Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.N(CC)(CCC)CCC.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCN(CC)CCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9 H), 1.5-1.7 (br, 1 H), 2.1-2.4 (m, 2 H), 2.5-2.7 (m, 2 H), 2.83 (br, 1 H), 3.57 (s, 2 H), 4.1-4.3 (br, 1 H), 4.9-5.1 (br, 1 H), 7.15-7.35 (br, 4 H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([OH:17])[CH2:14]CC.BrBr.CC1C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C(O)CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:10][CH2:14][CH2:13][O:17]2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)=O
Reactant: CCCCO
Agent: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Solvent: c1ccccc1
Product: COc1cc(Cl)ccc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 27.5 parts of 1-(4-chloro-2-methoxyphenyl)ethanone in 160 parts of butanol are added dropwise 24 parts of bromine. After stirring for 1 hour at room temperature, there are added successively 9.3 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid and 450 parts of benzene. Stirring is continued overnight at reflux temperature with water-separator. The reaction mixture is evaporated and the residue is taken up in benzene. The mixture is washed with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is crystallized from methanol, yielding 27.6 parts (60%) of 2-(bromomethyl)-2-(4-chloro-2-methoxyphenyl-1,3-dioxolane; mp. 110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12](SC)=[N:13][CH:14]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12]([NH:22][CH2:19][CH2:20][CH3:21])=[N:13][CH:14]=1
Reactant: CCCN
Reactant: CSc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Product: CCCNc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 100 °C
Yield: 64.7 %

Procedure:
To a sealed tube was added 0.15 g (0.57 mmol) of 5-(2,4-dimethyl-phenyl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one and 3 ml (50 mmol) of propyl amine. The mixture was heated to 100° C. for 48 h. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 50% ethyl acetate/hexanes gave 0.1 g (67%) of product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([N:15]2[C:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[N:22]([CH3:30])[CH:21]=3)=[N:18][NH:17][C:16]2=[O:31])=[CH:6]1.[C-:32]#[N:33].[K+]>CN(C=O)C>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][C:32]#[N:33])[CH:6]=[C:7]2[N:15]1[C:16](=[O:31])[NH:17][N:18]=[C:19]1[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[N:22]([CH3:30])[CH:21]=1
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCBr)c3ccc(F)cc23)c2cc(F)ccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCC#N)c3ccc(F)cc23)c2cc(F)ccc21
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of the product from Example 18 (0.86 g, 1.77 mmol) in dry DMF (25 mL) was added potassium cyanide (0.18 g, 2.77 mmol) and the mixture was stirred and heated at 50° C. overnight under nitrogen. The solvent was evaporated, and the residue was distributed between ethyl acetate and water. The water phase was extracted twice with ethyl acetate, and the combined organic phases were washed with water and dried. After evaporation the crude product was chromatographed on silica gel (EtOAc) to yield 0.46 g (61%) of the title product.
Reaction SMILES: [CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:2][CH2:3][CH2:4][CH3:5].[Cl:17]CCl>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14]([Cl:17])=[O:16])=[CH:2][CH2:3][CH2:4][CH3:5]
Reactant: ClCCl
Reactant: CCCC=Cc1ccccc1C=CC(=O)O
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)Cl
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCCC=Cc1ccccc1C=CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-3-[2-((Z)-1-Pentenyl)phenyl]propenoic acid (1.08 g) was dissolved in a mixture of dichloromethane (10 ml), oxalyl chloride (0.5 ml) and N,N-dimethylformamide (0.05 ml). After stirring for 1 hour under nitrogen atmosphere at room temperature, the solvent was evaporated. The residue was dissolved in n-hexane and the mixture was filtered. Filtrate was evaporated to give (E)-3-[2-((Z)-1-pentenyl)phenyl]propenoyl chloride (1.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH2:27][OH:28])[CH:26]=1)[O:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][C:15]2[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]1=[O:23].[H][H]>[Pd].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH2:27][OH:28])[CH:26]=1)[O:5][CH2:6][C@H:7]1[C:8](=[O:23])[CH2:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(CCC[C@H]2C=CC(=O)[C@@H]2COc2cc(Cl)cc(CO)c2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCC[C@H]2CCC(=O)[C@@H]2COc2cc(Cl)cc(CO)c2)s1
Reaction time: 6 h
Yield: 29 %

