Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]([C:10](=O)[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-].C([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[C@H:28]([CH2:37][CH2:38][N:39]2[C:43]([CH2:44][OH:45])=[CH:42][N:41]=[CH:40]2)[CH2:27]1)(=O)C>>[CH2:34]([O:33][C:31]([N:29]1[CH2:30][C@@H:26]([S:25][C:10]2[C@H:11]([CH3:12])[C@H:13]3[N:14]([C:15](=[O:20])[C@@H:16]3[C@H:17]([OH:19])[CH3:18])[C:3]=2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH2:27][C@H:28]1[CH2:37][CH2:38][N:39]1[C:43]([CH2:44][OH:45])=[CH:42][N:41]=[CH:40]1)=[O:32])[CH:35]=[CH2:36]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cncc1CO
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cncc3CO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 59.6 %

Procedure:
Allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (709 mg) and (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(5-hydroxymethylimidazol-1-yl) ethyl]pyrrolidine (849 mg) were reacted in substantially the same manner as that of Example 2-3) to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(5-hydroxymethylimidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (802 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[Cl:29].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:18]=[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[Cl:29])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)cc2Cl)c1NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)cc3Cl)n(CCCCO)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A suspension of methyl 4-chloro-3-{[(2-chloro-4-methoxyphenyl)carbamothioyl]amino}-2-[(4-hydroxybutyl)amino]benzoate (1.57 g, 3.32 mmol), triethylamine (509 μL, 3.65 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (700 mg, 3.65 mmol) in tetrahydrofuran (15 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale brown solid (1.31 g, 2.98 mmol, 90%).
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH2:28][OH:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH2:38][CH:39]=[CH2:40])[C:31](=O)OC(C)(C)C)[S:24]2)[C@H:20]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH:28]=[O:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:31])[CH2:38][CH:39]=[CH2:40])[S:24]2)[C@H:20]1[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
A solution of DMSO (9.2 g, 118 mmol) in dry dichloromethane (70 mL) was treated with (COCl)2 (11.6 g, 92 mmol) at −78° C. for 30 minutes, followed by addition of tert-butyl N-[(3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-5-(hydroxymethyl)-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazol-2-yl]-N-(prop-2-en-1-yl)carbamate (8 g, 15 mmol) in dichloromethane (15 mL) slowly. The resulting solution was stirred for 3 hours at −30° C., then cooled down to −78° C. again before addition of triethylamine (20 g, 180 mmol). After additional 30 minutes at −50° C., the resulting mixture was quenched by water (50 mL), and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layer was dried over sodium sulfate, and concentrated to afford crude 140 as a light yellow syrup, which was dissolved into anhydrous THF (100 mL). The solution was treated with bromo(methyl)magnesium (20 ml, 40 mmol, 2M in THF) at 0° C. overnight. The reaction was then quenched with saturated aqueous NH4Cl solution (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography with 10%-20% ethyl acetate in petroleum ether to afford 143 as a yellow syrup (7 g, 87%, two isomers, the ratio is 1:3.8 determined by 1HNMR). (ES, m/z): [M+H]+ 555.0; 1H NMR (300 MHz, CDCl3): 7.38-7.25 (m, 10H), 6.13-6.11 (m, 1H), 5.82-5.70 (m, 1H), 5.99-4.96 (m, 2H), 4.76-4.56 (m, 2H), 4.54-4.27 (m, 6H), 4.13-3.73 (m, 3H), 1.50 (s, 9H), 1.28-1.20 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[CH2:6]2.[C:15]([O:18][C:19](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][O:18][CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CC(=O)NC2=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(OC)cc21

