Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC.Cl[C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>C(O)C(C)C>[CH2:7]([O:8][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH:6]([CH3:10])[CH3:5]
Reactant: O=C(O)c1ccccc1Cl
Agent: CNC
Solvent: CC(C)CO
Product: CC(C)COc1ccccc1C(=O)O
Temperature: 100 °C
Yield: 141.4 %

Procedure:
In a pressure-resistant sealed vessel, were dissolved 1.14 g of o-chlorobenzoic acid (7.3 mM) and 0.18 g of cuprous chloride (1.8 mM) in 5 g of an isobutyl alcohol solution containing 20% dimethylamine (about 6.0 ml) prior to addition of isobutyl alcohol to a total volume of 50 ml, followed by heating to 100° C. as in Example 4. The reaction mixture solution was analyzed periodically over time by GC-MSE1 in the same manner as in Example 4, in order to follow the progress of the reaction. As a result, 20 hours later, the completion of the reaction was confirmed. Effecting the subsequent process in the same manner as in Example 4, 1.0 g of 2-isobutoxybenzoic acid was obtained (yield of 70.6%). The ester of the above product (3%) and benzoic acid (5%) were also obtained as the byproducts, which were confirmed by 1H-NMR and GC-MSE1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:30][N:31]([C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:32](=[O:47])[C@H:33]([NH:45][CH3:46])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15](=[O:17])[N:45]([CH3:46])[C@@H:33]([C:32](=[O:47])[N:31]([CH3:30])[C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([S:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:20][C:12]2[CH:13]=[C:14]([Cl:19])[C:15]([S:17][CH3:18])=[CH:16][C:11]=2[Cl:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CSc1cc(Cl)c(O)cc1Cl
Reactant: Cc1cc(F)cc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1cc(Cl)c(Oc2cc(C)nc(F)c2)cc1Cl
Temperature: 0 °C

Procedure:
Amounts of 12.9 gm (0.1 mol) of 2,4-difluoro-6-methylpyridine, 20.7 gm (0.1 mol) of 2,5-dichloro-4-methylmercaptophenol, and 13.8 gm (0.1 mol) of potassium carbonate in 100 ml of dimethylformamide were stirred for 10 hours at 100° C. The resulting solution was then poured onto 500 ml of ice water, and the precipitate formed was recovered by suction filtration and washed with water. It was then taken up in methylene chloride, and this solution was dried over sodium sulphate and evaporated down. The oil obtained was purified over a silica gel column (ethylene chloride as the eluant) and 16.3 gm (57% of theory) of the desired ether were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2cccc(-c3ccc(C(C)C)cc3)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(-c2cccc(-c3cccc(C(=O)O)c3)n2)cc1
Yield: 84.7 %

Procedure:
Part C. A solution of ethyl 3-[6-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (90 mg) in 3 mL methanol-1 mL water is treated with lithium hydroxide hydrate (50 mg). The solution is heated to between 40 and 50° C. for 12 h. with stirring, then cooled and neutralized to pH 7 with 3 N aq. HCl. The mixture is extracted with ethyl acetate, and the extract is washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title product as a powder (70 mg, 85%), m.p. 215-216° C. NMR (300 MHz, CDCl3): δ 8.86 (1H, s), 8.47 (1H, d, J=8 Hz), 8.18 (1H, d, J=8 Hz), 8.08 (2H, d, J=9 Hz), 7.85 (1H, t, J=7 Hz), 7.77 (1H, d, J=7 Hz), 7.76 (1H, d, J=7 Hz), 7.62 (1H, t, J=8 Hz), 7.38 (2H, d, J=9 Hz), 2.99 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). MS (ES+): m/e 319 (20), 318 (100).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4NCC(C3C=CC=CC=3)C3C=CC=CC=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:45][CH2:46][CH:47]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1>>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4[NH:45][CH2:46][CH:47]([C:48]3[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=3)[C:55]3[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2nnn(Cc3ccccc3)n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Product: Oc1ccc(C(CNc2nc(Cl)nc3c2ncn3[C@@H]2O[C@H](c3nnn(Cc4ccccc4)n3)[C@@H](O)[C@H]2O)c2ccc(O)cc2)cc1

Procedure:
The title compound is prepared in an analogous fashion to (2R,3S,4R,5R)-2-(2-benzyl-2H-tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol (WO 99/38877) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bis-phenol (Intermediate A).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[OH:11][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14][CH2:13]1.CS>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:8]([N:14]1[CH2:13][CH:12]([OH:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[NH:9])[NH2:10]
Reactant: OC1CNCc2ccccc21
Reactant: CSC(=N)N
Agent: CS
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N1Cc2ccccc2C(O)C1
Reaction time: 36 h

