Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12>[Pd].C(O)(=O)C>[N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1[nH]nc2n1CCc1ccccc1C2

Procedure:
A mixture of 20 parts of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one, 400 volume parts of acetic acid and 15 parts of 5% palladium-on-carbon is hydrogenated at atmospheric pressure and temperature under stirring. After 2600 volume parts of hydrogen is absorbed, the catalyst is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is treated with diethyl ether to give 2,5,6,11-tetrahydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from ethanol gives colorless plates melting at 253° - 261° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32])=[O:26]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])=[O:26])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1noc(C)c1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1noc(C)c1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 154.76 mg (0.709 mmol) of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 230 mg of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: C[CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[N:10]1([CH:16]2CCCN2CC(O)=O)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:16][N:10]1[CH2:15][CH2:14][N:13]([C:7](=[O:9])[CH2:8][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:12][CH2:11]1
Reactant: CC1CC(=O)OC(=O)C1
Reactant: O=C(O)CN1CCCC1N1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 8 h
Yield: 171 %

Procedure:
1.6 g of 3-methylglutaric anhydride and then 2.62 g of piperazin-1-ylcarboxymethylpyrrolidine are added to 20 cm3 dioxane. After stirring for 8 hours, an additional 320 mg of 3-methylglutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure and then the resulting oil is dried at 45° C. (90 Pa) to give 4.5 g of 5-(4-methylpiperazin-1-yl)-5-oxopentanoic acid in the form of an orange-colored oil which is used as it is.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][N:6]=[C:7]=[S:8].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[CH2:5][NH:6][C:7]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[S:8]
Reactant: NCC(F)(F)F
Reactant: Fc1cc(CN=C=S)ccc1OCC(F)(F)F
Solvent: CCOC(C)=O
Product: Fc1cc(CNC(=S)NCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 24 h

Procedure:
3.15 g of 3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl isothiocyanate and 1.5 ml of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetate, and the solution was left to stand for 24 hours. Ethyl acetate was evaporated under reduced pressure. The resulting white crystals were recrystallized from hexane to give 3.92 g of the desired 1-[3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-3-(2,2,2-trifluoroethyl)thiourea.
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][C:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:20])([CH3:19])[O:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CO>C1COCC1>[Br:7][CH2:8][C@@H:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=2[CH:12]=1)[OH:10]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated with borane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After the addition was complete the solution was kept between 30 and 35° C. for 1 h and then cooled in ice and 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885) (3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperature below 5° C. The mixture was stirred under nitrogen for a further 0.5 h and then methanol (4 ml) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by chromatography on flash silica gel eluting with ethyl acetate-cyclohexane (1:4) to give the title compound (3.31 g) δ (CDCl3) 7.15 (1H, dd, J 8, 2 Hz), 7.03 (1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J 10, 4 Hz), 3.50 (1H, 9 Hz), 1.54 (6H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(OC)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,5-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 529.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[S:27][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=5)=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.Cl>>[N:6]1[CH:7]=[N:8][CH:4]([CH2:3][CH2:2][NH:1][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]3[S:27][C:20]4[C:19]([NH:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[NH:9][CH:10]=[CH:11]6)=[N:24][CH:23]=[N:22][C:21]=4[CH:25]=3)=[CH:35][CH:34]=2)[CH:5]=1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: C1=NC=NC1CCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from histamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.61 (s, 1H), 8.47 (s, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.57 (m, 2H), 7.38 (m, 2H), 7.24 (m, 1H), 6.95 (s, 1H), 6.42 (s, 1H), 4.22 (s, 2H), 3.15 (m, 2H)2.82 (m, 2H); LC-MS: 466 (MH+); HPLC RT: 3.76 minutes.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-nitrobenzylamine hydrochloride (0.55 g, 2.9 mmol) and triethylamine (0.32 g, 3.2 mmol) in methanol (5 ml) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.70 g, 2.5 mmol, yield: 95%) as colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH2:21][CH2:20][C:12]2(OCC(C)(C)C[O:13]2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CC(C)=O.O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH3:8])[CH:9]1[CH2:21][CH2:20][C:12](=[O:13])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC2(CC1)OCC(C)(C)CO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (3,3-dimethyl-1,5-dioxa-spiro[5,5]undec-9-yl)-methyl-carbamic acid tert-butyl ester (1.27 g, 3.63 mmol, 1.0 eq.) in acetone (40 mL) and water (20 mL) was added PPTS (228 mg, 0.25 eq.) and the resulting reaction was heated to reflux overnight, cooled to room temperature, concentrated to 20 mL, poured in saturated NaHCO3 and extracted with 3×EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes to 20% EtOAc/hexanes) to give methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (735 mg, 88%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)#[C:2][CH3:3]>P([O-])([O-])([O-])=O>[C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[NH:8][CH:17]=1)#[C:2][CH3:3]
Reactant: CC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Product: CC#Cc1c[nH]c(=O)[nH]c1=O
Reaction time: 24 h

