Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5].[OH-].[Na+].C1COCC1.Cl>CO>[CH3:33][C:2]([CH3:1])([CH3:34])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)CC(=O)O)cc1)CO2
Yield: 76.4 %

Procedure:
Ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate (150 mg, 0.32 mmol) obtained in Example 182, 1 N aqueous sodium hydroxide solution (2 mL) and THF (3 mL)-methanol (3 mL) were stirred at room temperature for 16 hours. To the reaction solution was added hydrochloric acid to make the solution acidic, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 107 mg (yield: 74%) of the title compound. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH:30]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])([CH3:32])[CH3:31]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C(C)C)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (5.94 g, 20 mmol) and powdered anhydrous potassium carbonate (3.31 g, 24 mmol) in DMF (40 mL), was added 2-iodopropane (2 mL, 20 mmol). The mixture was then stirred in an oil bath (50-60° C.) overnight and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 700 mg (10%) of 3-(3,5-diisopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (77) as a white solid. m.p. 278-280° C.; 1H-NMR (200 MHz, CDCl3) δ 1.11 (3H, d, J=7.0 Hz), 1.20 (3H, d, J=7.0 Hz), 1.37 (3H, d, J=6.6 Hz), 1.47 (3H, d, J=6.6 Hz), 2.19 (1H, m), 2.54 (3H, s), 3.55 (1H, m), 7.81 (1H, s), 7.98 (1H, s), 8.07 (1H, s), 9.09 (1H, s); m/z (EI) 339 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]=1[CH:16]=[CH2:17])=[O:4].BrBr.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[O:15][CH:17]=[CH:16][C:6]=12)=[O:4]
Reactant: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c2ccccc2nc2occc12
Yield: 43.2 %

Procedure:
To a solution of 2.6 g (11.2 mmol) Methyl-2-oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylate 5 in 200 mL chloroform was added slowly over a dropping funnel a solution of 2.16 g (13.5 mmol) bromine in 15 mL chloroform and subsequently 6.8 mL of triethylamine. The reaction mixture was heated at reflux for 4.5 hour. After evaporation of the solvent the residue was purified by column chromatography on silica gel, eluting with toluene/ethyl acetate/methanol 4:1:1, to give 1.1 g of the desired product 6.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:15]I>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cn(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
3-Acetyl-1H-indole (4.00 g, 0.025 mol) was dissolved in dry THF (100 ml), and treated with 80% sodium hydride (0.794 g, 0.0263 mol) with stirring under At. After 0.5 h, methyl iodide (2.36 ml, 0.038 mol) was added. After 20 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was then dried (Na2SO4), and evaporated under reduced pressure to give the title compound as a pale brown oil which crystallised on standing (4.20 g, 97%).
Reaction SMILES: [N:1]([Sn](CCCC)(CCCC)CCCC)=[N+:2]=[N-:3].[F:17][C:18]([F:52])([F:51])[C:19]1[CH:20]=[C:21]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:22][N:23]([C:42]#[N:43])[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:21]([CH:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:46]=1)[CH2:22][N:23]([C:42]1[NH:3][N:2]=[N:1][N:43]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Add azidotributyltin (0.19 mL, 0.68 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (180 mg, 0.34 mmol) in toluene (3.6 mL). Stir the mixture at 80° C. overnight. Cool down the mixture to room temperature; add ethyl acetate and 1N HCl (8.2 mL) and stir at room temperature for 1 h. Separate the layers, wash the organic phase with saturated KF, then with brine, dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with dichloromethane/methanol, and then by reverse phase purification to provide 198 mg (quantitative) of the title compound. MS (ES−): 575 (M−H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-benzyloxyindole-2-carboxylic acid ethyl ester in 600 ml of tetrahydrofuran and 200 ml of methanol is combined with 500 ml of 2N sodium hydroxide solution and stirred for 3 hours at room temperature. The reaction mixture is then acidified under ice cooling with 10% hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried, treated with active carbon, and concentrated. The residue is recrystallized from toluene, thus producing 35 g of 7-benzyloxyindole-2-carboxylic acid, mp 166°-168° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([O-])(O)=O.[Na+].[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:23]([C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([CH2:13][C:4]3[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:11][C:10]([CH3:12])=[C:9]4[C:5]=3[CH:6]=[CH:7][NH:8]4)=[N:15][C:16]=2[CH:22]=1)#[N:24]
Reactant: CC(=O)Cl
Reactant: Cc1cc(CN)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-((5-(aminomethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.063 mmol) in CH2Cl2 (1 mL)/5% aq. NaHCO3 (2 mL) was added acetyl chloride (45 μL, 0.634 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction was quenched by methylamine in EtOH (33%, 2 mL), and then stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with H2O and brine, dried over Na2SO4, and filtered. After concentration the residue was purified by silica gel flash column chromatography (CH2Cl2/2M NH3 in MeOH=94/6) to give the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.16 (br. s., 1H), 8.47 (t, J=5.31 Hz, 1H), 8.10 (s, 1H), 7.69 (d, J=8.30 Hz, 1H), 7.65 (dd, J=1.00, 8.30 Hz, 1H), 7.30 (dd, J=2.80, 3.00 Hz, 1H), 6.91 (s, 1H), 6.49 (dd, J=1.80, 3.00 Hz, 1H), 4.64 (s, 2H), 4.42 (d, J=5.31 Hz, 2H), 2.45 (s, 3H), 1.79 (s, 3H). HRMS calcd. for C21H19N5O (M+H)+ 358.1662. found 358.1660.
Reaction SMILES: [S:1]1[C:5]([NH:6][CH2:7][CH2:8][CH3:9])=[N:4][N:3]2[CH:10]=[CH:11][N:12]=[C:2]12.[I:13]N1C(=O)CCC1=O>C(#N)C>[I:13][C:10]1[N:3]2[C:2]([S:1][C:5]([NH:6][CH2:7][CH2:8][CH3:9])=[N:4]2)=[N:12][CH:11]=1
Reactant: CCCNc1nn2ccnc2s1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCCNc1nn2c(I)cnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.6 %

