Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O.P([O-])(OCC)(OCC)=[S:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23](=[S:28])[NH2:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOP([O-])(=S)OCC
Reactant: COC(=O)c1ccc(CC(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CC(C(N)=S)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A mixture of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)ethyl]benzoic acid methyl ester (8.76 g, 25.08 mmol), water (4.7 mL) and diethyl thiophosphate (4.67 mL, 27.8 mmol) was stirred and heated to 80° C. for two hours. The mixture was cooled and aqueous sodium hydrogen carbonate (100 mL, 10%) and ethyl acetate (200 mL) were added. The organic phase was washed with brine. Drying (MgSO4) and concentration in vacuo afforded 7 g of the crude material, which was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate:heptane 1:2, containing 2% ethanol. This afforded 2.6 g (27%.) of 4-[2-thiocarbamoyl-2-(4-trifluoromethoxy-phenyl)ethyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([O:18][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 58 (55 mg) in anhydrous tetrahydrofuran (3 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (10 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat ethyl bromoacetate (0.026 mL) in one charge the reaction was then allowed to warm to ambient temperature under an atmosphere of nitrogen over 30 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL). The extract was dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to provide the title compound (14 mg). LC/MS MH+ 391, Rt 1.84 min (5 min run).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[C:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>CO>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[C:15]([CH3:16])[CH3:17])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(C(=C(C)C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=C(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of the ester 19 (0.115 g, 0.304 mmol) in 75% aqueous methanol (3 mL) was added one pellet of potassium hydroxide (0.12 g), The mixture was stirred at 75° C. for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford the desired acid 20 as a white powder (0.11 g, 99%): m.p. 204°-206° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[NH2:29]C(C)(CC(C)C)C(O)=O>CN(C=O)C>[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH2:19][NH2:29])=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3ccn12
Reactant: CC(C)CC(C)(N)C(=O)O
Solvent: CN(C)C=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN)cc4)nc3ccn12
Temperature: 150 °C

Procedure:
A suspension of 4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde (13, 0.25 g, 0.69 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 0.101 g, 0.69 mmol) in DMF (3 mL) was heated at 150° C. for 30 min. The reaction mixture cooled and the solvent was removed in vacuo. The crude residue was dissolved in 3N HCl (2.5 mL) and was heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (5-65% acetonitrile/water over 15 min) to give, upon evaporation of the solvents, the title compound as a yellow solid. HRMS m/z (M+1) Calcd: 366.1713. Found 366.1715.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
50 g (0.247 mol) of 1-chloro-2,4-dinitrobenzene, 73.5 g (0.74 mol) of cyclohexylamine, 68 g (0.5 mol) of potassium carbonate and 20 ml of water were heated in 400 ml of dimethylformamide at 80°-90° C. for 3 h. The mixture was then concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure to yield 63.9 g (98%) of the product. Melting point 155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH2:37]C.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH2:36][CH3:37])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]
Reactant: CCC(=O)Cl
Reactant: COc1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3cccc(OC)c3)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 4 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-3′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.226 mmol). Added to the vial was 4N HCl in dioxane (2.0 mL). The vial was capped and the solution was stirred at room temperature for 2 h. The solution was concentrated in vacuo. Into the vial were place dichloromethane (1 mL) and N,N-diisopropylethylamine (0.14 mL). The solution was cooled in an ice bath. Into a separate vial, propanoyl chloride (0.217 mmol) was taken up in dichloromethane (1 mL) and then 0.5 ml, of this solution was added to the cold reaction. The vial was capped and stirred for 1 h, allowing the ice bath to slowly warm to room temperature. Since it was determined that the reaction was not complete, additional 0.10 mL of propanoyl chloride solution in dichloromethane was added to the reaction. After 1 h, the reaction was complete. Dichloromethane (1 mL) and saturated aq NH4Cl were added to the reaction. The vial was lightly agitated and the liquid phases were allowed to separate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (21 mg, 21%). MS(ES)+ m/e 424.9 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=1.CCCCCC>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:24][CH:25]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+.
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reaction time: 1 h

