Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][C:16]#N.C([O:20][C:21](=[O:27])C(OCC)=O)C.C([O-])C.[Na+].[Na].Cl.S(=O)(=O)(O)O>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]2[CH:15]=[C:16]([C:21]([OH:27])=[O:20])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1c(Cl)cccc1Oc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1=Cc2c(Cl)cccc2Oc2ccccc21
Reaction time: 18 h
Yield: 60.3 %

Procedure:
10.82 g (44.40 mmol) of (2-chloro-6-phenoxy-phenyl)-acetonitrile and 7.85 g (53.72 mmol) of oxalic acid diethyl ester are added at room temperature to a freshly prepared sodium ethanolate solution (1.5 g (53.72 mmol) of sodium in 50 ml of ethanol) and the mixture is stirred for 18 hours. The mixture is rendered acidic with 1N hydrochloric acid, concentrated using a rotary evaporator and extracted 2× with ethyl acetate, and the organic phase is washed with brine, dried over sodium sulfate and concentrated to yield 15.99 g of crude intermediate (3-(2-chloro-6-phenoxy-phenyl)-2-hydroxy-4-nitrilo-but-2-enoic acid ethyl ester) 15.0 g (approximately 43.6 mmol) of the above intermediate are placed in 105 ml of glacial acetic acid and stirred for 20 minutes, 51.9 ml of water and 51.9 ml of sulfuric acid are slowly added, and the mixture is heated for 4 hours under reflux and then for 18 hours at room temperature. The reaction mixture is extracted with ethyl acetate, the organic phase is washed with water and 3× with 4N sodium hydroxide, and the aqueous phase is extracted 1× with ethyl acetate. The aqueous phases are rendered acidic with concentrated hydrochloric acid and extracted 3× with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated. 7.71 g (28.27 mmol)=60.3% of 1-chloro-dibenz[b,f]oxepine-10-carboxylic acid are obtained in the form of a yellow solid; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.21; 1H-NMR (CDCl3, 200 MHz): 7.15-7.47 (m, 7H); 7.68 (m, 1H), 8.39 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH2:11][C@H:12]([OH:15])[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[NH:10][CH2:11][C@@H:12]1[O:15][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H](O)CO)OCc1ccccc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(NC[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
(S)-2,3-Dihydroxy-1-propylcarbamate benzyl ester (2.11 g, 0.01 mol) in 100 ml flask was dissolved in CHCl3 (30 ml). 1-Chlorocarbonyl-1-methylethylacetate (1.8 ml, 0.013 mol) was added and stirred for 3 hours at ambient temperature. Sat. aqueous solution of NaHCO3 (20 ml) was added and extracted three times with ethyl acetate (50 ml). The organic layer was evaporated and dissolved in THF (50 ml). Sodium methoxide (0.53 g, 0.01 mol) was added and stirred for 6 hours. Sat. aqueous solution of NaHCO3 (50 ml) was added and extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The crude product was purified by column chromatography on silica gel to give (S)-2,3-epoxy-1-propylcarbamate benzyl ester (90%, optical purity>99%ee).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]([F:23])([F:22])[F:21])=[C:15]([CH2:33]O)[CH:14]=1.ClC1C=C(C=CC=1)CO.C1C=CC(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:58]([CH2:33][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=1[CH:19]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:20]([F:23])([F:22])[F:21])=[N+:59]=[N-:60]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)(F)F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: OCc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
DBU (0.483 mL, 3.23 mmol) was added to a stirred solution of N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.46 g of a 1:1.7 mixture with 3-chlorobenzyl alcohol) and DPPA (0.696 mL, 3.23 mmol) in THF (4 mL) at 0° C. The mixture was warmed to ambient temperature and after 3 h was partitioned between ether and water. The organic layer was washed with 1 M sodium hydroxide solution and brine, dried (Na2SO4) and evaporated to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 0-15% ethyl acetate/hexanes) to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 g) as an oil: 1H NMR (CDCl3, 400 MHz) δ 3.72 (s, 3H), 3.97 (d, J=7.3 Hz, 1H), 4.37 (d, J=14.1 Hz, 1H), 4.48 (d, J=14.1 Hz, 1H), 5.20 (pentet, J=7.1 Hz, 1H), 6.63 (d, J=9.0 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 7.37 (m, 2H), 7.55 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:20])[F:19])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F

Procedure:
To a solution of the compound obtained in (1) above in methanol (100 ml) was added 10% Pd carried on carbon (0.4 g). The mixture was hydrogenated under a hydrogen atmosphere to obtain the titled compound (2.8 g).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1Cl)n1ccc2c3c(ccc21)OCCNC3
Reaction time: 0.17 h

