Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)C1CC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)C3CC3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and cyclopropanecarboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=310.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:22]3[CH2:23][CH:24]([C:26]4([OH:29])[CH2:28][CH2:27]4)[CH2:25][CH:14]2[CH2:15][C:16]2([CH2:21]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.I[CH3:31]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:14]3[CH2:25][CH:24]([C:26]4([O:29][CH3:31])[CH2:28][CH2:27]4)[CH2:23][CH:22]2[CH2:21][C:16]2([CH2:15]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 46 mg, 1.16 mol) was added to a solution of 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55) (321 mg, 0.775 mmol) in THF (2 mL). The resulting solution was stirred for 10 minutes, after which iodomethane (72 μL, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 18 h and was subsequently diluted with EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, and concentrated to give 9-[(4-chlorophenyl)sulfonyl]-7-(1-methoxycyclopropyl)spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane] (56). MS (ESI) 428.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]3[C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=[C:22]4[NH:30][CH:31]=[CH:32][C:21]=34)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]3[C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=[C:22]4[NH:30][CH:31]=[CH:32][C:21]=34)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cnc2[nH]ccc2c1N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2[nH]ccc2c1N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 80 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
To a solution of (R)-methyl 4-((1-(2-((3,5-dichlorophenyl)amino)acetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (173 mg, 0.36 mmol, 1.0 eq) in CH3OH (20 mL) and water (10 mL) was added NaOH (73 mg, 1.82 mmol, 5.0 eq). The mixture was stirred at 80° C. for 10 h, cooled to rt, adjusted pH to 6 with HCl (1N) the aqueous layer was extracted with EtOAc (50 mL×3). The organic layer was separated and concentrated in vacuo to afford the title compound as a yellow solid which was used to next step without further purification (120 mg, yield: 71%) to use next step. 1H NMR (400 MHz, CD3OD) δ: 8.6˜88.63 (m, 1H), 7.37˜7.32 (m, 1H), 7.02˜6.95 (m, 1H), 6.6˜06.57 (m, 2H), 6.34 (s, 1H), 4.57˜4.41 (m, 1H), 4.10˜3.75 (m, 5H), 3.65˜0.362 (m, 1H), 2.22˜2.21 (m, 1H), 2.04˜1.79 (m, 3H). ESI-MS: 462.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: Oc1ccccc1Cl
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccccc3Cl)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-chloro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20]>>[OH:18][CH:17]([CH2:19][OH:20])[CH2:16][NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetradecylamine (28.80 g, 0.13 mole) was heated to 85° C. Glycidol (10.00 g, 0.13 mole) was added dropwise. The reaction solution was heated under nitrogen for 3 hours and then was stirred overnight at room temperature. A white solid was obtained (crude yield=38.45 g). The solid was recrystalized from hot hexane (yield=12.2 g).
Reaction SMILES: [OH-].[Na+].CO[C:5]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:6]=1[CH:7]=[CH:8][C:9]([OH:11])=[O:10].Cl[CH:19](Cl)[CH3:20].B(Br)(Br)Br>>[CH2:17]([O:16][C:13]1[CH:12]=[C:6]2[C:5](=[CH:15][CH:14]=1)[O:11][C:9](=[O:10])[CH:8]=[CH:7]2)[C:20]1[CH:19]=[CH:7][CH:6]=[CH:5][CH:15]=1
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Reactant: CC(Cl)Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccc2cc(OCc3ccccc3)ccc2o1
Temperature: 82 °C
Yield: 127 %

Procedure:
Equip a 5-L, three-neck, round-bottom flask with a large blade mechanical stirrer, thermocouple, an addition funnel, Claisen adapter, reflux condenser, and a sodium hydroxide scrubber. Charge the flask with 2,5-dimethoxycinnamic acid (182.3 g, 865 mmol, 1.0 equiv) and dichloroethane (2.5 L). Add boron tribromide (163.5 mL, 433.2 g, 1.73 mol, 2.0 equiv.) dropwise over 1 h, keeping the temperature below 35° C. Gas evolution can be monitored as the temperature of the reaction is gradually increased to reflux (82° C.). Reflux for 12 h, cool to 5° C., and quench by the careful addition of water (1.0 L). Filter the resulting yellow-red suspension/emulsion through a glass frit and wash with dichloroethane (1.0 L) and heptane (1.0 L) to afford a brown solid. Dry the wet material in a vacuum oven (30 in., 35° C.) for 18 h, to afford the coumarin (180.3 g, 127% theory) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.22 (d, J=9.9 Hz, 1H), 7.05 (m, 2H), 6.43 (d, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])C.O.[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:14][NH+:15]1[CH2:19][CH2:18][N:17](C)[CH:16]1Cl>C(O)C>[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:1][NH+:3]1[CH2:4][CH2:5][N:17]([CH3:18])[CH:16]1[N:15]([CH3:19])[CH3:14]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: CCNCC
Agent: COP(=O)([O-])OC
Solvent: O
Solvent: CCO
Product: CN(C)C1N(C)CC[NH+]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
1.14 g (15.59 mmol) of diethylamine and 10 ml of water are added with stirring to 2.0 g (7.73 mmol) of 1,3-dimethyl-2-chloroimidazolidinium dimethylphosphate. The reaction mixture is stirred for 10 minutes at room temperature, and 10 ml of ethanol are subsequently added. The solution is extracted 5 times with 30 ml of dichloromethane. Water is distilled off from the aqueous phase. The residue is dried for 4 hours under a reduced pressure of 7 Pa at an oil-bath temperature of 70-80° C., giving 1.85 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium dimethylphosphate, corresponding to a yield of 81%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[N:9][CH2:10][Si](C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:19])[CH3:18].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>O1CCCC1>[CH2:26]([O:25][C:21]([CH:22]1[CH2:23][CH2:10][N:9]([C:17](=[O:19])[CH3:18])[CH:8]1[C:7]1[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:24])[CH3:27]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)CN=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(C)=O)C1c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A stirred solution of (4-nitro-benzylidene)-trimethylsilanylmethyl-amine (3.2 g) in tetrahydrofuran (120 mL), at 40° C., was treated with a solution of acetyl chloride (1 mL) and ethyl acrylate (1.6 mL) in tetrahydrofuran (60 mL). After stirring at 40° C. for 20 hours the reaction mixture was evaporated. The residual oil was treated with ethyl acetate(300 mL) and water (100 mL) and the mixture was then stirred 1,5 for 20 hours. The organic phase was washed twice with water (100 mL), then dried and then concentrated under reduced pressure (2.7 kPa). The residue was subjected to flash chromatography on silica (700, 20-45 μm, 0.6 bar) eluting with a mixture of cyclohexane and ethyl acetate (90:10, v/v) to give the title compound (3.04 g). RF=37/162, thin layer chromatography plate ref. #05719, Merck KGaA, 64271 Darmstatd, Germany.
