Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43]Br>CN(C=O)C>[CH3:39][O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:9](=[O:12])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:25][CH:26]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 95 °C
Yield: 8 %

Procedure:
(±)-Cis-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid methyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (400 mg, 0.92 mmol) was dissolved in DMF (25 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate-70/30 dichloromethane/ethyl acetate) to afford the pure ester (40 mg, 8%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1nc(NCc2cccnc2)c2nc[nH]c2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(Cl)nc21
Temperature: 70 °C
Yield: 77.8 %

Procedure:
(2-Chloro-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (110.3 g, 0.37 mol) was dissolved in dry DMF (1.5 L) and warmed to 70° C. with stirring. K2CO3 (230 g, 1.67 mol) and 2-bromopropane (300 mL, 3.20 mol) were added and the reaction was stirred at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and K2CO3 was removed by filtration and washing with EtOAc. The combined filtrate and washings were concentrated on a rotary evaporator and then under high vacuum to remove most of the DMF. The resulting residue was stirred vigorously in H2O (1 L) and CH2Cl2 (1 L) until dissolution was complete. The aqueous layer was extracted with more CH2Cl2 (2×200 mL), the organic extracts were combined, dried over MgSO4, and evaporated to afford the title compound (87.2 g, 78%) as a beige powder. 1H-NMR (DMSO-d6): δ 1.50-1.53 (6H, d, —CH(CH3)2), 4.67-4.72 (3H, m, —CH2—NH— & —CH(CH3)2), 5.20 (1H, br. s, NH), 7.34-7.39 (dd, ArH), 7.76-7.79 (1H, d, ArH), 8.33 (1H, s, ArH, —N═CH—N—), 8.46-8.48 (1H, d, ArH), 8.61 (1H, s, ArH), 8.92 (1H, br. s, NH).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][S:25][C:26]2[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(B(O)O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 131.2 %

Procedure:
A mixture of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (152 mg, 0.5 mmol), cesium carbonate (489 mg, 1.5 mmol) and 4-mercaptophenyl boronic acid (75 mg, 0.5 mmol) in dimethylformamide (5 mL) was allowed to stir for 24 hours in a 60° C. oil bath. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield 277 mg of crude [4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]boronic acid and dimethylformamide. 1H NMR (400 MHz, d6-DMSO): δ 7.63-7.59 (m, 4H), 7.55-7.51 (m, 1H), 7.17 (d, J=8 Hz, 2H), 3.86 (s, 2H), 3.12 (septet, J=7 Hz, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][N:14]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1cnc(C)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ncc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1>O.C(O)C>[OH:12][C:13]1[C:14]([CH:19]=[N:10][NH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ncccc1O
Reactant: NNC(=O)Nc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1ncccc1O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Phenyl semicarbazide (4.91 g, 33 mmol) was added to a suspension of 3-hydroxy-2-pyridine carbaldehyde (4.0 g, 33 mmol) in a mixture of ethanol water (30 mL:40 mL). The reaction mixture was stirred at room temperature for 3 h and the yellow product was collected by filtration. The yellow precipitate was washed with EtOH/H2O 1:1 and dried under P2 O5 to yield 8.22 g (99%) of product. It can be recrystallized from EtOH/H2O; m.p. 201°-2° C. (dec.). 1H NMR (d6 -DMSO) d: 10.85 (br.s., 1H); 10.6 (br.s., 1H); 9.14 (s, 1H); 8.27 (s, 1H); 8.15 (d of d, 1H); 7.55 (d, 2H); 7.26-7.36 (m, 4H); 7.01 (t, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])([CH3:12])[C@H:9]3[O:18][C@H:8]3[C:7]=2[CH:19]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:28][C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])([CH3:12])[C@@H:9]([OH:18])[C@H:8]([N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:7]=2[CH:19]=1)#[N:2]
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 28.3 %

