Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>O1CCCC1.CN(C=O)C>[C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:11]([CH2:14][CH2:15][CH2:16][C:17]3=[O:19])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccc(Sc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(Sc3ccccc3)cc21
Reaction time: 1 h
Yield: 54.3 %

Procedure:
4-(4-Phenylsulfanyl-phenyl)-butyric acid (5.0 g, 18.4 mmol) was dissolved in 50 mL tetrahydrofuran (THF). Oxalyl chloride (1.8 mL, 20 mmol) and one drop of DMF were added, and the reaction mixture was stirred for 1 hour, and then evaporated to dryness under reduced pressure. The resulting residue was dissolved in 40 mL of 1,2-dichloroethane, and aluminum trichloride (0.85 g, 25 mmol) was added all at once. The reaction mixture was stirred for 1 hour, and quenched by addition of 2% HCl. This aqueous mixture was extracted twice with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4) and evaporated to yield 2.54 g (10 mmol, 55.5%) of 7-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a gummy residue. MS: 255 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:12]1[CH2:13][CH2:14][N:9]([CH:7]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: O=CCc1cccs1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C(=CN1CCOCC1)c1cccs1

Procedure:
A mixture of 1.5 g of 2-thienylacetaldehyde, 1.4 mL of morpholine, and 0.012 g of p-toluenesulfonic acid hydrate in 7.5 mL of toluene is heated at reflux under a Dean-Stark Trap with azeotropic removal of water for 3 hours. The solution is cooled, neutralized by the addition of solid sodium methoxide, and concentrated in vacuo. The residue is taken up in toluene, filtered, and concentrated in vacuo to afford the desired enamine as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.O>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1Br
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combined with 10 g of H2O. 1.11 g (10.45 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 22 mg of CuBr2 and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 2 mL H2O under nitrogen to give a deep purple solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 1 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The purity was determined by 1H NMR to be about 99%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.O>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Morpholine (1.1 ml) was added to a solution of [4-bromo-2-(trifluoromethyl)phenyl]sulfonyl chloride (2.03 g) in DCM (7 ml) at 0° C. and stirred at 20° C. for 16 h. Water was added and the mixture was extracted with DCM. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound 2.10 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[S:9]1(=[O:15])(=[O:14])[CH2:13][CH2:12][CH2:11][NH:10]1>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:10]2[CH2:11][CH2:12][CH2:13][S:9]2(=[O:15])=[O:14])=[CH:4][CH:5]=1
Reactant: O=S1(=O)CCCN1
Reactant: C=Cc1ccncc1
Solvent: CO
Product: O=S1(=O)CCCN1CCc1ccncc1
Reaction time: 7 h
Yield: 74.4 %

Procedure:
A mixture of 4-vinylpyridine (324 g), isothiazolidine-1,1-dioxide (373 g), and "Triton B" solution (129 ml, 40% w/v in methanol) was heated in D.M.F. at 50°-55° for 7 hours. The reaction mixture was then concentrated under vacuum, water (2.52 liters) was added, and the product was extracted into CH2Cl2 (3×1.87 liters). The combined methylene chloride extracts were washed with water and then evaporated to dryness. The residue was dissolved in ethyl acetate (1.3 liters) at 35° and hexane (0.87 liters) was added over 10 minutes. The resulting crystalline product was granulated at -5 to 0° for 4 hours, filtered, washed with hexane (0.37 liters) and dried in vacuum at 25°, to give 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide (518 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][NH:14][C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1.C(=O)([O-])O.[Na+].S([O-])(O)=O.[Na+].[Cl-:29].[Na+]>C(OCC)(=O)C.C(#N)C>[Cl:29][C:9]1[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[CH:8]=1
Reactant: [Cl-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65 %