Procedure:
To a stirred solution of 2′-deoxy-5-propynyluridine (European Patent Specification No. 272065) (20 g, 75 mmol) in aqueous phosphate buffer at pH 6.84 (1250 mL) was added purified E. coli thymidine phosphorylase (10,000 units) (T. A. Krenitsky et al, Biochemistry, 20, 3615, 1981; U.S. Pat. No. 4,381,344) and alkaline phosphatase (10,000 units) [Sigma type VII-S from bovine intestinal mucosa] and the whole mixture was incubated at 37° C. for 24 hours. The resulting white precipitate was filtered, washed with water (3×100 mL), ethanol (2×100 mL), ether (2×100 mL) and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)(=[O:11])[CH:9]=[CH2:10].[OH-].[K+].C(S)(S)CC.Cl>CC(O)C.O>[C:1]1([S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC1CO1
Reactant: Sc1ccccc1
Agent: CCC(S)S
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: O=C(CCSc1ccccc1)OCC1CO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,3-epoxypropyl 3-(phenylthio)propionate was prepared by adding 11.0 grams (0.1 moles) of benzenethiol to a solution of 12.8 grams of 2,3-epoxypropyl acrylate with 10 drops of Triton B® in 50 milliliters of 2-propanol. The addition was carried out over a period of 5 minutes during which the temperature of the reaction mixture rose to 54° C. The mixture was then stirred for 3.5 hours at ambient temperature. To this reaction mixture was added 0.5 grams of potassium hydroxide. After the potassium hydroxide had dissolved there was added 5.4 grams of propanedithiol and the reaction mixture was stirred for 3.5 hours. The mixture was then poured into a solution of 5 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The organic oil was separated by extraction with toluene and toluene was then removed from the extract by rotary evaporator. There was obtained 26.6 grams (0.091 moles) of a viscous liquid shown by its NMR spectrum to be 2,9 -dihydroxy-4,7-dithia-5-methyldecamethylene bis[3-(phenylthio)propionate].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([NH:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:19][CH:20]=1)[C:5]([OH:17])([C:10]#[C:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:6]([F:9])([F:8])[F:7].Cl.C(=O)(O)[O-].CCOCC>CO>[NH2:21][C:18]1[C:4]([C:5]([OH:17])([C:10]#[C:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]([F:7])([F:8])[F:9])=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1
Reactant: OC(C#Cc1ccco1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 g of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol (Example 9, Part B) in 20 mL of methanol was added 0.125 mL of 12 N aqueous hydrochloric acid, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extractec with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the residue was chromatographed over silica gel (elution with hexanes/ethyl acetate 3:1) affording after crystalization from hexane/ethyl acetate 280 mg of the title compound.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:36])[N:9]([CH3:35])[C:10]=3[N:17]=[CH:16][C:15]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([CH3:26])[CH3:25])=[CH:33][CH:32]=1
Reactant: CC(C)c1ccccc1-c1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1-c1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (35 mg, 0.069 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (5.8 mg, 0.138 mmol). The reaction was stirred for 15 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 45.4% yield) as white solid, 1H NMR (DMSO-d6) δ: 8.49 (s, 1H), 7.40-7.38 (m, 2H), 7.18-7.14 (m, 3H), 6.93 (d, J=7.2 Hz, 1H), 6.75 (d, J=8.4 Hz, 2H), 4.68-4.65 (m, 1H), 4.45 (s, 1H), 4.24-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.64 (s, 3H), 3.42-3.40 (m, 2H), 2.40-2.36 (m, 1H), 1.70-1.66 (m, 2H), 1.01-1.00 (d, 3H), 0.85 (d, J=7.2 Hz, 3H). LCMS: [MH+—OH] 478 and TR=3.454 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[S:29][C:30]6[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=6[N:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5nc6ccccc6s5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-benzothiazole following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 90° C. LC (method 3): tR=0.78 min; Mass spectrum (ESI+): m/z=492 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].S(Cl)([Cl:29])=O>CN(C=O)C>[C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([Cl:29])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (556 mg, 1.54 mmol) in thionyl chloride (6 ml) containing DMF (3 drops) was heated at 80° C. for 4 hours. The volatiles were removed under vacuum. The residue was dissolved in methylene chloride and the organic layer was washed with aqueous sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (530 mg, 90%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)/[C:17](=[N:21]/[OH:22])/[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[CH:23]([O:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](OC(C)C)=O)=[CH:29][C:28]=1[C:39]([F:42])([F:41])[F:40])([CH3:25])[CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH:23]([O:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]2[O:22][N:21]=[C:17]3[C:18]4[C:13]([CH2:14][CH2:15][C:16]=23)=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:20][CH:19]=4)=[CH:29][C:28]=1[C:39]([F:40])([F:41])[F:42])([CH3:25])[CH3:24]
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 39.8 %