Procedure:
A mixture of 6-methoxy-4H-isoquinoline-1,3-dione (400 mg, 2.1 mmole), 8 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.7 mL, 15.5 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed, the residue treated with hexane-ethyl acetate, the solid collected by filtration, washed with fresh hexane-ethyl acetate and dried to give a yellow solid, 317 mg, (65%), mp 245-7° C., MS (ESI): m/z 234.1 (M+H).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10])(C)(C)C.Cl[CH2:20]Cl>FC(F)(F)C(O)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]2[O:10][CH2:20][CH2:6][NH:7][CH2:8]2)=[CH:12][CH:13]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of [2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (90 mg) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous potassium carbonate (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in dry tetrahydrofuran (3 mL) and triethylamine (54 μL). Chloroacetyl chloride (31 μL) in dry tetrahydrofuran (1 mL) was added dropwise at 0° C. After 30 minutes the reaction was diluted with ethyl acetate (10 mL) and washed with water/brine (1:1, 3×10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in tert-butanol (5 mL). Potassium tert-butoxide (79 mg) was added and the reaction stirred at 25° C. for 1.5 hour. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and co-evaporated with toluene (2×5 mL). The residue was dissolved in dry toluene (5 mL) under argon and treated with sodium bis(2-methoxyethoxy)aluminium hydride (70% in toluene, 205 μL) dropwise and stirred at 25° C. for 5 hours. The reaction was quenched at 0° C. with 10% aqueous sodium hydroxide (5 mL), and the mixture was extracted with diethyl ether (2×15 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to furnish 60 mg (94%) of the title compound as a colorless oil. LC-MS (m/z) 182 (MH+); tR=1.06, (UV, ELSD) 78%, 98%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:14]3[C:13]([C:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:3]=4)=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1O
Reactant: CN1CCC(O)CC1
Product: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared from N-(3-hydroxy-4-methoxyphenyl) [2-(1H-indazol-6-ylamino) (3-pyridyl)]-carboxamide (Example 36) by a method similar to that described in Example 34 using 4-hydroxy-N-methylpiperidine. MS (ES+): 473 (M+H)+; (ES−): 471 (M−H). Calc'd. for C26H28N6O3−472.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH:23](OCC)[O:24]CC)[C:9](=[O:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClCCl>O1CCOCC1>[CH2:1]([N:8]([CH2:22][CH:23]=[O:24])[C:9](=[O:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(Cc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-Benzyl-N-(2,2-diethoxyethyl)-3-phenethyloxy-propanamide (Example 4a), 0.3 g) was dissolved in anhydrous dioxane (7 mL) and treated with concentrated hydrochloric acid (2 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was poured into dichloromethane (20 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.19 g) as a viscous oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[N:21]=[CH:20][N:19]=[C:18]2[CH:9]1[C:8]2[C:12](=[CH:13][C:5]([C:4]([F:3])([F:15])[F:16])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14]
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(C3C(=O)Nc4cc(C(F)(F)F)ccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.6 %

Procedure:
Sodium hydride (53 mg, 1.33 mmol) was added to a solution of 6-trifluoromethyloxindole (200 mg, 0.995 mmol), (prepared as described for the starting material in Example 49), in dry, degassed DMF and the suspension stirred for 15 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (111 mg, 0.332 mmol), (prepared as described for the starting material in Example 5), in a dry, degassed mixture of DMF (5 ml) and THF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 3 hours. The mixture was allowed to cool, the DMF was removed by evaporation, 1M hydrochloric acid was added until the aqueous phase was pH8 and ethyl acetate was added to dissolve the resulting precipitate. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (50 ml×3). The ethyl acetate fractions were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash column chromatography eluting with methylene chloride/methanol (10/1). The purified product was triturated with boiling ether and collected by filtration to give 6-methoxy-7-(3-morpholinopropoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline (51 mg, 31%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:57]([OH:59])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:71][C:72]1[C:77](O)=[C:76]([F:79])[C:75]([F:80])=[C:74]([F:81])[C:73]=1[F:82].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])[C:57]([O:59][C:77]1[C:76]([F:79])=[C:75]([F:80])[C:74]([F:81])=[C:73]([F:82])[C:72]=1[F:71])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
0.89 g (crude product, about 0.922 mmol) of (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl}-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}-propionic acid (Example 20O) are introduced into 50 ml of dichloromethane. At −25° C., 0.85 g (4.61 mmol) of pentafluorophenol, 0.21 g (1.11 mmol) of EDC and 45 mg (0.37 mmol) of DMAP are added under argon. The mixture slowly warms to RT overnight. The reaction mixture is concentrated in vacuo and briefly dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: O[CH2:2][C:3]1[O:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.[Cl:21]CCl.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[Cl:21][CH2:2][C:3]1[O:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(CO)n2)CC1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2noc(CCl)n2)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
1,1-Dimethylethyl 4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (7.4 g, 26 mmol) was taken into dichloromethane (100 mL) followed by addition of pyridine (5.3 mL, 65 mmol) and the solution was cooled to 0° C. Thionyl chloride (2.3 mL, 31.2 mmol) was added by syringe and the mixture was allowed to warm to room temperature and stirred an additional 12 hours. The mixture was then concentrated in vacuo and the residue partitioned with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed once with 0.1M aqueous hydrochloric acid then saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration, concentration and purification of the residue by silica gel flash chromatography using 3:1 hexanes:ethyl acetate provided 1,1-dimethylethyl 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (4.82 g, 61% yield) as a slightly yellow crystalline solid. 1H-NMR (400 MHz, CDCl3): 4.53 (s, 2H), 3.51 (tr, 4H), 3.43 (tr, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CO)cc1OCc1ccccc1