Procedure:
A solution of 1.3 g. of S-methyl-isothiourea sulfate in 5 ml. of water at about 20° C. was added to 1.2 g. of 4-hydroxy-1,2,3,4-tetrahydroisoquinoline. The resulting mixture was maintained at about 25°-30° C. with occasional shaking. After a short time, methyl-mercaptan began to escape and, upon standing for 1-2 days, crystals formed. The crystals were removed by filtration and rinsed with ice-cold water and with ether. Recrystallization from water yielded 2-amidino-4-hydroxy-1,2,3,4-tetrahydroisoquinoline sulfate, having a melting point of 264°-266° C. (uncorrected).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with dimethylamine (1.2 equiv) to give 500 (11.7 mg, M+1 341.0)
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([Cl:19])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][C:26]([NH:29][C:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([F:38])[CH:32]=1)([CH3:28])[CH3:27])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([Cl:19])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH2:25][C:26]([CH3:27])([CH3:28])[N:29]=[C:30]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([F:38])[CH:32]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C2=NC(C)(C)CN2C(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Formula I where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 taken together with R8 is 2-(3-Fluoro-4-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl-; W and Z are —N═; X and Y are —C═: A solution of (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide (121 mg, 0.219 mmol) in phosphorus oxychloride (2 mL) is heated at reflux. After 8 hours, the reaction mixture is allowed to cool to ambient temperature and concentrated under reduced pressure. The residue is dissolved in dichloromethane (10 mL) and washed with two 10 mL portions of saturated aqueous sodium bicarbonate. The combined aqueous layers are extracted with dichloromethane and the extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (3% methanol/dichloromethane) to give the title compound, (±)-3-benzyl-7-chloro-2-{1-[2-(3-fluoro-4-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-pteridin-4-one.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[Cl:21]C(Cl)(Cl)C(Cl)(Cl)Cl.[ClH:29]>O1CCCC1.CC(OC)(C)C.O>[ClH:21].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[Cl:29]
Reactant: Fc1cncc(Br)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: Fc1cncc(Br)c1Cl
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
A solution of diisopropylamine (101.2 g, 140.2 mL, 1.000 mol) in tetrahydrofuran (1.148 L) was cooled to between −25° C. and −20° C. Butyllithium (2.5M in hexanes) (400 mL of 2.5 M, 1.000 mol) was added at such a rate as to maintain the reaction temperature below −20° C. (addition 20 minutes). The mixture was then allowed to warm to 4° C. over 1 hour, then re-cooled to −78° C. 3-bromo-5-fluoro-pyridine (153.0 g, 869.6 mmol) in tetrahydrofuran (382.5 mL) was added over 40 minutes. The mixture was stirred for 90 minutes, then a solution of 1,1,1,2,2,2-hexachloroethane (205.9 g, 869.6 mmol) in tetrahydrofuran (350.0 mL) was added dropwise over 40 minutes. Once the addition was complete the mixture was allowed to warm to ambient overnight. The mixture was cooled to 0° C. then transferred into cold water (2 L), stirred for 20 mins then MTBE (2.5 L) added and stirred vigorously for 30 mins then transferred to separating funnel and organic layer separated. Aqueous was transferred back to reaction vessel and further extracted with MTBE (2.5 L), stirred for 10 mins vigorously then transferred to separating funnel and organic layer separated. Organics were combined, dried (MgSO4), filtered and concentrated to a brown oil. The oil was dissolved in pentane (500 ml) and ether (300 ml). HCl (2M in ether) (434.8 mL of 2 M, 869.6 mmol) was added slowly with stirring. On complete addition the mixture was stirred for 20 mins then solid collected by filtration, washed with ether and dried under vacuum for 1 h to leave product 18 as a beige solid (148.9 g, 69%); 1H NMR (500 MHz, DMSO-d6) δ 8.77 (2H, s); 19F NMR (500 MHz, DMSO-d6) δ −124.8; MS 210.8.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10].C(=O)([O-])[O-].[Na+].[Na+].[ClH:18]>O>[NH2:3][C:4]1[C:5]([Cl:18])=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: Nc1cncc(Cl)c1Cl
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(Cl)ncc(Cl)c1Cl
Temperature: 25 °C

Procedure:
Thirty percent aqueous hydrogen peroxide (3.0 g, 26 mmole) was added dropwise with stirring at 15° C. to a solution of 8.0 g (49 mmol) of 3-amino-4,5-dichloropyridine in 450 mL of 37 percent aqueous hydrochloric acid. After 30 min another 2.6 g (23 mmol) of 30 percent aqueous hydrogen peroxide was added and the solution was allowed to slowly warm to room temperature. The resulting mixture was diluted with water, neutralized with sodium carbonate, and extracted with ether. The ethereal extract was dried over magnesium sulfate and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a viscous oil. This oil was partially purified by column chromatography to obtain 2.5 g (26 percent of theory) of the title compound, a white solid melting at 88°-90° C., and 5.3 g of a mixture of the title compound and 3-amino-2,4,5,6-tetrachloropyridine.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:5]=2[N:6]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1O)[C:18](O)=O.C(OC)(OC)(OC)C>>[CH2:23]([CH:15]([NH:14][C:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)=[O:13])[CH2:16][CH2:17][CH3:18])[CH2:22][CH3:21]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Agent: COC(C)(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2oc(C)nc2c1
Temperature: 65 °C
Yield: 80 %