Procedure:
Palladium on carbon (10 wt. %, 1 mg) was added to a mixture of 12 and 13 (10 mg, ˜0.022 mmol) in EtOAc (0.42 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (10×) and the reaction mixture was stirred under a balloon of hydrogen for 6 h. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo. Purification of the resulting crude residue by flash column chromatography on silica gel (10% MeOH/CH2Cl2) afforded 7 mg (˜68%) of ester 14 and 2.7 mg (30%) of title compound 15.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=O.C(OCC)(=O)[C:13]([O:15]CC)=[O:14].[O-]CC.[Na+]>C(O)C.Cl>[F:11][C:2]([F:1])([F:10])[CH2:3][CH2:4][C:5](=[O:7])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCC(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)CCC(F)(F)F
Reaction time: 0.5 h

Procedure:
Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[S:24]1[C:28]2=[C:29]([C:33](O)=[O:34])[N:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:29]3[N:30]=[CH:31][CH:32]=[C:27]4[CH:26]=[CH:25][S:24][C:28]=34)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1nccc2ccsc12
Product: C[C@@]1(c2cc(NC(=O)c3nccc4ccsc34)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and thieno[2,3-c]pyridine-7-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:20]=1[NH2:21].CC(C)([O-])C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][C:20]3[C:19]([F:18])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[F:27])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Nc1c(F)cc(F)cc1F
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc(F)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(F)c1
Temperature: 85 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (800 mg, 2.4 mmol) in THF (10 mL) were added 2,4,6 trifluoroaniline (359 mg, 2.4 mmol) and sodium tert-butoxide (703 mg, 7.32 mmol) and the reaction mixture was heated to 85° C. for 45 min. The solution was cooled to room temperature, quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% hexane to 100% EtOAc, gradient elution) to afford 9-bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine. 9-Bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine was taken up in THF (10 mL) and 6 N HCl (10 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:14]=[N:13][CH:12]=1>O>[Na+:2].[Na+:2].[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])[N:14]=[N:13][CH:12]=1.[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])[N:14]=[N:13][CH:12]=1
Reactant: COc1ccccc1-c1cnnn1CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCn1nncc1-c1ccccc1O
Temperature: 50 °C
Yield: 85.4 %

Procedure:
Add a solution of NaOH (0.66 g, 16.53 mmol) in water (3 mL) to a suspension of 5-[5-(2-methoxy-phenyl)-[1,2,3]triazol-1-yl]-pentanoic acid (2.16 g, 8.27 mmol) and heat to 50° C. for 1 hour. Concentrate and dry in 50° C. vacuum oven overnight. Add Et2O, sonicate and filter out solids. Dry solids in 50° C. vacuum oven overnight (as solids are highly hygroscopic) to afford the title compound (2.0 g, 79%). MS (IS) 262 (M+1)+.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:27])[CH:22]=4)[N:17]([CH2:28][O:29][CH3:30])[C:16]=3[CH2:15]2)([CH3:13])[CH2:11][OH:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I>C1COCC1>[C:1]1([S:7]([C:10]([CH:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:27])[CH:22]=4)[N:17]([CH2:28][O:29][CH3:30])[C:16]=3[CH2:15]2)([CH3:13])[CH2:11][O:12][CH3:33])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(COC)S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 71.7 %

Procedure:
130 mg (0.29 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propan-1-ol in 5 mL of THF at 0° C. were treated with 14 mg (0.32 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min. 30 min. 30 μL (0.43 mmol, 1.5 eq) of MeI were added and the reaction mixture was stirred an additional 2 hours, partitioned between EtOAc and a saturated aqueous solution of NH4Cl. The organic phase was washed with brine, dried over Na2SO4, and evaporated. Column chromatography with heptane/EtOAc 1:2 gave 96 mg (72%) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole as a white solid, MS: 479 (MNH4+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]4)=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:7][CH:6]=1)[CH3:4].[C:35]([O:39][C:40](=[O:43])[CH2:41]Br)([CH3:38])([CH3:37])[CH3:36].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]([O:39][C:40](=[O:43])[CH2:41][O:27][CH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([O:20][C:18]2[C:19]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:3][CH3:4])=[CH:6][CH:7]=4)=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])[O:13][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:22]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC4CCCC(O)C4)c23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC4CCCC(OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 70 °C
Reaction time: 30 h