Procedure:
To 150 ml of acetonitrile solution containing 2.99 g (11.3 mmol) of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(b) was added 1.42 g (10.6 mmol) of N-chlorosuccineimide, the mixture was stirred at room temperature for 3.5 hours, 0.53 g (4.0 mmol) of N-chlorosuccineimide was further added to the mixture and the resulting mixture was stirred for 24 hours. After completion of the reaction, to the reaction mixture were added a saturated aqueous solution of sodium hydrogencarbonate, 5% sodium hydrogen sulfite and ethyl acetate, and the mixture was stirred for 1 hour. Then, a saturated aqueous solution of sodium chloride was added to the solution and the liquids were separated. The organic layer after separation was further washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=9:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.20 g of the title compound as a white solid. (Yield: 65%)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]([O-:15])=[O:14])[CH2:8]2.C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:21][CH2:22][C:23]([N:11]([CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[NH:12][C:13]([O:15][CH2:10][C:1]1[CH:8]=[CH:7][CH:9]=[CH:3][CH:2]=1)=[O:14])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: O=C([O-])NNC1C2CC3CC(C2)CC1C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(NN(C(=O)CCl)C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.8 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)hydrazinecarboxylate (800 mg, 2.66 mmol) in dichloromethane (30 mL) was added with sodium hydrogen carbonate (450 mg, 5.40 mmol) and chloroacetic acid chloride (300 mg, 2.66 mmol) were added at 0° C., and the resultant was stirred at room temperature for 3 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and benzyl 2-(2-chloroacetyl)-2-(adamantan-2-yl)hydrazinecarboxylate (726 mg, 72.4%) was obtained as a white crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
A mixture of 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (710 mg, 1.87 mmol), 1-bromo-2-methyl propane (305 μL, 2.80 mmol) and K2CO3 (412 mg, 2.99 mmol) in DMF (5 mL) was heated at 90° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water (3×) and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-15% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (562 mg, 69% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.72-7.55 (m, 2H), 7.57-7.56 (m, 2H), 7.58-7.43 (m, 2H), 7.13-7.09 (m, 1H), 3.53-3.08 (m, 2H), 1.66-1.63 (m, 1H), 0.90 (d, J=6.5 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H), LCMS (m/z, Method A) ES+ 436.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:2]([C:4]2[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=2)[CH:1]=[CH:16]1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2cccc([N+](=O)[O-])c2)n[nH]1

Procedure:
18 g of 3-nitroacetophenone are converted into the pyridazinone in accordance GWP 1.
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:51]=[CH:50][C:40]([CH2:41]P(=O)(OCC)OCC)=[CH:39][CH:38]=1>CCCCCC.O1CCCC1>[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH:41]=[C:28]2[CH2:27][CH2:26][N:25]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[CH:50][CH:51]=1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOP(=O)(Cc1ccc(C2=NCCO2)cc1)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Temperature: -60 °C
Reaction time: 0.42 h

Procedure:
6.25 ml of a 1.6M solution of n-butyllithium in hexane followed, after stirring for 20 minutes, by 3.4 g of N-trityl-4-piperidone (prepared from 4-piperidone hydrochloride hydrate and trityl chloride) in 20 ml of tetrahydrofuran are added dropwise at -60° C. to 2.97 g of diethyl 4-(2-oxazolin-2-yl)benzylphosphonate. The mixture is stirred at -60° C. for 25 minutes. The reaction solution is then allowed to warm to ambient temperature and is stirred for a further 1.5 hours at this temperature. The reaction solution is then stirred into 150 ml of ice-water, the mixture is extracted three times with 150 ml of ethyl acetate, and the organic phase is dried and evaporated down. The residue is purified by column chromatography on Silica gel (petroleum ether/ethyl acetate=1:1, v/v). 1.7 g of the title compound of melting point 110°-115° C. are obtained.
Reaction SMILES: [Na].Br[C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.O>CCCCCCCC>[CH3:9][C:3]12[CH2:10][CH:9]3[CH2:8][C:7]([CH3:13])([CH2:6][C:5]([C:14]45[CH2:14][C:5]6([CH3:11])[CH2:4][CH:3]([CH2:12][C:7]([CH3:13])([CH2:6]6)[CH2:8]4)[CH2:10]5)([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: [Na]
Solvent: CCCCCCCC
Solvent: O
Product: CC12CC3CC(C)(C1)CC(C14CC5CC(C)(CC(C)(C5)C1)C4)(C3)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 159.6 %