Procedure:
DMF (1 mL) was added to a mixture of tert-butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 10.0 mg, 0.035 mmol) and 60% NaH (5.56 mg, 0.139 mmol). The reaction mixture was stirred for 10 minutes at room temperature before 2-chlorophenylsulfonyl chloride (11 mg, 0.052 mmol) was added all in one portion. After 30 minutes TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.6 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O>[CH:14]1[C:10]2[C:11](=[O:12])[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:1](=[O:8])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 91.3 %

Procedure:
5 g of the purified benzoyl benzoic acid were heated at 100° C. for 2 hours in 50 g of fuming sulfuric acid (20% SO3). The mixture was run on 350 cm3 of water and ice and the precipitate obtained was filtered, washed and dried. 4.2 g of anthraquinone were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: C[C@@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (R)-2-hydroxypropanoic acid (0.90 g, 10 mmol, i.e. D-lactic acid) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil was formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.97 (d, J=6.8 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH:17]3[CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[C].[Pd].C(O)(=O)C>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH:17]3[CH2:32][CH2:33][NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC1NCCCC1Nc1nccc(N2CCCCCC2)n1
Yield: 96.6 %

Procedure:
The compound 19 (225 mg), acetic acid (4 mL) and 10% palladium carbon (20 mg) were stirred under hydrogen atmosphere at room temperature for 6 hours. The reaction solution was filtered and then the filtrate was concentrated. The residue was added aqueous 2N sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (155 mg) having the following physical properties.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:3]([OH:19])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](Nc1ccc(F)cc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H](Nc1ccc(F)cc1)c1ccccc1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
To a solution of (R)-(4-fluoro-phenylamino)-phenyl-acetic acid methyl ester (I252) (510 mg, 1.97 mmol) in dioxane (10 mL), is added 12N HCl (10 mL) and the mixture is heated at 70° C. for 12 hours. The organic solvent is evaporated, the mixture is cooled to 0° C. and the resulting solid is collected by filtration to obtain intermediate I255 as a brownish solid (420 mg, 87% yield).
Reaction SMILES: [F-].[K+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=1>CO>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]#[CH:17])=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC2CCCCO2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
KF (9.3 g, 160 mmol) was added to a stirred solution of 2 (22.6 g, 80 mmol) in MeOH (150 ml). The reaction mixture was stirred at room temperature for about 4 hours. After the reaction finshed (GC shows no starting material remaining), the solvent was removed under reduced pressure on a rotary evaporator. The residue was purified by column chromatography on silica gel (petroleum ether-ethyl acetate=9:1) to give a pale yellow crystals of 3. Yield 15.7 g(97%); mp 65° C., δH(CDCl3; 300 MHz): 7.42(d, J=8.7, 2H, Ar—H), 7.00(d, J=8.7, 2H, Ar—H), 5.43(t, J=3.2, 1H, OCHO), 3.87(m, 1H, THP, 3.60(m, 1H, THP), 2.99(s, 1H, C═C—H), 1.96˜1.56(m, 6H, THP).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([O:5][CH2:18][CH3:19])=[O:4]
Reactant: CCO
Reactant: NC(C(=O)O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(N)c1ccc(F)cc1
Yield: 65 %

Procedure:
To a cooled solution of 2-amino-2-(4-fluorophenyl)acetic acid (1.0 g, 6.17 mmol) in ethanol was added con. H2SO4 (1 mL) over a period of 1 min. The reaction mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The organic solution was washed with aqueous saturated NaHCO3 (15 mL×2), water (20 mL), brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-amino-2-(4-fluorophenyl)acetate (0.75 g, 65%) as crude compound (oily liquid). The crude compound was taken to the next step without further purification. LC-MS (M+H2O)+=198.0. 1H NMR (400 MHz, DMSO-d6): δ 7.44-7.40 (2H, m), 7.18-7.13 (2H, m), 4.51 (1H, s), 4.12-4.01 (2H, m), 2.26 (2H, s), 1.12 (3H, t, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([NH2:20])=O)[CH:16]=[CH:17][C:4]=2[O:3]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:20])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(N)=O)ccc2O1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Yield: 98.8 %

Procedure:
7.19 g of (-)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxamide were heated at 80° C. in 25 ml of phosphorus oxychloride for 30 minutes. The mixture was then cooled and evaporated. The residue was dissolved in dichloromethane and 2M sodium carbonate solution. The organic phase was separated, dried over sodium sulphate and evaporated to give 6.65 g of (-)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][C@H:8]([CH3:13])[C:9](OC)=[O:10]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[C@@H:8]([CH3:13])[O:7][C:6]=2[CH:14]=1
Reactant: COC(=O)[C@@H](C)Oc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H]1Oc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Yield: 96 %

