Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)O.[CH3:23][O:24][C:25]([C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][N:28]=1)=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:23][O:24][C:25]([C:27]1[N:32]=[CH:31][C:30]([N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH:2]([CH3:22])[CH3:1])=[CH:29][N:28]=1)=[O:26]
Reactant: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ncc(NC(=O)OC(C)(C)C)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ncc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (1.120 g, 3.630 mmol) (prepared as in Example 3.2 Step A) was combined with 5-tert-butoxycarbonylamino-pyrimidine-2-carboxylic acid methyl ester (0.920 g, 3.63 mmol) and dissolved in anhydrous tetrahydrofuran (20 mL). Triphenylphosphine (1.43 g, 5.45 mmol) was added and the reaction was brought to 0° C. Diisopropyl azodicarboxylate (1.43 mL, 6.90 mmol) was added dropwise over 5 min. The reaction was stirred as a yellow solution, allowing the bath to warm to room temperature. At 3 d, the reaction was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave impure (+/−)-5-{tert-butoxycarbonyl-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butyl]-amino}-pyrimidine-2-carboxylic acid methyl ester (1.501 g) as a pale yellow oil. MS (M+1): 544.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:21])([CH3:20])[C:18]#[N:19]>>[C:18]([C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:21])[CH3:20])#[N:19]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)(N)C#N
Product: CC(C)(C#N)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-propanenitrile (CAN 19355-69-2 as starting materials and isolated (50 mg, 78%) as colorless oil; LC-MS (UV peak area, m/z) 93.8%, 294.1001 (MH+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C@H:16]([NH:18]S(C2C=C(C)OC=2C(F)(F)F)(=O)=O)[CH3:17])=[CH:12][CH:11]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:18][C@@H:16]([C:13]2[CH:12]=[CH:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:32])[F:33])=[CH:15][CH:14]=2)[CH3:17])(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1
Reactant: Cc1cc(S(=O)(=O)N[C@H](C)c2ccc(-c3ccccc3OC(F)(F)F)cc2)c(C(F)(F)F)o1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: C[C@@H](NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F)c1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Prepared in a similar manner to (R)-5-methyl-2-trifluoromethyl-furan-3-sulfonic acid [1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethyl]-amide (Example 3) using 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride instead of 5-methyl-2-trifluoromethyl-4-furan-3-sulfonyl chloride. Title compound: 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.55-7.4 (m, 5H), 7.25 (s, 4H), 4.5 (m, 1H), 1.38 (d, 3H) ppm; MS (ESI) m/z: 584.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].[ClH:36]>C(O)C>[ClH:36].[OH:35][NH:34][C:32]([NH:31][N:30]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)=[NH:33]
Reactant: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CC(=NNC(=N)NO)c3c(C)ccnc3C2)s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (257 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (285 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue in ethanol (1 ml) was stirred at room temperature for 15 hours to give crystals, which were filtered and dried to give 5-(1-hydroxyguanidin-3-yl)imino-4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 98) (163 mg) as pale yellow crystals.
Reaction SMILES: [NH3:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([O:13]C)=O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([NH2:1])=[O:13]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: N
Solvent: CO
Product: NC(=O)C1Cc2ccccc2N1
Reaction time: 18 h
Yield: 85 %

Procedure:
Gaseous NH3 was bubbled into a solution of methyl (±)-indoline-2-carboxylate (4.3 g, 24.2 mmol) in methanol (50 mL) at RT for 30 min. The reaction was stirred for 18 h, then was filtered to afford the title compound (3.35 g 85%) as a colorless solid: MS (ES) m/e 163.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:21]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[C:16](=[CH2:21])[CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCC(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-(2,3-Dichloro-4-butyrylphenoxy)propionic acid (6.65 g, 0.022 mole), dimethylamine hydrochloride (12 g, 0.15 mole), paraformaldehyde (2.3 g, 0.077 equiv.) and acetic acid (1 ml) were mixed and stirred while heating on a steam bath for 2.5 hours. N,N-dimethylformamide (25 ml) was added to the mixture and stirring and heating continued for another 1.5 hours. The mixture was poured into ice water (600 ml) and the precipitate that formed removed by filtration, washed with water and dried. After recrystallization from butyl chloride, 58 g 3-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid remained.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][C:19]=2[O:18]1>>[F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:28](=[O:29])[C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[NH:21][C:17](=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:31])[CH2:9][CH2:10]1
