Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]=[O:35])[CH2:30][CH2:29]1.Cl>O1CCCC1.O>[OH:35][CH:34]([CH:31]1[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]1)[CH:6]1[C:5](=[O:8])[C:4]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]1
Reactant: COC1CCC(C=O)CC1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OC)CC2)C1
Temperature: 25 °C

Procedure:
To a solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (2 g, 8.7 mmol) in dry tetrahydrofuran (25 ml) at −78° C. is added a solution of lithium diisopropylamide (5.8 ml, 10.4 mmol, 1.8 M in hexane/THF/ethylbenzene) dropwise over 20 minutes. The resultant solution is stirred for 30 minutes at −78° C. before adding 4-methoxy-cyclohexanecarbaldehyde (1.4 g, 9.8 mmol) dissolved in tetrahydrofuran (15 ml). The reaction mixture is allowed to warm to room temperature overnight then diluted with water, acidified with 2 N HCl and extracted with ethyl acetate (3×15 ml). The combined organic extract are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an brown oil. The residue is purified by flash chromatography to 5-[Hydroxy-(4-methoxy-cyclohexyl)-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1.7 g).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N+:24]([O-:9])([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc1-c1ccccc1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3ncc(Br)c(-c4ccccc4)n3)O1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
mCPBA (0.060 g, 0.266 mmol) was added to a suspension of (R)—N-(5-bromo-4-phenylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.1 g, 0.241 mmol) in THF (10 ml). The mixture was stirred at room temperature for 18 h, concentrated, and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (S)-2-(5-bromo-4-phenylpyrimidin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide as an off-white solid (0.066 g, 0.149 mmol, 62%). 1H NMR (400 MHz, MeOD) δ ppm 8.72 (1H, s), 7.74 (2H, dd, J=6.92, 2.64 Hz), 7.39-7.53 (3H, m), 4.01 (1H, d, J=10.58 Hz), 3.85 (1H, d, J=10.32 Hz), 3.61-3.74 (2H, m), 3.37-3.50 (3H, m), 3.19-3.26 (1H, m), 2.37-2.51 (1H, m), 2.26-2.33 (1H, m), 1.95-2.20 (3H, m). LC/MS RT=1.78; [M+2]+=432.19.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[C:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:3]=1
Reactant: COC(OC)c1cc(Br)ccc1O
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(OC)c1cc(Br)ccc1OCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 4-bromo-2-dimethoxymethylphenol (6.00 g, 24.3 mmol) in benzene (100 ml) were added triphenylphosphine (7.63 g, 29.1 mmol) and t-butyl 2-hydroxyethylmethylcarbamate (5.10 g, 29.1 mmol) synthesized in step 1). The reaction solution was cooled to 0° C. in an ice bath, and diisopropyl azodicarboxylate (5.88 g. 5.73 ml, 29.1 mmol) was dropwise added thereto, after which it was allowed to react for 1 hour. Following extraction with brine and ethyl acetate, the organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified through column chromatography (ethyl acetate/n-hexane=1/20) to afford the object compound (colorless oil, 11.30 g, 96.1%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:11]([CH3:41])[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:25][C:22]1[CH:23]=[CH:24][C:16]([C:12]2[C:13]([CH3:15])=[CH:14][C:9]([OH:8])=[CH:10][C:11]=2[CH3:41])=[C:17]2[C:21]=1[C@H:20]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:19][CH2:18]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[Si](C)(C)C(C)(C)C)cc5C)ccc(F)c43)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21

Procedure:
Methyl 2-((S)-6-((R)-4-(4-(tert-butyldimethylsilyloxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (440 mg) and tetrabutylammonium fluoride in tetrahydrofuran (1 M; 3.1 mL) are stirred in tetrahydrofuran (5 mL) at ambient temperature overnight. The reaction mixture is partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→60:40) to give the title compound. Yield: 280 mg.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:3]([NH:2][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)OC
Reaction time: 1 h
Yield: 99.7 %