Procedure:
The title compound (106 mg, 28%) was prepared using (2S,3S,4S)-6-cyano-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-2H-1-benzopyran (210 mg, 0.8 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (167 mg, 0.8 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[C:26]([O:29][Si](C(C)(C)C)(C)C)[CH:27]=[CH:28][C:15]3=4)[C:11](=[O:37])[NH:10][C:9]2=[O:38])[CH:5]=[CH:4][N:3]=1.[NH:39]1[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:29][C:26]1[CH:27]=[CH:28][C:15]2[CH:14]([C:12]3[C:11](=[O:37])[NH:10][C:9](=[O:38])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:39]5[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]5)[N:7]=4)[CH:13]=3)[C:20]3[N:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:25]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)C=Cc1cc(O)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O

Procedure:
The product from step (ix) was treated with 3-azetidinecarboxylic acid (0.096 g) and N,N-diisopropylethylamine (0.445 ml) in N,N-dimethylformamide (10 ml) at 85° C. for 4 hours. The mixture was partitioned between 1N HCl and ethyl acetate. The aqueous layer was adjusted to pH 6 and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give a solid. Purification was by reverse phase chromatography eluting with 50% methanol in 0.1% aqueous ammonium acetate solution.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH3:17])[C:14]=2[CH:15]=O)=[CH:6][CH:5]=1.C(OP([CH2:26][C:27]([O:29]CC)=[O:28])(OCC)=O)C.Cl>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH3:17])[C:14]=2/[CH:15]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:6][CH:5]=1
Reactant: Cn1ncc(-c2ccc(F)cc2)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
Sodium hydride (60% in oil, 60 mg) was added to a mixture of 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (168 mg), ethyl diethylphosphonoacetate (400 mg) and N,N-dimethylformamide (3 ml) at 0° C. and the mixture was stirred at room temperature for 15 min. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (18 ml) and acetic acid (2 ml). The mixture was stirred for 1 hr. with heating under reflux. The reaction mixture was concentrated and poured into water. 1N Sodium hydroxide was added for neutralization. The precipitated solids were collected by filtration, washed with water, and dried to give (2E)-3-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]acrylic acid (159 mg, 78%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][CH2:22][CH2:21][OH:20])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2nc(Cc3ccc(Cl)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccc2nc(Cc3ccc(Cl)cc3)sc2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.05 g (3.8 mmol) of 2-(4-chlorobenzyl)-6-hydroxy-benzothiazole and 0.67 g (7.6 mmol) of ethylene carbonate are dissolved in 20 ml of dimethylformamide and after the addition of 2.1 g (15.2 mmol) of potassium carbonate the mixture is stirred for 2 hours at 120° C. It is then added to water and extracted with ethyl acetate. After the extracts have been evaporated down the residue is purified by column chromatography on silica gel (eluant: ethyl acetate). Yield: 1.6 g (69% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[O:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OC)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2noc(CCC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-[3-(4-methoxyphenyl)methyl-1,2,4-oxadiazol-5-yl]propionate (2.4 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (10 ml). Sodium hydroxide (3 g) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was concentrated. 2N hydrochloric acid was added to the residue to become acidic, which was extracted with ethyl acetate. The extract was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17](=[S:26])[NH:16][CH:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41]Cl>CC(C)=O>[Cl:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41][S:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:13])[CH3:12])=[CH:15][N:16]=1
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Reactant: Fc1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(F)cc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (170 mg, 0.46 mmol) and K2CO3 (95 mg, 0.69 mmol) in acetone (5 mL) was stirred for 30 min at room temperature. The resulting mixture was charged with 2-chloro-1-(chloromethyl)-4-fluorobenzene (98 mg, 0.55 mmol) and then heated at reflux overnight. The reaction mixture was cooled to room temperature and filtered through a Celite™ pad. The filtrate was evaporated in vacuo to give a crude product, which was purified by flash chromatography to afford the title product (208 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 1H), 7.20 (s, 1H), 7.04 (dd, 1H), 6.86 (td, 1H), 6.74 (m, 2H), 6.64 (d, 1H), 6.45-6.43 (m, 2H), 6.21 (m, 2H), 4.25 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 1.47 (s, 6H); MS (EI) m/z 515 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21]>CS(C)=O>[C:8]([CH:7]1[C:6](=[O:12])[C:5]2[S:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:14][C:4]=2[CH2:3][CH:2]1[CH3:1])([O:10][CH3:11])=[O:9]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccccc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (5.52 g, 30 mmole) and 2-aminothiophenol, 6 (X=H, 3.75 g, 30 mmole), in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4a, (R=H), mp 218-221° C. occurs as light orange crystals; yield: 1.47 g (55.0%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41]S(C)(=O)=O)[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.1 %