Procedure:
1.4 ml of an 11.25N sodium hydroxide solution is added at 70° C. to a solution of 700 mg (1.62 mmol) of 3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol in 15 ml of toluene. After adding 55 mg (0.16 mmol) of tetra-n-butylammonium hydrogensulphate and 631 mg (3.24 mmol) of bromoacetic acid tert-butyl ester, stir the reaction mixture at 70° C. for 30 hours. Then add a further 330 mg (1.69 mmol) of bromoacetic acid tert-butyl ester to the reaction mixture and stir at 70° C. for another 14 hours. After cooling to room temperature, adjust to pH 7 with conc. hydrochloric acid. Extract with dichloromethane. Wash the organic phase with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate under reduced pressure. Purify the residue by means of preparative RP-HPLC (eluent:water/acetonitrile gradient). 632 mg (69% of theory) of the desired product are obtained as a racemic diastereomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:11](=[O:12])[NH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cc(C)ccc2C(=O)O)cc1
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-methoxybenzoyl)-4-methylbenzoic acid with hydrazine hydrate.
Reaction SMILES: C1(CCCCNC(C2N=C(C3C=CC(/[C:25](/C4C=NC=CC=4)=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=CC=3)OC=2)=O)CCCCC1.N1C=CC=CC=1C(C1C=CC=CN=1)=O.[Br-].C(CCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.CC([O-])(C)C.[K+]>C1COCC1.CO>[C:31]([OH:33])(=[O:32])/[CH:30]=[CH:29]/[CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: O=C(O)CCCC/C=C(\c1ccc(-c2nc(C(=O)NCCCCC3CCCCC3)co2)cc1)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(c1ccccn1)c1ccccn1
Solvent: CO
Solvent: C1CCOC1
Product: CCCC/C=C/C(=O)O

Procedure:
(Alternative preparation of Example 2)-G: (E)-7-[4-[4-[[(4 -Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic Acid: Prepared as above from 0.952 g (2.2 mmol) of the pyridyl ketone, 2.00 g (4.4 mmol) of (5-carboxy-pentyl)triphenylphosphonium bromide, and 8.8 mL (8.8 mmol) of 1.0 M t-BuOK in 6.0 mL of THF at 0° C. for 2 h. Preparative HPLC with MeOH--AcOH--CH2Cl2 (2:1:97) furnished total amount of 1.06 g (90%) of the (E)- and (Z)-product (E/Z=8.7:1) from which 941.8 mg of (E)-heptenoic acid was separated cleanly: mp 52-56° C.; 1H NMR (CDCl3) δ8.55 (br s, 1H), 8.47 (d, J=2.7 Hz, 1H), 8.27 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.33 (buried, 1H), 7.12 (t, J=5.9 Hz, 1H), 6.18 (t, J=7.5 Hz, 1H), 3.43 (ddd, J=6.9, 6.8, 6.6 Hz, 2H), 2.31 (dd J=7.2, 6.9 Hz, 2H), 2.19 (ddd, J=7.3, 7.2, 7.1 Hz, 2H), 1.68-0.82 (m, 21H); FDMS 530 (M+1). Anal. (C32H39N3O4.0.2 C2H4O2) C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[N:35][OH:36])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:48](OCC)(=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[CH2:34][C:48]([OH:54])([C:49]([O:51][CH2:52][CH3:53])=[O:50])[O:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=NO)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(O)CC(c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)=NO1
Reaction time: 1 h
Yield: 21 %