Procedure:
While under nitrogen, a stirred mixture of methyl 2-amino-3-(4-chlorophenyl)propanoate hydrochloride (3.13 g, 12.5 mmol) in methylene chloride (42 mL) was cooled in an ice-water bath and carefully treated with pyridine (2.23 mL, 27.5 mmol) and ethyl chloroformate (1.27 mL, 13.3 mmol). After stirring for 1 h, the solution was diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous phase was re-extracted with ethyl acetate (2×25 mL), and the combined organic phase was washed with saturated aqueous sodium chloride (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give methyl 3-(4-chlorophenyl)-2-(ethoxycarbonylamino)propanoate (3.56 g, 99%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2 H), 7.08 (m, 2 H), 5.12 (m, 1 H), 4.65 (m, 1 H), 4.13 (q, J=8 Hz, 2 H), 3.74 (s, 3 H), 3.10 (qd, J=16, 4.0 Hz, 2 H), 1.25 (t, J=8 Hz, 3 H). LC-MS gives ESI+ MS found for C13H16ClNO4 m/z 308.0 (M+Na), 286.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1C[C@@H]1[C@H](C)CCCN1C(OCC1C=CC=CC=1)=O.[F:30][C:31]1([F:47])[CH2:36][CH2:35][N:34]([C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH:33]([CH2:45]O)[CH2:32]1>>[F:30][C:31]1([F:47])[CH2:36][CH2:35][N:34]([C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH:33]([CH2:45][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:32]1
Reactant: C[C@@H](c1ccccc1)N1CCC(F)(F)CC1CO
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Product: C[C@@H](c1ccccc1)N1CCC(F)(F)CC1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for (2S,3R)-benzyl 2-((1,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate in Example A1 using (4,4-difluoro-1-((S)-1-phenylethyl)piperidin-2-yl)methanol (1.1 g, 97%). MS (ESI) 285 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:13][C:14]([C:18]4[CH:19]=[N:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:38][C:39]([CH3:44])([CH3:43])[C:40](O)=[O:41].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[OH:38][C:39]([CH3:44])([CH3:43])[C:40]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[N:13][C:14]([C:18]4[CH:19]=[N:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[N:22][CH:23]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(N)c4)cc3n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(NC(=O)C(C)(C)O)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
In a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.1 g, 0.0002 mol), 2-hydroxy-2-methylpropanoic acid (0.052 g, 0.0005 mol) and DMF (10 mL) were added. To the flask, HATU (0.152 g, 0.0004 mol) and TEA (0.081 mL, 0.0006 mol) were added and then stirred at room temperature for 12 hours. To the reaction mixture was added water to provide a precipitate. The precipitate was collected by filtration to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to obtain the title compound (0.06 g, 60%). LC-MS (ESI) Calculated mass. 585.2, Observed mass [M+H]+: 586.1 (RT=0.83 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[C:13]#[C:14][C:15]1([OH:25])[CH2:24]CC2(OCCO2)CC1.[CH3:26][CH2:27][OH:28]>C1COCC1.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[CH2:13][CH2:14][CH:15]1[CH2:24][O:28][C:27]2([CH2:11][CH2:12][CH:3]([OH:2])[CH2:4][CH2:26]2)[O:25]1
Reactant: COc1ccc2ncnc(C#CC3(O)CCC4(CC3)OCCO4)c2c1
Reactant: CCO
Agent: O=[Pt]
Solvent: C1CCOC1
Product: COc1ccc2ncnc(CCC3COC4(CCC(O)CC4)O3)c2c1

Procedure:
Platinum oxide (0.46 g) was added to a solution of 8-(6-methoxy-quinazolin-4-ylethynyl)-1,4-dioxa-spiro[4.5]decan-8-ol (0.96 g, 2.88 mmol) in EtOH (40 ml) and THF (10 ml), and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The reaction mixture was stirred in the presence of activated carbon (5 g) and filtered. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc:MeOH 9/1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[F:34][C:35]([F:49])([F:50])[C:36]1[CH:37]=[C:38]([C:39]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=2)=[O:40])[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2ccc(Cl)c(F)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccc(Cl)c(F)c2)C1

Procedure:
Using the compound obtained in step 1 and 3,5-bis(trifluoromethyl)benzoic acid, and by the reaction and purification in the same manner as in Reference Example 1, step 5, the title compound was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:8]([C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:13]1)[CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:8]([C@H:12]1[CH2:13][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:15][CH2:16][N:17]1[S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCCC
Reaction time: 8 h

Procedure:
Chloroethylsulfonylchloride (0.038 mL, 0.314 mmol) was added to a solution of 3(S)-butyl-1-(1-naphthoyl)piperazine (0.095 g, 0.285 mmol) and diisopropylethylamine (0.119 mL, 0.685 mmol) in dichloromethane (3 mL). The reaction was stirred overnight under nitrogen, quenched with saturated sodium bicarbonate and extracted into ethyl acetate. After drying with magnesium sulfate, the title compound was isolated.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:14]2=[O:40])[CH2:9][CH2:8]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([N:15]2[CH2:16][C:17]3[C:18](=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:21][CH:22]=3)[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]3)[C:14]2=[O:40])=[CH:33][CH:34]=1
Reactant: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)N(c2ccc(OC)cc2)C3)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O)CC2)C(=O)N(c2ccc(OC)cc2)C3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.14 g, 0.15 mmol) (from Example 20a supra) in dichloromethane (5 mL) was added trifluoroacetic acid (2.5 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to give crude product which was recrystallized from ethyl acetate-hexanes to give 3-(4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 61 mg, 55%).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:5]#N)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)C(O)=[O:35]>CCCCCC.C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:5]=[O:35])[CH3:3]
Reactant: O=C(O)C(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C=O)C(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (856 mg, 3.0 mmol) in n-hexane (30 ml) was added a 0.5M solution of diisobutylaluminium hydride in toluene (6 ml) with stirring at -70° C. under argon atmosphere. After one hour, water (3 ml) was added, the cooling bath was removed, and the reaction mixture was stirred well. Resultant white precipitates were filtered and washed. The filtrate was concentrated to give a residue, which was dissolved in n-hexane (10 ml). The n-hexane solution was combined with a 10% aqueous solution of oxalic acid (5 ml) and stirred for 3 hours. The organic layer was extracted and separated, washed with water, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=10:1) to obtain 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal (865 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[C:13]([NH:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1)([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([NH:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:3]([O:2][CH3:1])=[O:4])[CH:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)NC(=O)Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)Nc1cccc(CC(=O)NC(C)(C)C)c1
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
10.45 g (0.1 mol) of chloroformic acid methyl ester, followed by 10.1 g (0.1 mol) of triethylamine, were added dropwise to a solution of 20.6 g (0.1 mol) of 3-amino-phenylacetic acid tert.-butylamide in 200 ml of acetone whilst cooling at 15 to 20° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had precipitated was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue which hereupon remained was stirred with very dilute hydrochloric acid, filtered off, dried and recrystallized from a little carbon tetrachloride. 22 g (83.5% of theory) of 3-methoxycarbonylamino-phenylacetic acid tert.-butylamide of melting point 123°-124° C were obtained.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH:9]([O:12][CH2:13][CH3:14])=[CH:10][CH3:11]>Cl>[CH2:13]([O:12][CH:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11])[CH3:14]
Reactant: CC=COCC
Reactant: CCOC(=O)C(C)O
Agent: Cl
Product: CCOC(=O)C(C)OC(CC)OCC
Temperature: 75 °C
Yield: 82.6 %

Procedure:
To a 250 mL containing 37.0 g (0.31 mole) ethyl lactate and four drops 32% hydrochloric acid at 30° C. is added 71 g (0.82 mole) ethyl propenyl ether. The mixture is heated to 75° C. for thirty minutes, cooled to 25° C., then quenched with 100 g 5% sodium bicarbonate solution. The organic material was flash distilled yielding 52.3 g (90%) ethyl 2-[(1'-ethoxy)propoxy]propanoate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 21 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 41 (21% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.13 and 2.17 (2s, 3H), 2.65 and 2.93 (2t, 2H), 3.51 and 4.06 (2t, 2H), 4.42 and 4.94 (2s, 2H), 6.29 and 6.75 (2d, 1H), 6.80 and 7.00 (2dm, 1H), 7.75-7.85 (m, 1H), 7.91-8.03 (m, 3H), 8.11-8.24 (m, 2H), 8.36 and 8.45 (2s, 1H), 8.69-8.74 (m, 2H); MS (ESI) m/z 464 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8](C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:52])([CH2:44][O:45][CH:46]2[CH2:51][CH2:50]CCO2)[C:12]1=[O:53])[C:2]1C=CC=C[CH:3]=1>CO.[Pd]>[CH:41]([N:27]([C:25]([C:18]1[C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:15]2[O:14][C:13]([CH3:52])([CH2:44][O:45][C:46]#[C:51][CH3:50])[C:12](=[O:53])[N:11]([CH2:10][CH2:9][NH:8][C:1]#[C:2][CH3:3])[C:16]=2[CH:17]=1)=[O:26])[C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:29]1)([CH3:43])[CH3:42]
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COC1CCCCO1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC#CNCCN1C(=O)C(C)(COC#CC)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 29.9 %

Procedure:
tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (24.9 g) was dissolved in methanol (300 mL), and thereto was added a 10% palladium/carbon (50% wet.: 30.0 g), and the mixture was vigorously stirred under hydrogen atmosphere at room temperature for 36 hours. After the reaction was complete, the mixture was filtered on celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. tert-Butyl (3R)-3-[{[4-(2-aminomethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate was dissolved in dichloromethane (300 ml), and thereto were added propionyl chloride (2.7 ml) and triethylamine (6.5 mL), and the mixture was stirred for one hour. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (5.48 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[CH2:25]([O:27]CC)C>ClCCCl.CO.C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:25][O:27][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: CCOCC
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.750 g, 1.79 mmol) in 1,2-dichloroethane is diluted with methanol, treated with silver trifluoromethanesulfonate (0.610 g, 2.37 mmol), stirred overnight at room temperature, and filtered through diatomaceous earth. The resultant filtrate is washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel, and 2% and 5% diethyl ether in methylene chloride solutions gives the title product as a white solid (0.600 g, mp 161-163° C.) which is identified by 1H NMR spectral analysis.