Reactant: Fc1ccc(CC2CCNCC2)c(F)c1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(F)cc2F)CC1

Procedure:
The title compound is prepared from 4-(2,4-difluoro-benzyl)-piperidine and N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) according to the method described in Example 43f. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 231° C. (isopropanol)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)([CH3:26])[CH3:23]
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CC(C)=O
Product: CC(C)NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 41 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), acetone (116 mg, 2.00 mmol), and NaBAH3CN (125 mg, 2.00 mmol) gives the title compound (139 mg) as a white foam. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.13 (d, 1H), 7.21-7.13 (m, 2H), 6.90-6.87 (m, 2H), 6.27 (br. s, 2H), 2.97 (m, 1H), 2.91-2.75 (m, 3H), 2.62-2.41 (m, 2H), 1.83-1.63 (m, 4H), 1.07 (d, 6H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[Pt]=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(/C=C/c3ccccc3)c2)cc1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2cccc(CCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of methyl 4-[[3-((E)-2-phenylethenyl) phenyl]methoxy]benzenepropanoate (0.35 g, 0.95 mmol) in methanol (15 mL) and tetrahydrofuran (25 mL) was added platinum oxide (0.018 g, 0.078 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hrs. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15:1) to give the title compound (0.21 g, yield 58%). oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:11]([Si:18]1(C2C=CC=CC=2)[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:11]([Si@H:18]1[CH2:19][CH2:20][C@H:21]([C:24]([O:10][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:25])[CH2:22][CH2:23]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1cc(F)c(F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4,5-trifluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.ClCCl>[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:4][CH2:3][CH2:2][F:1])[N:7]=1
Reactant: OCCF
Reactant: Clc1cncc(Cl)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: FCCOc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K-t-BuO (1.32 g, 11.8 mmol) was added portionwise to a stirred mixture of 2-fluoroethanol (2.16 g, 33.7 mmol) and 2,6-dichloropyrazine (1.61 g, 10.8 mmol) in dioxane (2 mL) at 0° C. (ice-bath). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (19×4 cm) using n-hexane/ethyl acetate (85:15) as eluent. This furnished 1.49 g (78%) of the title compound as a beige liquid. Anal. (C6H6FClN2O) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH2:10][CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=32)[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]([C:3]2[C:4]3=[N:5][C:6]4[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=4[N:8]3[CH2:9][CH2:10][C:2]=2[OH:1])=[O:17])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)C1=C(O)CCn2c1nc1ccccc12

Procedure:
The pyridobenzimidazo derivative VII (4.0 g, 15.5 mmol) and 4-aminopyridine (2.82 g, 30.0 mmol) were combined in xylenes (200 mL) and heated at reflux for 6 h in a flask fitted with a Dean Stark trap. The resulting solid was isolated from the cooled reaction mixture and recrystallized from a mixture of methylene chloride and EtOH to give the title compound as a crystalline solid: mp 274°-276° C.; MS: 307 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].CN(C=O)C>O>[C:10]1([C:5]2([CH2:4][CH2:3][CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[O:9][CH2:8][CH2:7][O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCC1(c2ccccc2)OCCO1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC1(c2ccccc2)OCCO1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
Add 2-(3-chloropropyl)-2-phenyl-[1,3]dioxolane (38 g, 168 mmol) and potassium phthalimide (34.2 g, 184.4 mmol) to DMF (80 mL) and stir for 40 min at 150° C. Cool the reaction to RT, dilute with water (1 L) and extract the mixture with a mixture of EtOAc (500 mL) and hexanes (500 mL) and DCM (2 L). Dry (sodium sulfate), concentrate and recrystallize the solid from hot ethanol (600 mL). Filter and dry the residue under vacuum to isolate the title compound as a white solid (47.62 g, 84%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11]>O>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+:11].[Na+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