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(NC(C)c2ccccc2)cc1

Procedure:
N-(α-methyl benzylidene)-p-dodecyl aniline (80 g) prepared by the procedure described in Example IIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent to give N-(α-methyl benzyl)-p-dodecyl aniline (VI). VI had a boiling point of 188° C. at 0.03 millimeter.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])=[CH:19][CH:18]=2)[C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]1=2)=[O:4].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C=O)C.C(OCC)(=O)C.O>[C:29]1([CH2:28][CH2:27][NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:8]3[C:9](=[O:15])[C@H:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[N:5]([C:3](=[O:4])[CH2:2][N:43]4[C:42](=[O:44])[C:41]5=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]5[C:39]4=[O:49])[C:6]4[CH:38]=[CH:37][CH:36]=[CH:35][C:7]3=4)=[CH:22][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a solution of (3aR*,10aS*)-4-(chloroacetyl)-9-[4-[3-(2-phenylethyl)ureido]benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (53 mg, 0.1 mmol) in DMF (1 mL) was added potassium phthalimide (20 mg, 0.11 mmol) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol-diethyl ether to provide 15 mg (yield 23%) of the title compound. m.p. 145°-147° C.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:37][CH3:38])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:38]1[CH:37]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: COc1ccc([C@H](CO)NC(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 28 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]ornithine amide hydrochloride (3.33 g; 7.37 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (2.60 g; 8.10 mmol; see Example 1(c) above), triethylamine (2.23 g; 22.11 mmol) and CH2Cl2 (200 mL), reaction time 60 hours. The resulting yellow solution was submitted to aqueous work up, dried, filtered and concentrated to give the crude product as an off-white solid (4.76 g). The crude product was chromatographed twice on silica gel eluting with CH2Cl2 :MeOH (98:2). Concentration of the product containing fractions gave the sub-title compound as a white solid (0.63 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][O:15]C(=O)C)[C:8]=2[N:7]=[C:6]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].O.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][OH:15])[C:8]=2[N:7]=[C:6]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 95.9 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (Example 103) (1.45 g, 3.38 mmol) dissolved in methanol (19 mL) and water (1.0 mL) was added K2CO3 (0.40 g). After 30 min. the reaction was concentrated, redissolved in EtOAc, and washed with NaHSO4 (10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. Recrystallization of the crude product from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxymethylbenzimidazole (1.25 g, 3.24 mmol, 96% yield). M.p. 157-158° C. 1H-NMR (300 MHz, CD2Cl2): δ7.54 (m, 1H, H4′), 7.43 (d, J=7.9 Hz, 1H, H7), 7.30-7.22 (m, 2H, H6,4″), 7.18 (d, J=7.5 Hz, 1H, H5), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.37 (s, 2H, CH2PhF2), 5.06 (d, J=5.4 Hz, 2H, CH2O), 3.51 (t, J=5.4 Hz, 1H, OH).
Reaction SMILES: C(OC([CH:6]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[O:9][C:8]([CH2:16][O:17][CH3:18])([CH3:15])[C:7]1=[O:19])=O)C.S(=O)(=O)(O)O>O1CCOCC1.[Cl-].[Na+].O>[CH3:18][O:17][CH2:16][C:8]1([CH3:15])[C:7](=[O:19])[CH2:6][C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[O:9]1
Reactant: CCOC(=O)C1C(=O)C(C)(C)OC(C)(COC)C1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCC1(C)OC(C)(C)C(=O)CC1=O
Temperature: 110 °C
Yield: 16.2 %

Procedure:
To a solution of 2-methoxymethyl-2,6,6-trimethyl-3,5-dioxotetrahydropyran-4-carboxylic acid ethyl ester (2.11 g, 7.72 mmol) in dioxane (2.5 ml) is added 20% aqueous sulfuric acid (2.5 ml) and the mixture is heated at 110° C. for 2.5 hours. The mixture is cooled to room temperature, diluted with saturated brine and extracted with dichloromethane. The crude material is extracted into aqueous sodium hydroxide, the aqueous phase washed with dichloromethane, then acidified with concentrated hydrochloric acid and extracted into dichloromethane (2×15 ml). The organic phase is concentrated in vacuo to give a crude oil which is purified by flash column chromatography on silica gel (isohexane/diethyl ether 7.5:1.5 ratio) to afford 2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.250 g) as a pink solid.