Procedure:
2-methyl benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (1.5 g, 9.79 mmol) and trimethyl orthoacetate (15 mL, large excess) was heated at 65° C. for 5 hrs under argon. The reaction mixture was cooled to room temperature, filtered, washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a yellow solid (1.4 g, 80%): 1H NMR (500 MHz, CD3OD) δ 8.26 (d, J=1.7 Hz, 1H), 8.07 (dd, J=8.5, 1.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 2.67 (s, 1H); MS(APCI, M+1): 178.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:35][CH:36]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Product: COC(=O)Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (4-bromomethyl-phenyl)-acetic acid methyl ester (7398-42-7). Brown solid (45%). MS (Turbo Spray): m/z=539.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][C@H:42](O)[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:39][O:40][CH2:41][C@@H:42]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:43]
Reactant: COC[C@@H](C)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3 mmol/g loading, 155 mmol) and (R)-(−)-1-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>C(Cl)CCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:29]=3)[CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=S(=O)(NC1Cc2ccccc2C1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 3 h

Procedure:
38.5 g (0.289 mol) of anhydrous aluminium chloride and 12.4 g (0.124 mol) of succinic anhydride are suspended in 250 ml of ethylene chloride and 25.4 g (0.082 mol) of 2-p-chlorobenzenesulphonamido-indane are then added, with vigorous stirring. In the course of this, a clear solution is formed. After 3 hours, the product is decomposed by means of ice and hydrochloric acid, and the reaction product is isolated from the organic phase. It is recrystallised from glacial acetic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1nnc(N)s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nnc(Nc2cc(Br)cn(C)c2=O)s1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-methyl-1,3,4-thiadiazol-2-amine (1.15 g, 10.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.00 g, 15.0 mmol), Pd2(dba)3 (916 mg, 1.0 mmol), Xantphos (1.16 g, 2.0 mmol), Cs2CO3 (6.52 g, 20.0 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 267a (2.2 g, 73%) as white solid. MS-ESI: [M+H]+ 301.2
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[NH:15][C:14]3=O)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.N>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3[Cl:27])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(C)[nH]c(=O)c2cc1OCCCN1CCOCC1
Agent: N
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Cl)c2cc1OCCCN1CCOCC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A mixture of 6-(3-morpholinopropoxy)-7-methoxy-2-methylquinazolin-4(3H)-one (600 mg), thionyl chloride (20 mL) and DMF (0.5 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The solution was basified with ammonia solution and extracted with chloroform (3×100 mL). The combined CHCl3 layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (500 mg, 79%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 7.36 (1H, s), 7.25 (1H, s), 4.25 (2H, t, J=6.6 Hz), 4.03 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.79 (3H, s), 2.58 (2H, t, J=7.2 Hz), 2.49 (4H, t, J=4.4 Hz), 2.12 (2H, pentet, J=6.8 Hz); LC-MS (positive ion mode): m/z 352, 354 (M+H)±.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)(O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.O>C(#N)C>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: NCc1ccccn1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)NCc3ccccn3)coc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Compound 151 (0.15 g) obtained in Example 151 was dissolved in acetonitrile (3.0 ml), and carbonyldiimidazole (0.086 g) was added thereto under ice-cooling, followed by stirring at 60° C. for 30 minutes. 2-(Aminomethyl)pyridine (0.050 ml) was added to the mixture at room temperature followed by stirring for one hour. Water was added to the mixture and a precipitate was collected by filtration. The obtained crystals were recrystallized from DMF/water to give 4-[2-(3,5-dichloro-4-pyridyl)-1-oxoethyl]-7-methoxy-3-[(2-pyridylmethyl)aminocarbonylmethyl]benzofuran (0.13 g, 68%) as white crystals. Then, substantially the same procedure as in Example 51 was repeated using the obtained crystals to give Compound 157.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]I)[CH2:34][CH2:33]1)=O)(C)(C)C.O>CC(C)=O>[CH2:17]([N:8]1[C:9]2[C:14]([O:15][CH2:38][CH:35]3[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:16]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:18]
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cncc(OCC3CCNCC3)c21
Reaction time: 6 h
Yield: 39 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol) and K2CO3 (0.112 g, 0.812 mmol) in acetone (3 ml) at −78° C. was treated with 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (Villalobos, A; et al, J. Med. Chem., 1994, 37(17), 2721) (0.145 g, 0.447 mmol) and heated at reflux for 18 hours. A further portion of 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.447 mmol) was then added and the heating continued for a further 6 hours. The reaction was then cooled, poured into water, extracted with dichloromethane, dried with NaSO4 and reduced. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.071 g, 39%); MS (ES+) m/e 444 [M+H]+.