Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19]OC)(=[O:17])[CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:19][O:18][C:14](=[O:17])[CH2:15][CH3:16])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)OCOC
Reactant: OC(CCl)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: CCC(=O)OCOC(CCl)COCc1ccccc1

Procedure:
204.0 g of 3-benzyloxy-1-chloro-2-propanol, 660 ml of hexane, 626.3 g of methoxymethyl propionate and 5.79 g of p-toluenesulfonic acid mono-hydrate were placed into a 2-liter 3-neck round bottom flask equipped with a thermometer, mechanical stirrer, nitrogen inlet and an efficient distillation column. The reaction mixture was heated to reflux. The distillate was taken off at about 10:1 to 15:1 reflux ratio keeping the head temperature below 60° C. Samples were taken to monitor the progress of the reaction. The reaction was quenched when the desired level of methyl acetal was reached which is usually less than about 4% methyl acetal. The quench was carried out by rapidly adding a solution of 11.55 g of sodium carbonate in 310 ml of water directly to the hot reaction mixture. The aqueous layer was washed with additional water and/or base to remove any residual propionic acid. The volatiles were removed to leave the crude product as a mobile liquid. Yield: 285.2 g, (97.8%); 92.6% pure..
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCNC(=O)OC(C)(C)C)ccc2c1
Yield: 82.4 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9 mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and 1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH2Cl2 (200 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The filtrate was concentrated, dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath to precipitate the remaining dicyclohexyl urea and then filtered. The filtrate was concentrated, dissolved in CH2Cl2 (15 mL) and hexane (200 mL) and then stirred until the product precipitated. The solid was dried under vacuum to give the title compound (10.12 g, 82% yield). Mp 82-84° C. 1H NMR (300 MHz, CDCl3) δ 7.72-7.65 (m, 3H), 7.42-7.38 (m, 1H), 7.16-7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 155.6, 135.4, 133.6, 129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2, 39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)+. Anal. calcd. for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N, 3.66.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([CH3:29])[CH:16]=3)=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:38][CH2:37][CH2:36][N:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OCCCN1CCOCC1
Yield: 53 %

Procedure:
Using an analogous procedure to that described in Example 38, 6-hydroxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 3-morpholinopropyl chloride to give 7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(3-morpholinopropoxy)quinazoline in 53% yield;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]2[N:4]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2nccc(-c3cccnc3)n2n1
Yield: 40.3 %

Procedure:
A reaction mixture of 0.98 g of 3-amino-5-methyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours. The procedure was continued as for Example 1 to give 0.85 g of the product of the Example as colorless crystals, mp 244°-245° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)/[CH3:28])[CH:26]=1
Reactant: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
4-(morpholinosulfonyl)benzohydrazide (100 mg, 0.350 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (59.8 mg, 0.350 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-4-(morpholinosulfonyl)benzohydrazide (80 mg, 0.177 mmol, 50.6% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (m, 2H), 7.89 (m, 2H), 7.67 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.64 (m, 4H), 2.92 (m, 4H), 2.49 (s, 3H). Mass [M+H]+:438.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[CH:34]([C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40])=O.CO.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:34][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41][CH3:42])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CN2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (100 mg, 0.21 mmol, 1.00 equip), methyl 3-formylbenzoate (68 mg, 0.41 mmol, 2.00 equip), methanol (10 mL), NaBH3CN (66 mg, 1.03 mmol, 5.00 equip), and acetic acid (0.1 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate as a yellow solid. LCMS (ES, m/z) 626 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([OH:19])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2.C(C1NC=CN=1)(C1[NH:23]C=CN=1)=O.N>Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:23])=[O:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN(C)Cc1cnc2ccc(Cl)c(CC(=O)O)c2n1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Hydrochloric acid (4 M in dioxane, 8 drops) was added to a solution of the above (6-chloro-3-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid in N,N-dimethylformamide (3 ml). A solution of carbonyl diimidazole (188 mg, 1.16 mmol, 1.2 equiv) in N,N-dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Concentrated aqueous ammonia (25%, 10 ml) was added, and after 10 minutes at room temperature, volatiles were removed in vacuo. The residue was purified via flash chromatography (gradient of CH2Cl2/MeOH 95:5 to 70:30) to afford the title compound (180 mg, 67%) as a foam. 1H NMR (400 MHz, d6-DMSO): δ=9.02 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.54 (br s, 1H), 6.98 (br s, 1H), 4.7-4.5 (br, 2H), 4.32 (s, 2H), 2.78 (br s, 6H). MS (ES+): 279.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH:12]2OCC[O:13]2)[CH:3]=1.FC(F)(F)C(O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: N#CCOc1ccc(Cl)cc1C1OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#CCOc1ccc(Cl)cc1C=O
Reaction time: 8 h
Yield: 93.7 %

Procedure:
At room temperature, a mixture of (4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-acetonitrile (28.68 g, 0.12 mol) and trifluoroacetic acid (41.04 g, 0.36 mol) in EtOAc (500 mL) was stirred overnight. Then the solution was washed with water, saturated NaHCO3 solution twice, dried over anhydrous Na2SO4, and concentrated to give crude product (22 g). The crude product was directly used for next step without further purification.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)[C:9]([NH2:11])=[NH:10]>N1C=CC=CC=1.O>[C:5]([N:10]=[C:9]([NH2:11])[NH:8][C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)(=[O:7])[CH3:6]
Reactant: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=NC#N)NCCSCc1csc(NC(N)=NC(C)=O)n1
Reaction time: 2 h