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]#[CH:20].C(O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][C:19]#[CH:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 35% potassium hydride in oil (6.04 g, 35% w/w, 53 mmols of potassium hydride) in 240 ml of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmols). The mixture was stirred at 0° C. for 1 hour. Propargyl bromide (53 mmols) was added and the mixture stirred at 0° C. for 30 min., then at room temperature for 16 hours. The resulting mixture was treated with 4.8 ml of 50% acetic acid, then poured into 480 ml of water. The mixture was extracted with ether (2×250 ml). The ether extracts were combined, dried over magnesium sulfate, and concentrated to a brown oil. Chromatography on 250 g of flash silica gel (10% ether in hexane eluent) gave the product as a white solid mp 63°-65° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:33])[NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:9])(C)(C)C.NCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)C.CCN=C=NCCCN(C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][CH2:12][C:13]1[N:22]=[C:21]([N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:33]
Reactant: COc1ccc(N(C)c2nc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)nc3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(CNC(=O)[C@H](C)N)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
[(S)-1-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester: To (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (210 mg, 0.74 mmol), Boc-L-Ala-OH (140 mg, 0.74 mmol), EDCI (170 mg, 0.89 mmol) and HOBt-hydrate (136 mg, 0.89 mmol) in DMF (3 mL) was added ethyl-diisopropyl-amine (383 μL, 2.2 mmol). The reaction was stirred at room temperature overnight, diluted with EtOAc and quenched with 10% aqueous HCl followed by saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc (4×15 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Purification by gradient MPLC (0-20% MeOH/CH2Cl2 with 0.1% NH4OH) gave 285 mg (83%) of the title compound as a yellow solid. 1H NMR (MeOH-d4) δ 7.69 (d, 1H), 7.61-7.57 (m, 1H), 7.1 (d, 2H), 7.03-6.98 (m, 4H), 4.61-4.49 (m, 2H), 4.23 (q, 1H), 3.83 (s, 3H), 3.62 (s, 3H), 1.44 (s, 9H), 1.4 (d, 3H); LC-MS (ESI+; 466 ([M+H]+)).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCCBr)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2ccc(Cl)cc2)CC1
Yield: 26.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.6 g) as starting compound, potassium carbonate (2.3 g) and 7-bromo-1-(4-chlorophenyl)-1-heptanone (2.2 g) were reacted and treated in the same manner as in Example 172 to give 0.60 g of 4-amino-5-chloro-N-((1-(7-(4-chlorophenyl)-7-oxoheptyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: O[CH:2]1[CH:9]2[CH2:10][C:5]3([C:11]4[NH:19][C:18]5[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=5[N:12]=4)[CH2:6][CH:7](O2)[CH:3]1O3.[C:28]([OH:34])(=[O:33])[CH2:29][C:30](O)=O.N1C=CC=C[CH:36]=1>N1CCCCC1>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:5]34[CH2:7][CH2:3][C:2]([CH:30]=[CH:29][C:28]([OH:34])=[O:33])([CH2:36][CH2:6]3)[CH2:9][CH2:10]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CC(=O)O
Reactant: c1ccncc1
Reactant: CCCn1c(=O)c2[nH]c(C34CC5OC(C3)C(O4)C5O)nc2n(CCC)c1=O
Solvent: C1CCNCC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
4-(2,6-Dioxo-1,35-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane 1-carbaldehyde (XI, Example 9, 0.490 g, 1.32 mmol) is added to a mixture of malonic acid (0.275 g, 2.64 mmol), pyridine (2 ml), and piperidine (1 drop). The mixture is heated to 1000 for 16 hours. Four additional equivalents of malonic acid are added and heating continued for another 16 hours until consumption of aldehyde ceases, to give the title compound.
Reaction SMILES: [C:1]([C:6]([S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:8])[CH3:7])([O:3]CC)=[O:2].O.O1CCCC1.[OH-].[K+]>C(O)C>[C:1]([C:6]([S:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)([CH3:7])[CH3:8])([OH:3])=[O:2]
Reactant: CCOC(=O)C(C)(C)SCc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(CSC(C)(C)C(=O)O)cc1
Yield: 81.2 %

Procedure:
Dissolve 2-(carboethoxy)-2-(4-methoxybenzylthio)propane (1.05 g, 3.91 mmol)in a mixture of 95% ethanol (18 mL), water (9 mL) and tetrahydrofuran (10 mL). Add potassium hydroxide (1.4 g, 25 mmol) and stir at room temperaturefor 2 hours then at 55° C. for hour. Evaporate the solvent in vacuo and partition between water (50 mL) and ether (50 mL). Acidify to pH 1 with concentrated hydrochloric acid and extract into methylene chloride (50 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give 2-(carboxy)-2-(4-methoxybenzylthio)propane as a tan solid (763 mg).