Procedure:
Iron powder (1.91 g, 34.15 mmol) and (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-16 (525.0 mg, 1.71 mmol) were heated at 50° C. in glacial acetic acid (10.5 mL) for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over a pad of celite, and rinsed with ethyl acetate (80 mL). The filtrate was successively washed with water (2×30 mL), a saturated aqueous solution of sodium bicarbonate (40 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting white crystalline solid (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-A-17 (399.4 mg, Yield=96%) was used as such for next step without purification. MS (ESI) [M+1]+ 242, 244.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)=[CH2:22]
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a stirred suspension of 4-{[4-(trifluoromethyl)phenyl]oxy}benzaldehyde (4.68 g, 17.58 mmol) and methyl(triphenyl)phosphonium bromide (6.28 g, 17.58 mmol) in dry THF (50 mL) was added NaH (3 g, 75 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 3 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (890 mg, 19% yield) as a light green oil. LCMS: rt=4.19 min, [M+H+]=265
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[C:24]([O:28][C:29](=[O:44])[NH:30][C@H:31]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C@H:32]([OH:34])[CH3:33])([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:44])[NH:30][C@H:31]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C@H:32]([O:34][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:33])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In nitrogen atmosphere, tert-butyldiphenylsilyl chloride (2.0 mL) was added dividedly four times to a DMF solution (3 mL) of [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)-propyl]carbamic acid tert-butyl ester (610 mg) and imidazole (817 mg). The resulting reaction solution was stirred at room temperature for 3 hr, and ethyl acetate and water were added thereto. The organic layer was separated and washed with 1 N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution, and saturated saline in this order. Then, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:diethyleter=49:1 to 19:1) to give 684 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(N(CC)CC)C>ClCCl>[O:16]=[C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:7](=[CH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([O:26][CH3:25])=[O:36])[O:8]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C=C2OC(=O)C3=C2CCCC3)c1

Procedure:
A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate (10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) in dichloromethane (125 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was stirred with a mixture of ethyl acetate and water. The precipitated solid was filtered, washed with water, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.Br[CH2:37][C:38]([NH2:40])=[O:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][N:32]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:31][C@H:30]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(C)c(-c2nc3c(c(N4CCNC[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Reactant: NC(=O)CBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(-c2nc3c(c(N4CCN(CC(N)=O)C[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (43 mg, 0.053 mmol), 2-bromoacetamide (14.6 mg, 0.106 mmol) and DIEA (0.074 mL, 0.424 mmol) in DCM (2 mL) was stirred at rt for 16 h. The reaction was then diluted with EtOAc, and washed successively with sat aq NaHCO3, and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC(C18, 15-85% acetonitrile in H2O with 0.1% NH4OH) to provide (R)-2-(4-(2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6, at 120° C.) δ ppm 7.58 (s, 1 H) 7.08-7.18 (m, 5 H) 6.99 (d, J=1.64 Hz, 1 H) 6.87 (dd, J=7.71, 1.64 Hz, 1 H) 4.01-4.09 (m, 1 H) 3.89-4.01 (m, 2 H) 3.48-3.58 (m, 1 H) 3.37-3.47 (m, 1 H) 2.97 (t, J=5.87 Hz, 2 H) 2.81-2.90 (m, 3 H) 2.78 (d, J=10.36 Hz, 1 H) 2.61 (dd, J=11.62, 1.77 Hz, 1 H) 2.47 (s, 3 H) 2.40 (dd, J=11.31, 3.35 Hz, 1 H) 2.23-2.34 (m, 4 H) 2.20 (s, 3 H) 1.28 (d, J=6.44 Hz, 3 H) 1.19 (dd, J=6.95, 1.52 Hz, 6 H); MS (ESI+) m/z 527.4 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[N:7]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:15][CH:16]=2)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)NCc1ccc(CN2CCN(C(C)=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Yield: 92.6 %

Procedure:
A solution of N-(4-((4-acetylpiperazin-1-yl)methyl)-phenylmethyl)acetamide (11.5 g) and sodium hydroxide (4.0 g) in ethanol (20 ml)-water (20 ml) was refluxedunder heating for 18 hr. The reaction mixture was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown oil (9.1 g). The obtained pale-brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol:aqueous ammonia=9:1:0.3) to give the title compound (7.4 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C(N)CCC>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH:9]=[CH:10][CH:11]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Solvent: CCCCN
Product: CC(=Cc1cccc(OC(F)(F)F)c1)[N+](=O)[O-]
Yield: 70 %

Procedure:
32 g (0.17 mol) of 3-trifluoromethoxy-benzaldehyde, 32 ml of nitro-ethane and 2 ml of n-butylamine are introduced into a 100 ml flask surmounted by a condenser. The mixture is heated for 20 hours at the reflux temperature and then rectified. 29 g (70% yield) of 1-(3'-trifluoromethoxy-phenyl)-2-nitro-1-propene are collected as a yellow oil b.p. 90°-110° C./2mm. Hg.