Procedure:
A mixture of 1.100 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.939 g of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.56 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a dark oil which was purified by high pressure liquid chromatography using 40% ethyl acetatehexane to give 2.413 g (69% yield) of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1.[Mg].S(=O)(=O)(O)O>CCOCC>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:4]([OH:6])([CH3:5])[CH2:3][CH2:2][OH:1])=[CH:9][CH:10]=1
Reactant: CC(=O)CCO
Reactant: Fc1ccc(-c2ccc(Br)cc2)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
0.44 g. of 1-hydroxy-3-butanone in 40 ml. of ether is added dropwise, at 20° stirred Grignard solution obtained from 2.69 g. of 4-bromo-2',4'-difluorobiphenyl and 0.24 g. of magnesium in 100 ml. of ether. The mixture is stirred for 2 hours more and the resulting alcoholate is decomposed with dilute sulfuric acid. The ether phase is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]([F:66])([F:65])[O:55][C:56]1[CH:64]=[CH:63][CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59]>C1COCC1>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:58](=[O:59])[C:57]4[CH:61]=[CH:62][CH:63]=[CH:64][C:56]=4[O:55][C:54]([F:53])([F:65])[F:66])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4OC(F)(F)F)nc3cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.3 %

Procedure:
To a solution of D5 (849 mg), TBTU (987 mg; 3.07 mmol) and DIPEA (1 ml) in THF (25 ml) is added drop-wise a solution of 2-trifluoromethoxy-benzoic acid (737 mg; 3.58 mmol) in THF (5 ml) at 0° C. over a period of 15 min. The reaction mixture is warmed to RT and stirred for 20 h. After completion of the reaction the solution is filtered over Alox B and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with cyclohexane/EtOAc yield the desired compound (736 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f58) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][O:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:16]
Reactant: CCC(C)CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
20 g of 4-hydroxy-4'-biphenylcarboxylic acid, 53 g of (-)2-methylbutanol, and 4 g of conc. sulfuric acid were refluxed for 20 minutes, admixed with 500 ml of benzene, and heated in a container provided with a Dean-Stark reflux condenser. Generated water was removed. After the reaction mother liquor was cooled and washed with water, the solvent was distilled off to obtain crude 4-hydroxy-4'-biphenylcarboxylic acid 2-methylbutyl ester. The product was recrystallized from benzene-heptane mixed solvent to obtain a purified product having a melting point of 115° to 116° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:10](=[O:19])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]3[CH3:1])=[CH:13][CH:14]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-methyl-3-(4-hydroxyphenyl)-4 (3H)quinazolinone synthesized according to Example 1-(1) and -(2) (1.0 g, 3.96 mmol), N-(t-butoxycarbonyl)-4-piperidinol (956 mg, 4.75 mmol) and triphenylphosphine (1.56 g, 5.94 mmol) were dissolved in dry tetrahydrofuran (2 mL) in a current of nitrogen, and cooled on an ice bath. Diethylazodicarboxylate (1.17 mL, 5.94 mmol) was dripped in at 0° C., and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, ether was added, the solid precipitate was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3), and the target substance (1.1 g, 64%) was obtained as a light brown solid.