A mixture of 10 g of aspartic acid (0.0751 mole) in 28 ml of water plus 26.6 g of monoamino polyoxyalkylene (Jeffamine M-2070, 0.47 meq NH2/g, 0.0125 mole NH2) was mixed with 4.7 g of 50% NaOH. The salt of sodium aspartate and polyoxyalkylene amine was formed by lyophilization, and a sample of 0.05 g of 4-methoxyphenol was added as an antioxidant. This mixture was heated in a flask in an oil bath at 180° C. for 20.5 hours. Subsamples were taken at 2, 4, 7, and 13.5 hours.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][N:12]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>O>[CH3:11][N:12]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:9]=[O:10])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: CN(c1ccccc1)c1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(c1ccccc1)c1ccc(C=O)c2ccccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Phosphorus oxychloride (POCl3, MW 153, 0.06M, 9.18 g) was added dropwise to DMF (MW 73, 0.36M, 26.3 g), maintaining the temperature at <10° C. with external cooling. 1-(N-Methyl-N-phenylamino)-naphthalene (MW 233, 0.06M, 14 g) was added and the reaction stirred at 100° C. for 3 hours. After cooling to room temperature and pouring into water (140 ml) the mixture was neutralised to pH 6 using saturated sodium acetate solution. The aqueous mixture was extracted using dichloromethane (2×50 ml), the combined extracts washed with water (3×100 ml) before drying over MgSO4. The solvent was evaporated under reduced pressure to give 10.4 g of 1-(N-methyl-N-phenylamino)-4-formyl naphthalene as an oil (66% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([O:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1CN(Cc2ccccc2)CCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-hydroxyethyl)-4-benzylmorpholine (27.7 g), triethylamine (28 ml), and ethyl acetate (100 ml) is dropwise added acetic anhydride (17.8 ml). The reaction mixture is stirred at 25° C. for 1 hour and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. Fractions containing the title compound are pooled and evaporated to give the title compound (29.1 g) as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([O:23]C)=[O:22])[CH:16]=[CH:17][C:18]=1[OH:19]>CO.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isopropylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isopropylbenzyl chloride with methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 146.5°-148° C. in a methanol-water 2:1 mixture.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](O)C1
Temperature: 60 °C
Reaction time: 7 h
Yield: 103 %

Procedure:
To a solution of cis-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine (2.0 g) in dimethylformamide (40 ml) was added potassium phthalimide (1.44 g), and the resulting mixture was stirred at 60° C. for 7 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2.4 g of cis-1-tert-butoxycarbonyl-4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)methyl-3-hydroxypiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12][N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:36][CH:37]=1)[CH2:22][C:23]#[CH:24]
Reactant: OC1CCNCC1
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCC(O)CC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.230 g, 0.42 mmol) in anhydrous dichloromethane (4 ml) under argon was added a solution of 4-hydroxypiperidine (0.424 g, 4.2 mmol) in anhydrous CH2Cl2 (4 ml). The clear solution was stirred at room temperature for 1.5 hours under argon, then partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (100 ml). The organic layer was washed with 5% aqueous sodium carbonate (100 ml), and dilute brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with ether to give a white precipitate, which was collected by filtration , washed with ether and dried in vacuo over P2O5 (0.206 g, 89%), mp 208-210° C.; 1H-NMR (DMSO-d6) 1.50 (s, 9H, But), 1.33 (m, 2H), 1.65 (m, 2H), 2.17 (m, 2H), 2.72 (m, 2H), and 3.50 (m, 1H), (piperidine ring protons), 3.24 (s, 1H, C≡CH), 3.57, 3.60 (2×s, 5H, N3-Me , 2-CH2), 4.39 (s, 2H, CH2C≡C), 4.55 (d, J=4.1 Hz, 1H, OH), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.81, 7.87 (2×s, 2H, 5-H, 8-H); MS (ESI, m/z) 551, 553 [(M+H)+, 100%, 37% rcspectively; Cl isotopic pattern].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:24])=[C:20](/[F:23])\[CH2:21][OH:22])[CH3:2].C[N+]1([O-])CCOCC1>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:17])[CH3:18])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:24])=[C:20](/[F:23])\[CH:21]=[O:22])[CH3:2]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2
Agent: C[N+]1([O-])CCOCC1
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure M, (2E)-3-(7-ethoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-en-1-ol (Compound 85, 114 mg, 0.36 mmol) and 4-methylmorpholine N-oxide (85 mg, 0.72 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:30])[C:15](=[O:29])[CH2:16][NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([N+:25]([O-])=O)=[C:20]([CH3:28])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([NH:17][CH2:16][C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH3:30])=[O:29])=[N:19][C:20]=1[CH3:28]
Reactant: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
Compound 62 (93 mg) and zinc (147 mg) were suspended in acetic acid (2 mL) and the suspension was stirred at room temperature (20 to 30° C.) for 3 hours. Subsequently, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:1 to 3:1) to give 25.4 mg (29% yield) of the desired product as a pale yellow amorphous.