Procedure:
To a stirred solution of 1-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-N-hydroxyethanimine (10 g, 44 mmol) was added drop wise 2 M n-ButLi in hexane (45 mL, 44 mmol) at −78° C. and the stirring was continued for 1 hour at −78° C. then for ½ hour at room temperature. After recooling at −78° C., a solution of diethyl oxalate (3.22 g, 22 mmol) in THF (50 mL) was cannuled into the cloudy solution. The mixture was warmed at rt over 16 hours before the addition of a NH4Cl saturated solution (100 mL). The organic and aqueous layers were separated and the latter was diluted with ethyl acetate and thoroughly washed with brine. After drying over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane 7/5, to provide the title compound (2.7 g, yield 17%).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)CC1.C(O)(C(F)(F)F)=O>CO>[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][N:40]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)[CH2:39][CH2:38]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reactant: CC1(N)CCNCC1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1

Procedure:
The title compound was prepared from 7B and excess 4-amino-4-methylpiperidine (WO 9732880) by a route analogous to that used for the preparation of 7C. Analytical HPLC retention time=1.43 min. (YMC Xterra S7 C 18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=495.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][PH3+].[CH2:19]([O:21][C:22](=[O:33])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=O)[CH3:20]>C(Cl)Cl.C1COCC1.C1COCC1>[CH2:19]([O:21][C:22](=[O:33])/[C:23](/[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])[CH3:20]
Reactant: CC(C)(C)CC[PH3+]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(SC)cc1
Temperature: 25 °C

Procedure:
Add sodium bistrimethylsilylamide(4.67 mL, 2.0 M in THF, 9.35 mmol) to a solution of (3,3-Dimethyl-butyl) phosphonium bromide (4.00 g, 9.35 mmol)in CH2Cl2/THF at 0° C. Dissolve (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (prepared as described by I. T. Barnish et. al. J. Med. Chem. 1981, 24, 399-404) in THF and add the resulting solution to the reaction mixture at 78° C. Stir at room temperature over-night. Add water and extract 3 X with dichloromethane, dry over sodium sulfate and concentrate under vacuum to afford 2.79 g raw material as a yellow oil. Further purify this material via silica gel chromatography, eluting with a gradient from 100% hexane to 50:50 hexane:dichlormethan to afford a colorless oil (700 mg). MS (m/e): 293 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([CH:11]1[CH2:15][S:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])[NH:12]1)([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([N:12]1[CH:11]([C:8]([OH:10])=[O:9])[CH2:15][S:14][CH:13]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CSC(c2ccccc2OCCO[N+](=O)[O-])N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1C(C(=O)O)CSC1c1ccccc1OCCO[N+](=O)[O-]
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 0.9 ml of acetic anhydride in THF was added slowly at 0° C. to a solution of 2 g of the compound from Example XVI and 2.1 g of potassium carbonate in H2O. The resulting solution was stirred for 1 hour, after which 1.0 g of potassium carbonate was added to the reaction mixture, followed by the addition of 1 ml of acetic anhydride. The reaction mixture was stirred for one and a half hours, after which a further 1.0 g of potassium carbonate and 1 ml of acetic anhydride were added. After finally stirring for a further 30 minutes, the solution was concentrated under vacuum and cooled in ice. The addition of dilute sulphuric acid gave a precipitate. This precipitate was filtered off, dried and recrystallised from methanol/ether. Yield 60%. Empirical formula C14H16N2O7S. Molecular weight 356. Melting point 159°-162° C. TLC system: ethyl acetate:methanol/1:1. Rf 0.50.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]2)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=1)C1C=CC=CC=1>[Pd].CN(C)C=O>[OH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]2)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(O)cc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Ammonium formate (9.5 g, 150 mmol) and 10% palladium on carbon (500 mg) were added to a solution of 7-(benzyloxy)-5-isopropoxyquinazolin-4(3H)-one (4.6 g, 15.0 mmol) in dimethylformamide (40 ml) and the mixture stirred at ambient temperature for 4 hours. The mixture was filtered through Celite and then evaporated under reduced pressure. The residue was stirred in water (100 ml) for 30 minutes and then filtered and washed with water (25 ml) and then dried to leave 7-hydroxy-5-isopropoxyquinazolin-4(3H)-one (3.3 g, 100% yield) as a white solid: