Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)(SC2C=CC=CC=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[CH:7][CH:8]=2)[CH2:3]1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1ccc2c(c1)CN(C)C(=O)C2(Sc1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CN(C)C(=O)C2c1cc(Cl)cc(Cl)c1

Procedure:
A solution of 2-methyl-4-(3,5-dichlorophenyl)-4-(phenylsulfanyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolone (1.0 g) and nickel chloride hexahydrate (3.8 g) in methanol-tetrahydrofuran (3:1, 50 ml) was cooled to 0° C. Sodium borohydride (0.66 g) was added in small portions during 30 minutes at a temperature not exceeding 5° C. The slurry was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (200 ml) and aqueous sodium hydroxide (2M, 200 ml). The organic phase was dried and concentrated to dryness leaving crude 2-methyl-4-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydro-3(2H)-isoquino-linone (0.7 g). The crude product was purified by chromatography on silica gel using a mixture of dichloromethane and ethyl acetate (8:2) as eluent. Crystallization from methanol afforded the pure title compound, m.p. 163-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1)=[O:24]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:30][CH:29]=2)[N:32]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1
Yield: 75.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 and step-2 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.300 g, 4.2 mmol) and tert-butyl 2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 1.150 g, 3.8 mmol) in TFA (5-7 mL) and DCM (40 mL). The reaction mass was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.44 (d, J=5.7 Hz, 2H), 7.49 (t, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.04-8.13 (m, 4H), 10.07 (m, 1H), 12.69 (s, 1H); MS (m/z): 453.14 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:24](=[O:26])[NH2:25])[CH:15]2[CH3:27])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>Cl>[CH3:27][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:24]([NH2:25])=[O:26])[C:21]=2[C:22](=[O:23])[N:14]1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCNCC1
Yield: 97.6 %