Procedure:
A solution of 0.35 mol of the compound obtained in Step 1 in 400 ml of methanol and 1.5 equivalents of sodium borohydride is stirred for 6 hours at ambient temperature and then 500 ml of acidified water are slowly added. The precipitate obtained is taken up in ether; the organic phase is subsequently extracted, dried, filtered and then evaporated off under reduced pressure, allowing the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[C:13]1([CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCCC(N)c1ccccc1
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCCC(NC(=O)c1ccc(OC)c(C)c1)c1ccccc1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-phenyl-butylamine. MS (M+H, 298.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:19]=1
Reactant: COc1cccc(C)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1cccc(C)c1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
2-(2-Methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g, 5.74 mmol) was suspended in benzene after which was added N,N-dimethylaniline (1.1 mL, 8.62 mmol) and POCl3 (1.61 mL, 17.27 mmol). The reaction mixture was refluxed for 3 hours during which the color changed from yellow to dark red. The reaction mixture was cooled to room temperature, diluted with 40 mL toluene and poured onto ice. Saturated aq. NaHCO3 was carefully added until the pH remained constant at 7 and no more gas formed. The layers were separated, and the water layer was extracted with toluene. The organic layers were combined and washed with respectively 50 mL saturated aq. NaCl, 60 mL 0.5 N HCl, 40 mL 5% NaHCO3 and 50 mL saturated aq. NaCl. The solution was dried over Na2SO4 and evaporated to dryness to yield 1.7 g of the impure product. The product was filtered through silica gel and washed with CH2Cl2:heptane (2:1) to yield of 4-chloro-2-(2-methoxy-6-methyl-phenyl)-7-methyl-quinazoline (1.22 g, 71%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:27][NH2+:28][CH3:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:28]([CH3:29])[CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: C[NH2+]C
Agent: [Cl-]
Product: CN(C)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and dimethylammonium chloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.C(O)=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([C@H:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=CO
Product: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A 100 mL flask was charged with ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-oxoacetate (2.4 g, 5.5 mmol, 1.0 equiv) and sealed with a rubber septum. The flask was purged with argon and to this was charged ACN (11 mL) and NEt3 (1.9 mL, 13.6 mmol, 2.5 equiv) and stirring was initiated. The solution was cooled to 0° C. and then HCO2H (0.63 mL, 16.7 mmol, 3.0 equiv) was added to the solution at a rate to maintain an internal temperature not more than 20° C. Upon completion of the addition, the solution was allowed to cool back to 0° C. Argon was then bubbled through the solution using a porous gas dispersion unit. To the stirring solution at 0° C. was charged the prepared catalyst solution (0.5 mL, 0.05 equiv) from the catalyst preparation above. The solution was stirred at 0° C. with the bubbling of argon through the solution until TLC indicated complete consumption of starting material (10-18 h). The reaction was quenched with H2O then diluted with EtOAc and allowed to warm to room temperature. The layers were separated and the organic extract was washed once more with H2O. The organic extract was then dried over Na2SO4, filtered through a small pad of silica gel eluting with EtOAc, and concentrated in vacuo. The resulting crude residue was chromatographed using a 80 g RediSep normal phase silica gel cartridge (EtOAc/Hex, 5%→20%) on a CombiFlash system to give the desired product. TLC (20% EtOAc/Hex) Rf=0.27; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.53-7.43 (m, 2H), 7.37 (m, 2H), 5.23 (d, J=2.2 Hz, 1H), 4.19 (m, 2H), 3.29 (d, J=2.2 Hz, 1H), 2.48 (d, J=0.5 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:22])[CH3:21])[CH3:12])=[CH:10][CH:9]=1
Reactant: CC(N)CCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCc1ccc(O)cc1

Procedure:
4-(3-Aminobutyl)phenol (510 mg, 3.087 mmol) and triethylamine (1.3 ml, 9.26 mmol) were dissolved in 30 ml of ethyl acetate. At 0° C., acetic anhydride (029 ml, 3.087 mmol) was added. The cooling bath was removed after 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 472 mg (74%) of N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide, M+H+: 208.14 and 54 mg (7%) of 4-(3-acetylaminobutyl)phenyl acetate, M+H+: 250.13.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.[Cl:25]CCl>>[C:1]([S:18][C:12]1[CH:17]=[CH:16][C:15]([Cl:25])=[CH:14][CH:13]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Sc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 96 %

Procedure:
A solution of cinnamoyl chloride (26.0 g, 156.3 mmol) in dichloromethane (100 mL) was added to a solution of thiophenol (22.6 g, 156.3 mmol) and pyridine (12.6 mL) in dichloromethane (200 mL) in an ice-water bath. After 18 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 mL, 1N), brine (100 mL), dried (MgSO4) and was concentrated to afford 41.0 g (96%) of the desired thioester as a crystalline solid.