Procedure:
663 mg of imidazo[2,1-b][1,3,4]thiadiazol-2-yl-propyl-amine were dissolved in 20 ml of acetonitrile. 822 mg of N-iodosuccinimide were added to the solution. The reaction mixture was stirred for 4 h at room temperature. For work-up, the mixture was cooled on ice and filtrated. 410 mg of the desired product were obtained.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[CH3:25][C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:27])[F:28])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH2:2][O:26]1
Reactant: CC(=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Trimethylsulfoxonium iodide (2.5 g, 11.6 mmol) was gradually added to a suspension of sodium hydride (484 mg, 12.1 mmol) in dimethylsulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-{4-(4-trifluoromethylphenyl)piperazin-1-yl}propan-2-one (3.4 g, 11.9 mmol) in dimethylsulfoxide (20 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resultant filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 1-(2-methyl-2-oxiranylmethyl)-4-(4-trifluoromethylphenyl)piperazine (3.2 g, yield 98%)as a light yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:2].O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([C:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: OCCCN1CCCC1
Reactant: CCC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Product: CCC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-ethyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-3 and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]2[CH2:30][C:29](C(O)=O)([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.CS(C)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2)[CH2:26][C@H:27]1[CH2:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28]1
Reactant: O=C(O)C1(C(=O)O)CC(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)[C@H]1C[C@H](Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
3-((3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-cyclobutane-1,1-dicarboxylic acid (0.360 g, 0.716 mmol) was treated with 4 mL DMSO, fitted with a water cooled reflux condenser, and heated to 160° C. After 4 h, the reaction mixture was cooled to rt. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water once, satd NaCl once and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a light yellow solid, as an approximately 2:1 mixture of isomers. Separation by SFC (Gradient with Chiralpak IC (21×250 mm, 5 micron), pure methanol with CO2 70 mL/min) gave (trans)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzyl)cyclobutanecarboxylic acid as a white solid. MS (ESI) m/z: calculated: 458.2; Observed: 459.1 (M++1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][F:14])[CH:12]=1)[CH2:8][OH:9])=[N+:2]=[N-:3].[C:15](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1)[C:16]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=1.CN(C=O)C>N1C=CC=CC=1>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([C:15]([O:9][CH2:8][C:7]2[CH:6]=[C:5]([CH:12]=[C:11]([CH2:13][F:14])[CH:10]=2)[CH2:4][N:1]=[N+:2]=[N-:3])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]2[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=NCc1cc(CO)cc(CF)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(C(OCc2cc(CF)cc(CN=[N+]=[N-])c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
From a reaction system containing 3-Azidomethyl-5-fluoromethylbenzylalcohol (36) (142 mg, 0.73 mmol), the air was evacuated and then Ar was charged therein. To this were added DMTrCl (323 mg, 0.95 mmol), DMF (2.0 mL), and pyridine (2.0 mL), and stirred for 22 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the solvent was removed in vacuo. The residue was subjected to extraction with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=20:1 to 5:1) to isolate
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[CH3:24]>>[CH3:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[NH:13][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Cc1cc(C(F)(F)F)ccc1N
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: Cc1cc(C(F)(F)F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Yield: 21.4 %