Procedure:
A solution of tert-butyl-4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-1-carboxylate (2.8 g, 7.5 mmol) in 4M hydrochloric acid in dioxane (18 mL, 75 mmol) was stirred at 50° C. for 2 hours until HPLC analysis revealed the disappearance of the starting material. The solvent was removed under reduce pressure and the product was dissolved in diethyl ether and decanted to obtain the title compound (2 g 95%) as its hydrochloride.
Reaction SMILES: C(N(CC)CC)C.[C:8]([S:27][CH:28]1[NH:31][C:30](=[O:32])[CH2:29]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C=O)C.O.CCOCC>[Si:34]([N:31]1[CH:28]([S:27][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:29][C:30]1=[O:32])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
Triethylamine (1.62 ml, 11.6 mmoles) was added dropwise in 5 min to a cooled (0°) and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-t-butyldimethylsilane (1.68 g, 12.7 mmoles) in DMF (35 ml). The reaction mixture was stirred at room temperature for 18 h, diluted with water (250 ml) and ether (200 ml). The organic phase was washed with water (3×50 ml), dried and concentrated to leave an oil (4.33 g). Crystallization from pentane gave a total of 4.1 g(89%) of the title compound as a white solid, m.p. 113°-4°. δ (ppm, CDCl3): 7.45 (15H, m, aromatics), 4.2 (1H, dd, H-4), 2.63 (1H, dd, J=4, J=16, H-3), 2.13 (1H, dd, J=2, J=16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s, Me). νc=o 1735 cm-1. Anal. calc'd for C28H33NOSSi: C, 73.15; H, 7.24; N, 3.05; S, 6.97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([Br:19])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
1,3,5-Tri-t-butylbenzene (150 g, 0.6 mol) was dissolved in 600 mL of carbon tetrachloride in a three-neck flask painted black to avoid light; The flask was equipped with an overhead stirrer, a thermometer, and an addition funnel under argon. Ferric chloride (3.0 g, 0.018 mol) was added and the solution was cooled to 0° C. A solution of bromine (120 g, 0.75 mol) dissolved in 200 mL of carbon tetrachloride was then added over a 2-hour period. The solution was stirred for an additional 1 hour at 0° C. and quenched with ice water. The layers were separated and the organics washed with 10% sodium hydroxide solution. The solution was then washed with salt brine and dried over magnesium sulfate. The solvent was removed under vacuum and the product was distilled through a 2-ft (60-cm) column under vacuum two times. The fractions boiling at 90°-110° C. at 0.4 mm Hg were combined and recrystallized from heptane to give 100 g of pure 3,5-di-t-butylbromobenzene (60% yield).
Reaction SMILES: [Br:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[O:9]1C2N=CCC(=O)[C:12]=2[CH:11]=[CH:10]1.CO>C(#N)C>[Br:1][N:2]1[C:6]2[O:8][CH:3]=[CH:4][C:5]=2[C:10](=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CC=Nc2occc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CO
Product: O=C1CCN(Br)c2occc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-bromosuccinimide (63.16 g, 354.9 mmol) as a solution in anhydrous acetonitrile (480 mL) to a suspension of 5H-furo[3,2]pyridin-4-one (36.9 g, 273 mmol) in anhydrous acetonitrile (740 mL) at 0° C. over 1 hour. Warm to room temperature, add anhydrous methyl alcohol (1.5 L) and stir at room temperature for 18 hours. Quench with water (20 ml) and saturated sodium bicarbonate (20 mL), concentrate to a volume of 1.3 liters, and pour into water (1.3 L). Collection of the precipitate by filtration and drying (vacuum oven 2 days 40-60° C.) gives the title compound as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=2[N:20]=1)[CH2:11][CH2:12][C:13](=[O:15])[CH3:14])(C)(C)C.CS(O)(=O)=O>C1COCC1>[NH2:7][CH2:8][CH2:9][N:10]([C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=2[N:20]=1)[CH2:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CCN(CCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2o1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CC(=O)CCN(CCN)c1nc2cc(Cl)ccc2o1
Temperature: 5 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
MVK adduct 10 (15.04 kg, 39.38 mol) was charged to a vessel and THF (150.4 L) was added. The resulting slurry was cooled to 5° C. and methane sulfonic acid (7.57 kg, 78.8 mol) was added via a diaphragm pump maintaining an internal temperature below 25° C. The batch was heated to 60° C. and allowed to age overnight. After aging overnight HPLC showed the reaction to be 83% complete, thus a further charge of methane sulfonic acid (3.78 kg, 39.3 mol) was added via a diaphragm pump and heating was continued for a further 2 h. It is important to note that charging 3 equiv. of MSA directly to the reaction mixture led to the product oiling out during the course of the reaction. Initially charging 2 equiv. of MSA allowed a seed bed to form which controlled the crystallization during the remainder of the reaction after the final equivalent of MSA had been added. After 2 h HPLC confirmed complete consumption of the starting material. The batch was cooled to 20° C. then filtered and the cake was washed with THF (20 L). The resultant solid was dried in a vacuum oven (T=60° C.) for 36 h, to give 12 (17.4 kg, 36.7 mol) as a pale tan solid. 2% lost to the liquors. m.p. 126.4° C. 1H NMR (400 MHz, d6-DMSO): δ 7.86 (bs, 3H), 7.44 (d, 1H, J=8.5 Hz), 7.35 (d, 1H, J=1.1 Hz), 7.06 (dd, 1H, J=8.5 Hz, 1.1 Hz), 3.75 (t, 2H, J=5.6 Hz), 3.69 (t, 2H, J=6.9 Hz), 3.15 (m, 2H), 2.93 (t, 2H, J=5.6 Hz), 2.36 (s, 6H), 2.14 (s, 3H). 13C NMR (100.6 MHz, d6-DMSO): δ 207.8, 163.1, 147.7, 144.7, 128.6, 120.6, 115.7, 110.6, 46.7, 44.2, 41.3, 40.1 (identified by dept), 37.4, 30.5. HRMS (ESI): m/z [M++H] calcd for C13H16ClN3O2: 282, 1009. found: 282, 1012.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN([Si](C)(C)C)C(=O)C(F)(F)F.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][S:30]([NH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:32])=[O:31]
Reactant: Nc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(N2CCOCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-4-morpholin-4-ylbenzoic acid (230 mg; 1.04 mmol) in CH2Cl2 (3 mL) was added N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.4 mL; 2.1 mmol) via syringe at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux for 10 minutes, then allowed to cool to room temperature. Methanesulfonyl chloride (1.2 eq.) and triethylamine (1.2 eq.) were added, and the resulting mixture allowed to stir for 2 hours. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (2×10 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo to provide the sulfonamide as a white solid (280 mg; 90%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[C:14]=[S:15]>>[OH:4][CH2:3][CH:2]([NH:1][C:14]([NH:13][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: COc1ccc(C(N)CO)cc1
Product: COc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-methoxyphenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.42 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.1 Hz, 3H), 6.76 (d, J=8.3 Hz, 2H), 6.66 (s, 3H), 6.30 (d, J=8.2 Hz, 3H), 5.19-5.01 (m, 1H), 3.50-3.23 (m, 2H), 3.20 (s, 3H); ESIMS m/z 514 ([M+H]+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([NH:26][C:27](=[O:34])OCC(Cl)(Cl)Cl)[C:17]([CH3:25])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>CCCCCC.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:27]([NH:26][C:16]1[C:17]([CH3:25])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:35])=[O:34]
Reactant: NCCCO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NCCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 65 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 65%. Melting point: 145-146° C. (hexane-ethyl acetate).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][O:33][CH2:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(OC([NH:49][CH2:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=O)=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:49][CH2:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][O:33][CH2:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH3:6])=[O:56]
Reactant: CN(C)C(=O)COC[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)COC[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)c1cccc(CN)c1
Reaction time: 0.17 h