Procedure:
To the LDA solution at 0° C. was added 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.212 g, 1.132 mmol) as a solution in THF (1 mL), dropwise over a period of 1 min. After 15 min. isopropyl 4-isopropoxy-3-(trifluoromethyl)benzoate (Preparation 14A, 0.329 g, 1.132 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to yield a dark oil. To this oil was added toluene (5 mL). The contents were sonicated for 2 min. and p-toluenesulfonic acid monohydrate (0.431 g, 2.265 mmol) was added at room temperature. The contents were heated at 110° C. for 25 min. The reaction mixture was concentrated and partitioned between dichloromethane (15 mL) and sat. aq. sodium bicarbonate (10 mL). The dichloromethane layer was dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane/ethyl acetate). Product fractions were collected and concentrated to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole as a semi-solid (180 mg). LC/MS M+1=400.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:30]([C:32]3[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[F:40])=[O:31])[N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2SC(C3C=CC=C(OC)C=3O[Si](C(C)C)(C(C)C)C(C)C)N(C(C3C(F)=CC(F)=CC=3F)=O)N=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:102][C:103]([O:105][CH3:106])=[O:104]>>[CH3:106][O:105][C:103](=[O:104])[CH2:102][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[N:10]([C:30](=[O:31])[C:32]2[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=2[F:40])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:12]1
Reactant: COC(=O)CBr
Reactant: CC(C)[Si](Oc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [F-]
Product: COC(=O)COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (3.4 mmol), prepared in a similar manner as described for [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone in example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF) (5.1 mmol) at room temperature for 40 minutes. Methyl bromoacetate (5.1 mmol) is then added. After 12 hours, the reaction is complete as determined by LC/MS. Purification is accomplished by silica flash chromatography (25% EtOAc/hexane) to give {2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.54 (m, 2H), 7.04 (m, 3H), 7.01 (d, J=8.4 Hz, 1H) 6.95 (bs, 2H), 4.94 (s, 2H), 4.01 (s, 3H). MS: (ES+) 535.1 (M+1); LC/MS (ES+): 535.1 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C([O:37][C:38](=[O:53])[C@H:39]([CH2:48][CH2:49][C:50](O)=[O:51])[NH:40]C(OC(C)(C)C)=O)(C)(C)C>>[ClH:28].[NH2:40][C@@H:39]([CH2:48][CH2:49][C:50](=[O:51])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[C:38]([OH:53])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: N[C@@H](CCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-glutamic acid 1-tert-butyl ester by using the same method as in Example 96.
Reaction SMILES: FC1C=CN=C2C=1CCCN2.Br[C:13]1[C:14]([F:26])=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([C:41]3([OH:47])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:38]=[N:39][CH:40]=2)O1>>[F:26][C:14]1[C:13]([C:35]2[CH:40]=[N:39][CH:38]=[C:37]([C:41]3([OH:47])[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH:36]=2)=[CH:22][N:21]=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][N:19]2[C:23]([NH2:25])=[O:24]
Reactant: CC1(C)OB(c2cncc(C3(O)CCOCC3)c2)OC1(C)C
Reactant: NC(=O)N1CCCc2c1ncc(Br)c2F
Agent: Fc1ccnc2c1CCCN2
Product: NC(=O)N1CCCc2c1ncc(-c1cncc(C3(O)CCOCC3)c1)c2F

Procedure:
5-Fluoro-1,2,3,4-tetrahydro-[1,8]naphthyridine is converted to 6-bromo-5-fluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide according to Step 1 and Step 2 of Example 121. 6-Bromo-5-fluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide is coupled with 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol (which is prepared according to Step 4 of Example 119) to give the titled product using Suzuki Coupling Method VI.