Procedure:
Acetic anhydride (0.39 g.) was added to a stirred suspension of 2 -guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.10 g.) in pyridine (6 ml.) at room temperature. After stirring for two hours, the mixture was diluted with water (50 ml.), extracted with methylene chloride (3×30 ml.) and the combined extracts washed with water (100 ml.) and dried over magnesium sulphate. The solution was filtered and evaporated to dryness to leave a gum which was purified by column chromatography (silica column, eluted with ethyl acetate/ethanol/ammonia (s.g. 0.880) 6:1:1 v/v/v) to give 2-(2-acetylguanidino)-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole as an amorphous solid. The n.m.r. spectrum in d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 2.1 (3H, singlet); 2.7 (5H, multiplet); 3.3 (multiplet, obscured by H2O); 3.7 (2H, singlet); 6.8 (1H, singlet); 7.0 (2H, broad multiplet; 9.0 (2H, very broad) and 10.7 (1H, broad).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[NH2:26][C:24]([C:23]1[CH:22]=[C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])[S:20][C:19]=1[NH:18][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: COC(=O)c1cnnn1Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COC(=O)c1cnnn1Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was synthesized from methyl 1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazole-5-carboxylate (166 mg, 0.56 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (175 mg, 0.56 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>C1COCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:29])[C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(=O)C(CN2C(=O)c3ccccc3C2=O)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide solution (1.8M in hexane, 6 ml, 10 mmol) was provided in absolute tetrahydrofuran (10 ml). The solution was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (1.1 g, 5 mmol), dissolved in dry THF (5 ml), was added in drops within 1 min. The batch was left for 30 min at −78° C. Then, N-(bromomethyl)phthalimide (3.6 ml, 15 mmol), dissolved in dry THF (20 ml), was added in drops within 1 min. The reaction mixture was stirred for 1 h at −78° C., then the cooling was removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with saturated NH4Cl solution (1×40 ml). The organic phases were then mixed with 1N HCl (50 ml) and thoroughly shaken out. The acid aqueous phase was separated and the organic phase was washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 2N NaOH (70 ml). An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. One of the two possible diastereoisomers of the ketone was isolated from the obtained residue (2 g) with a yield of 223 mg (12%) by means of chromatographic purification [silica gel 60 G (50 g); cyclohexane/ethyl acetate 1:10 (700 ml)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[O:16]([CH:8]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][N:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(OC(Oc2ccccc2)c2ccccn2)cc1

Procedure:
To a solution of 10.42 grams (g) (0.032 mole (m)) of 6-chloro-2-(diphenoxymethyl)pyridine, 8.02 g (0.079 m) of triethylamine in 200 milliliters (ml) of absolute ethanol in a Parr shaker bottle was added 0.5 g of 5 percent palladium on charcoal. Hydrogen was passed over the liquid surface using a Parr hydrogenator until ~3 pounds (0.3 m) had been consumed. The reaction mixture was filtered and the solvent removed by evaporation under reduced pressure. The residue was poured into a solution of 50 ml of water and 50 ml of 10 percent sodium hydroxide. This solution was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and the solvent stripped away under vacuum. The residue was heated at 0.02 millimeters of mercury to 110° C. to remove lower boiling impurities. The above named product was recovered as a pale yellow oil in a yield of 6.8 g and was ~99 percent pure. The Nuclear Magnetic Resonance spectrum (NMR) confirmed the product. The product has a refractive index of n25/d=1.5946 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 77.78, 5.56 and 4.92 percent, respectively, as compared with the theoretical contents of 77.98, 5.24 and 5.05 percent, respectively, as calculated for the above named compound (Compound 1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33]Cl)[C:31]=2[Cl:32])=[O:26])=[CH:11][CH:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:31]=2[Cl:32])=[O:26])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2cncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.8 %

Procedure:
To a solution of 1,2,4-triazole (0.40 g, 5.7 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.23 g, 5.7 mmol) and the mixture stirred at ambient temperature. After 10 min, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.90 g, 1.9 mmol) in DMF (5 mL) was added and stirring continued. After 18 hours, the mixture was poured onto water and extracted with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.99 g (77% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-dr/TFA) 11.2 (s, 1), 10.7 (s, 1), 9.3 (s, 1), 8.5 (s, 1), 8.3 (d, 1), 8.0 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.5 (s, 2) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]([NH:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=[CH:16][N:17]=1)=[O:31]
Reactant: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: O=C(Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1)Nc1c(Cl)cccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate. Faintly violet solid, HPLC: tR=3.74 min (purity: 100%, gradient F), ESI-MS: 459.3/461.3 [MH]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.O[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1
Reactant: OCC1CCOCC1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(OCC2CCOCC2)c1

Procedure:
Prepared from tetrahydro-2H-pyran-4-yl-methanol and ethyl 3-hydroxybenzoate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15]Br)=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:14][CH2:15][CH2:11][C:10](=[O:12])[C:8]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCOc2ccc(Br)cc21
Reaction time: 20 h
Yield: 69.7 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol) in THF (˜50 mL) at room temperature was added 1-(5-bromo-2-(2-bromoethoxy)phenyl)ethanone (8.07 g, 25.1 mmol). The reaction mixture was slowly heated to reflux and allowed to stir for 20 h. The solvent was removed under vacuum pressure and the concentrated residue was absorbed onto silica gel and purified by column chromatography (4:1 ethyl acetate/petroleum ether). The product was afforded as a yellow oil after the solvents were removed, providing 4.22 g (70%) of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one. 1H NMR (CDCl3) δ 7.87 (d, J=2.6 Hz, 1H), 7.50 (dd, J=2.6, 8.1 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.15-2.29 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:28]([OH:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6 M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 183°-184° C.