Procedure:
The title compound (D32) (330 mg) was prepared according to the experimental procedure described in Description 30 starting from 1-Boc-3-azetidinone (800 mg, 4.67 mmol) and 4-Amino-3-methylbenzotrifluoride (818.4 mg, 4.67 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)/[C:8]([OH:10])=[O:9])[N:6]=1.N12CCN(CC1)CC2.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].O>CC(N(C)C)=O>[CH2:30]([O:29][P:27]([O:9][C:8](=[O:10])/[C:7](/[C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)=[N:11]\[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([O:32][CH2:33][CH3:34])=[S:28])[CH3:31]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Nc1nc(/C(=N/OC2CCCCO2)C(=O)O)cs1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC1CCCCO1)c1csc(N)n1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 30 g (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid (80.5 mmol) and 90 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.80 mmol) in 300 ml dimethylacetamide was added under argon over 45 min 17 ml diethyl chlorothiophosphate (104.9 mmol). Stirring was continued at 0° C. for 1 h. The reaction was followed by HPLC. To the slightly turbid reaction mixture was added dropwise over 50 min 450 ml water. The precipitated product was filtered, washed with water and dissolved in dichloromethane. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure until the product started to crystallize. To the residual solution was added dropwise over 30 min n-hexane. The resulting suspension was cooled to 2° C., stirred for 1 h and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid diethoxythio-phosphoryl ester was obtained as a white solid (28.01 g, yield=82%) and was stored under argon at -20° C. No further purificiation was necessary and the product was used as isolated for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>N1C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:24](=[O:27])[CH2:25][CH3:26])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Solvent: c1ccncc1
Product: CCC(=O)Oc1cc(OC)cc(OC)c1C(=O)C=Cc1ccc(OC)cc1
Yield: 90 %

Procedure:
A solution of 500 mg of 2'-hydroxy-4,4',6'-trimethoxychalcone and 0.15 ml of propionyl chloride in 5 ml of pyridine was stirred at room temperature for 6 hours. After removal of the solvent, the residue was treated with 10 ml of ice-water and 30 ml of chloroform. The mixture was shaken, and the chloroform layer was separated, washed with three 10 ml portions of water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The oily residue was washed with a small amount of hexane, and the resulting solid was crystallized from ethanol/hexane, yielding 530 mg (90% yield) of 2',4,4'-trimethoxy-6'-(propionyloxy)chalcone as pale yellow needles; m.p. 117°-118° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]([C:14](=O)[CH3:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1)#[N:2].[NH2:19][C:20]([NH2:22])=[NH:21].C(O)(=O)C>CCO>[NH2:22][C:20]1[N:21]=[C:10]([OH:11])[C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)=[C:14]([CH3:15])[N:19]=1
Reactant: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Reactant: N=C(N)N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1

Procedure:
A mixture of the crude product from step (i) and guanidine (16 g) in EtOH (350 ml) was heated under reflux for 5 h. The mixture was cooled, neutralised with acetic acid, and the solid filtered and dried, 22.1 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:6]1[CH:7]=[C:8]([S:12][CH3:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: NC(N)=S
Reactant: CSc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: CSc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 44.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylthio)phenyl)ethanone (4.64 g, 17.0 mmol) and thiourea (1.29 g, 17.0 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 120 min. The solution was concentrated and mixed with water (50 mL) and saturated aqueous Na2CO3 (4.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4 (methylthio)phenyl)thiazol-2-amine (1.9 g) as light yellow solids in 45% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 2 H), 6.26 (s, 1 H), 2.47 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28]C)[O:7][C:8]1[C:22]([CH3:23])=[CH:21][C:11]2[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=2[C:9]=1[CH3:24])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>ClCCl>[OH:28][C:27]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:22]([CH3:23])=[CH:21][C:11]3[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=3[C:9]=2[CH3:24])=[CH:5][C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(OC)c(C(C)C)c3)c(C)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(O)c(C(C)C)c3)c(C)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
34 mg (0.09 mmol) of ethyl 2-[6-(3-isopropyl-4-methoxyphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate in 3 ml of dichloromethane are added, at 0° C., to 34 mg (0.26 mmol) of aluminum trichloride and 83 mg (1.3 mmol) of ethanethiol. The mixture is stirred at room temperature for 6 hours, concentrated in vacuo and purified chromatographically (toluene/ethyl acetate). 24 mg (73%) of ethyl 2-[6-(4-hydroxy-3-isopropylphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate are obtained.