnel to remove water. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting residue was washed with ethanol to afford the objective compound as a orange solid (84%), which was used for next reaction without further purification: 1H-NMR (400 MHz, DMSO-d6) δ2.31 (s, 3H), 3.45 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 6.59 (s, 1H), 6.77 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.03 (dd, 1H, J=9.0, 2.5 Hz), 7.14 (d, 1H, J=9.0 Hz), 7.68 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2]>CO.[C].[Pd]>[CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OCCNC(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc(C)c1OCCNC(C)C
Yield: 99 %

Procedure:
N-isopropyl-[2-(2,6-dimethyl-4-nitrophenoxy)]ethylamine (5.5 g) solution in methanol (70 ml) was subjected to hydrogenation reaction with 10% palladium carbon catalyst at ambient pressure. After completion of hydrogenation reaction, catalyst was removed by filtration. Filtrate was concentrated to obtain 4-[2-(isopropylamino) ethoxy]3,5-dimethylaniline (4.80 g) as pale brownish oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66]O)[CH:64]=[CH:63][N:62]=[CH:61]1.C(O)(=O)C>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:66][CH2:65][N:60]3[CH:64]=[CH:63][N:62]=[CH:61]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCn1ccnc1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Diethyl azodicarboxylate (160 mg, 1.4 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol), (J. Med. Chem. 1993, 25, 4052-4060), in methylene chloride (5 ml) and the mixture stirred for 1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was added and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration, dried under vacuum and purified by chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (250 mg, 76%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:42][CH:41]=3)=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=O)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:42][CH:41]=3)=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Yield: 87.2 %

Procedure:
Prepared using General Procedure 18: A solution of (S)-tert-butyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (436 mg, 0.6 mmol) in THF (25 mL) was hydrogenated in the H-Cube using a 10% Pd/C CatCart at 60° C. (Full hydrogen, 1 mL/min). The reaction mixture was passed over the catalyst a second time at 65° C. The solvent was removed to give 307 mg (83%) of (S)-tert-butyl 1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate INT-26 as a white powder. LCMS-ESI (m/z) calculated for C35H46N4O4: 586.4. found 587.4 [M+H]+, tR=6.99 min (Method 10).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][N:8]3[CH:11]=[CH:12][CH:13]=[C:7]3[CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:5]2[C:4]3[CH:3]=[CH:2][S:1][C:10]=3[CH2:9][N:8]3[CH:11]=[CH:12][CH:13]=[C:7]3[CH2:6]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc2n(c1)Cc1sccc1NC2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2sccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3 mmol of 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 10 ml of methylene chloride under argon is added 5 mmol of triethylamine followed by ice bath cooling. A solution of 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[O:17])=[CH:14][CH:13]=1
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 2,3-dichloroanisole (35.4 g.; 0.20 mole), 4-fluorobenzoyl chloride (34.8 g.; 0.22 mole) and methylene chloride (300 ml.) at 5° C. was stirred vigorously and treated with finely powdered aluminum chloride (28.0 g.; 0.21 mole). The reaction mixture was slowly heated and refluxed for two hours. The reaction mixture was cooled to room temperature and decomposed with ice and hydrochloric acid (50 ml.). The aqueous solution was extracted twice with methylene chloride. The combined methylene chloride solution was washed with aqueous sodium bicarbonate solution and finally with water. The organic layer was dried (MgSO4) and filtered. The solvent was removed in vacuo, and the residue on triturating with pet. ether gave the product 32 g. (50%); m.p. 138°-140°. This product was used for Step B without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:19])[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C)C=O.C(OCC)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:19])[CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:31][C:28]2[S:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[N:30][CH:29]=2)[CH2:17][CH2:18]1
Reactant: Nc1ccccc1C(=O)CCC1CCNCC1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
To a suspension of the compound prepared in Example 308 (323 mg) and the compound prepared in Example 139 (267 mg) in 1,2-dichloroethane (10 mL) and N,N-dimethylformamide (4 mL) was added diisopropylethylamine (0.89 mL) and sodium triacetoxyborohydride (813 mg). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 50-75% ethyl acetate/hexane) to furnish the title compound (222 mg) with the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:10](=[O:12])[CH3:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)cc1
Product: CC(=O)Nc1ccc(C#N)cc1

Procedure:
By the reaction in the same manner as in Example 35-i) using 4-aminobenzonitrile (5.51 g) and acetic anhydride (5.7 ml), the title compound (5.88 g) was obtained as colorless needle crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4]C(=O)[O-].[Cl-].[NH4+].CC1C=CC(S(O[C@H:21]2[CH2:25][O:24][C@@H:23]3[C@@H](Br)CO[C@H:22]23)(=O)=O)=CC=1.N>O.CC(O)C.[Zn].CO>[NH2:4][CH2:3][C@H:2]([C@@H:23]1[CH:22]=[CH:21][CH2:25][O:24]1)[OH:1]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Reactant: O=C([O-])NCCO
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Preparation of Benzyl (R)-2-(S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18). Zinc and ‘One-pot’ procedure. A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL) was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) in propan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was then added in portions over 4 minutes and the mixture was stirred for 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol), then divided into two equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.I[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:14]=[CH:15][CH:16]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>[Cu](I)I.C(OCC)(=O)C.CS(C)=O>[O:1]=[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:15]1[CH:16]=[CH:11][CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:14]=1
Reactant: O=Cc1ccc[nH]c1=O
Reactant: O=C1COCCN1c1cccc(I)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cccn(-c2cccc(N3CCOCC3=O)c2)c1=O
Temperature: 25 °C
Yield: 25.2 %

Procedure:
30 mL microwave reaction vessel was flushed with nitrogen gas and charged with 2-oxo-1,2-dihydropyridine-3-carbaldehyde 1-1 (100 mg, 0.812 mmol), 4-(3-iodophenyl)morpholin-3-one 3-1 (296 mg, 0.974 mmol), 8-hydroxyquinoline (48.0 mg, 0.324 mmol), copper iodide (31.0 mg, 0.162 mmol), potassium carbonate (152 mg, 1.09 mmol) and DMSO (1.7 mL) under a nitrogen atmosphere. The resulting mixture was irradiated in a microwave apparatus (Biotage) at 150° C. for 15 minutes. The reaction was cooled to room temperature and poured into a mixture of 10% aq. ammonium hydroxide and ethyl acetate. The resultant mixture was filtered through a pad of Celite and washed with ethyl acetate three times. The layers were separated with the aqueous portion being back extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (0-100% EtOAc in hexane) gave 61.0 mg (24%) of 3-2 as a light brown solid: 1H NMR (400 MHz, CDCl3) δ 10.33 (1H, d, J=0.4 Hz), 8.14 (1H, dd, J=6.8, 2.3 Hz), 7.27 (1H, dd, J=6.8, 2.3 Hz), 7.60 (1H, t, J=8.1 Hz), 7.53 (1H, t, J=2.1 Hz), 7.47 (1H, ddd, J=8.1, 2.1, 1.2 Hz), 7.32 (1H, ddd, J=8.1, 2.1, 1.2 Hz), 6.43 (1H, dt, J=6.8, 0.4 Hz), 4.34 (2H, br, s), 4.03-4.06 (2H, m), 3.84-3.86 (2H, m); ESI-MS m/z 299 [C16H14N2O4+H]+.