Procedure:
A four-neck 1000 ml flask provided with a thermometer, stirrer, and reflux tube was charged with metal sodium 14 g (0.6 mol) and n-octane 600 ml and was cooled to an inside temperature of 0° C. While vigorously stirring, 1-bromo-3,5-dimethyl adamantane 73.0 g (0.3 mol) previously dissolved in n-octane 300 ml was gradually added dropwise. While dropping, the inside temperature was kept at 0° C. to 5° C. After the end of the dropwise addition, when the temperature no longer rose, the reaction was continued for 1 hour. After that, the reactant was poured into cold water 1500 ml, then the crude product was separated by filtration, rinsed with pure water, and dried. Further, the crude product was recrystallized by hot hexane. The obtained recrystallized product was dried under reduced pressure to obtain the product 78.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([Si:17]([CH3:19])([CH3:18])[N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF (250 mL) was added sodium hydride (60% suspension in mineral oil, 10.22 g, 0.255 mol) portionwise and maintaining the solution at 0° C. The reaction mixture was stirred at 0° C. for 20 min, then a solution of tert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF (20 mL) was added and the solution stirred at RT for 25 h. The reaction mixture was poured into H2O and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4), then concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, cyclohexane:DCM 100% to 50:50) to provide the title compound as a colourless oil (41.2 g, 74%).
Reaction SMILES: [CH3:1][N:2]([C@@H:12]([C:24](=[O:39])[N:25]([CH3:38])[C@@H:26]([C:34](=[O:37])[NH:35][CH3:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:3](=[O:11])/[CH:4]=[CH:5]/[CH2:6][C:7]([NH2:10])([CH3:9])[CH3:8].C(O)(=O)C.[Si:44]([O:51][C@H:52]([CH3:55])[CH:53]=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].C([BH3-])#N.[Na+]>CO>[Si:44]([O:51][C@H:52]([CH3:55])[CH2:53][NH:10][C:7]([CH3:8])([CH3:9])[CH2:6]/[CH:5]=[CH:4]/[C:3]([N:2]([C@H:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:24]([N:25]([C@H:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]([NH:35][CH3:36])=[O:37])[CH3:38])=[O:39])[CH3:1])=[O:11])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide (318 mg, 0.60 mmol) was dissolved in methanol (20 ml) and glacial acetic acid (0.48 ml, 8.4 mmol). 3 Å mol sieves (9 g) and a solution of (2R)-2-(tert-butyldimethylsilyloxy)propanal (1.33 9, 7.06 mmol) in methanol (10 ml) were added successively. Sodium cyanoborohydride (220 mg, 3.53 mmol) was added as a solid. The reaction mixture was stirred at room temperature for 45 min, before a second batch of sodium cyanoborohydride (220 mg, 3.53 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. The mol sieves was filtered off through a plug of celite. The celite was washed with methanol (200 ml). The solvents of the combined filtrates were removed in vacuo. The residue was dissolved in 1 N sodium hydroxide solution (50 ml) and tert-butyl methyl ether (50 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (35 g), using ethyl acetate/heptane/triethylamine (20:10:1) as eluent, to give 99 mg of (2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-butyldimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:25]=1[NH2:26]>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:31])=[CH:30][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solid was filtered, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (1.0 g, 87%)
Reaction SMILES: [CH:1]1([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C(O)=O)CCCC1.C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:84][N:85]=[CH:86]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:84][N:85]([CH3:86])[C:8](=[O:9])[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Agent: N
Agent: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Product: CN(O)C(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
The desired material was prepared according to the procedures described in Example 4 substituting 2-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for 2-cyclopentyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid and Example 6 substituting 2-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]-phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 0.7 (m, 1H), 1.0 (m, 1H), 1.15 (m, 4H), 1.55(m, 2H), 1.65 (m, 2H), 1.85 (m, 1H), 3.03 (s, 3H), 3.86 (d, 1H, J=7Hz), 4.84 (s, 2H), 7.0 (d, 2H, J=7Hz), 7.2 (d, 2H, J=7Hz), 7.62 (d-t, 1H, J=8Hz and 2Hz),7.68 (d, J=8Hz, 1H), 7.8 (dt, J=8Hz, 2Hz, 1H,), 8.0 (t, J=8Hz, 2H), 8.43 (d, J=8Hz, 1H), 9.8 (s, 1H). IR (CDCl3):3520, 1610 cm-1. MS (DCI/NH3) m/e 405 (M+H)+. Analysis calcd for C25H28N2O3 : C, 74.23; H, 6.98; N, 6.93. Found: C, 73.96; H, 7.04; N, 6.74.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([O:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:19]I>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH2:12][CH:11]([O:14][CH3:19])[CH2:10]2)[CH2:15][CH2:16]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)CC(OC)CO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
8-Ethoxycarbonyl-3-hydroxy-1-oxa-8-azaspiro[4.5]decane (1 g, 0.0044 mol) was dissolved in anhydrous THF (40 ml) under nitrogen and cooled with an ice-bath. Sodium hydride (0.22 g, 5.5 mmol as a 60% oil dispersion) was added and the reaction was stirred at 0° C. for 20 minutes. Methyl iodide (2.0 g, 0.9 ml) in THF (10 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 3 hours. An additional 0.9 ml of methyl iodide was added at 0° C. and stirring was continued overnight. The cooled reaction was diluted with water (10 ml). The aqueous THF was washed with saturated brine and dried over Na2SO4. The solvents were evaporated and the residue was purified by flash chromatography on silica gel by elution with ammoniated 2% methanol/chloroform. Evaporation of the solvents gave 0.97 g of a pale orange oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@H:11]([O:13][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of methyl (2S,4R)-1-Bochydroxypyrrolidine-2-carboxylate (8 g, 32.65 mmol) prepared in Step B in DCM was added dropwise TEA (11.99 ml, 81.56 mmol) and methanesulfonyl chloride (3.77 ml, 48.9 mmol) at m° C. After the reaction mixture was stirred at rt for 3 h, the organic extracts were washed with a saturated NaHCO3 aqueous solution, 1N HCl and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (9.4 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[CH2:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:24][CH2:25]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNC1CCN(Cc2ccccc2)CC1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-amino-1-benzylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=476.