Procedure:
To a mixture of 0.21 g of iron powder, 3 ml of acetic acid, and 0.3 ml of water was added dropwise a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine in 1.2 ml of acetic acid, while the temperature of the reaction mixture was kept at 35° C. or lower. After completion of the dropwise addition, the mixture was stirred for 1 hour and then filtered through Celite. The filtrate was diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel chromatography to give 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine as a mixture of diastereoisomers.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])[CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][N:42]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:28])[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)C2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (229.5 mg, 0.5 mmol) in DMF (4 mL) was added piperidine-4-carboxylic acid ethyl ester (79 mg, 0.5 mmol), PyBrop (233.1 mg, 0.5 mmol) and triethylamine (0.1 mL). The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. After the evaporation of solvents, the residue was purified through flash column chromatography using ethyl acetate and hexanes. The desired fraction was evaporated and triturated with ether and petroleum ether (2:1) to give a yellow solid as 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester. LC-MS showed a single peak with a retention time of 3.54 min. LRMS calcd for C31H33F3N4O5 (M+H) 599.24, obsd 599.3
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)Cl
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoic acid (3.2 g; 9.1 mmol) from Step 3 above in THF was added thionyl chloride (1 mL; 13.7 mmol) and pyridine (2 drops) while under a nitrogen atmosphere. The solution was stirred for 4 hours and then concentrated under reduced pressure to dryness. The residue was suspended in ether and filtered, and the filtrate was concentrated to dryness to yield 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].C(O)C>O1CCCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]([CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
Sodium hydride (4.4 grams) and 10.7 grams of diethyl carbonate are suspended in 60 ml of tetrahydrofuran and 10 grams of 2-acetylfuran is gradually added thereto by keeping the inner temperature at 40°to 50° C. A small amount of ethanol is added thereto, heated to reflux for three hours, and the reaction is made stopped by addition of 20 ml of ethanol. The mixture is poured into ice water, extracted with ether, the ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distilling in vacuo to give 10 grams of pale yellow oily product, b.p. 90° C./3 mmHg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>>[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOC(=O)c3ccccc3Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chloro-benzoyl chloride analogously to the procedure described in Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-[3-(2-chloro-benzoyloxy)-propyl]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 614.6, 616 (M+H)+.
Reaction SMILES: C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2)=[O:29]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]3)[CH2:39]1)[CH2:33]2)=[O:29]
Reactant: O=C(O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Yield: 82.3 %

Procedure:
Isobutylchloroformate (0.575 ml) and triethylamine (0.63 ml) were added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid (Example 6c, 1.64 g) in tetrahydrofuran (30 ml) at 0° C. After 1 h the precipitates were removed by filtration and the filtrate added portionwise to a solution of sodium borohydride (0.18 g) in water (10 ml) at 10° C. After a further 1 h the reaction mixture was poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was extracted twice with dilute hydrochloric acid, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography (eluting with dichloromethane/methanol 96:4); yielded the subtitled compound as a solid (1.3 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[ClH:1].[C:35]([C:34]1[CH:37]=[CH:38][C:31]([CH2:30][O:18][C:12]2[CH:11]=[C:10]3[C:15]([C:6]([NH:5][C:4]4[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=4[F:2])=[N:7][CH:8]=[N:9]3)=[CH:14][C:13]=2[O:16][CH3:17])=[CH:32][CH:33]=1)#[N:36]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (187 mg, 0.75 mmol), (prepared as described for the starting material in Example 22), 4-bromomethylbenzonitrile (147 mg, 0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 50° C. for 1 hour. Methanol (5 ml) and potassium carbonate (138 mg, 1 mmol) were added and the mixture stirred at 65° C. for 2 hours. The solvent was removed by evaporation, water was added to the residue and the mixture adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with ether, collected by filtration and dried. The solid was dissolved in methylene chloride/isopropanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate collected by filtration, washed with methylene chloride and dried under vacuum to give 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (60 mg, 25%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of benzyl (1S,2S,3S,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3.1.0]hexan-3-ylcarbamate (2.0 g, 5.540 mmol) in THF (20) at room temperature was added 1 M tetrabutylammonium fluoride in THF (55 mL, 55.4 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (1.2 g, 92%) as a white solid. MS (ES+) C14H17NO3 requires: 247, found: 230 [M+H−H2O]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>C1COCC1>[C:13]1([C@H:11]([O:10][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CS(N)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.1 g, 0.2 mmol), methanesulfonamide (0.08 g, 0.8 mmol), and N,N′-carbonyldiimidazole (0.15 g, 0.6 mmol) were combined in THF (4 mL). Diisopropylethylamine (0.5 mL) was added, and the reaction was stirred at 65° C. overnight. The mixture was acidified and extracted with CH2Cl2. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.