Procedure:
Half of the crude N-((1R)-1-{N-[(1R)-1-(((dimethylcarbamoyl)methoxy)methyl)-2-phenylethyl]-N-methylcarbamoyl}-2-{2-naphthyl}ethyl) -N-methylcarbamic acid tert-butylester (132 mg, 0.23 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (2 ml) and stirred for 10 min. The mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 1 ml 1N hydrochloric acid, diluted with water to a volume of 50 ml and lyophilized. This lyophilized product was dissolved in dichloromethane (5 ml) and diisopropylethyl amine (171 μl) was added. To this mixture was added a solution in dichloromethane (5 ml) of 3-tert-butyloxycarbonylaminomethylbenzoic acid (503 mg, 2.0 mmol) which immediately before had been converted to the symmetrical anhydride by stirring with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (191.6 mg, 1.0 mmol) for 15 min. The reaction mixture was then concentrated to an oil and redissolved in ethyl acetate (25 ml). This mixture was extracted sequentially with 5% aqueous sodium hydrogencarbonate (50 ml), 5% aqueous potassium hydrogen-sulfate (50 ml) and water (50 ml) and the organic phase was dried (sodium sulfate) and concentrated by a stream of nitrogen to dryness. This product was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (4 ml). After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 5 ml 70% acetonitrile/0.1% trifluoroacetic acid and diluted with water to a volume of 50 ml. The crude product of the title compound was then purified by semipreparative HPLC in four runs on a 25 mm×250 mm column packed with 7μ C-18 silica which was preequilibrated with 29% acetonitrile in 0.05M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[NH:23][C:22]=2[CH:30]=1.NC1C=C(Cl)C=CC=1O.BrC(C)(C)C(Br)=O>>[CH3:27][C:25]1([CH3:28])[C:24](=[O:29])[NH:23][C:22]2[CH:30]=[C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)[CH:19]=[CH:20][C:21]=2[O:26]1
Reactant: CC1(C)Oc2ccc(Cl)cc2NC1=O
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Agent: CC(C)(Br)C(=O)Br
Agent: Nc1cc(Cl)ccc1O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C(C)(C)O5)nc23)cn1

Procedure:
8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine is coupled with 6-chloro-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, available by reaction of 2-amino-4-chlorphenol with 2-bromo-2-methyl-propanoyl bromide under basic conditions, using general procedure 2 gave the title compound as a solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[C:31]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>C(Cl)Cl.O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1]([NH:2][NH:3][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[O:27][CH2:28][CH2:29][O:30][C:31]=3[C:22]=2[CH3:21])=[O:33])=[O:4])=[CH:8][CH:9]=1
Reactant: Cc1c(C(=O)Cl)ccc2c1OCCO2
Reactant: COc1ccc(COC(=O)NN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)NNC(=O)c2ccc3c(c2C)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
17.85 g (90.98 mmol) of 4-methoxybenzyl carbazate was dissolved in 50 mL of CH2Cl2 in a 250 mL flask and then cooled in ice water. 21.42 g (155 mmol) of potassium carbonate dissolved in 80 mL of water was added. While the reaction mixture was being stirred in the ice bath, 17.0 g (79.95 mmol) of 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl chloride in 60 mL of CH2Cl2 were slowly added. The reaction mixture was stirred at room temperature overnight and then transferred to a separatory funnel with 200 mL of CH2Cl2 and 200 mL of H2O. After shaking, a floating white precipitate was filtered off, washed with water, dried in a vacuum oven to give 29.1 g of N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)hydrazinecarboxylic acid 4-methoxy-benzyl ester. The CH2Cl2 solution was dried and concentrated to give 5.19 g of a residue consisting of the original acid chloride, 4-methoxybenzyl carbazate, and some product. TLC Rf=0.38 (streak 1:1 ethyl acetate:hexane). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.4-6.7 (m, 6H), 5.139 (s 2H), 4.279 (s 4H), 3.81 (s, 3H), 2.303 (s, 3H).
Reaction SMILES: COC1C=CC(CN2C(C(OCC)=O)=NN=N2)=CC=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[N:31]=[N:30][C:29]([C:32]([O:34]CC)=[O:33])=[N:28]2)=[CH:24][CH:23]=1.S1(CCCC1)(=O)=O.[OH-].[K+:47]>C(O)C.O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[N:31]=[N:30][C:29]([C:32]([O-:34])=[O:33])=[N:28]2)=[CH:37][CH:38]=1.[K+:47]
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Agent: CCOC(=O)c1nnnn1Cc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(Cn2nnc(C(=O)[O-])n2)cc1
Yield: 35.4 %

Procedure:
A mixture of ethyl 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate and ethyl 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylate (11.7 g) (prepared as described below and still containing a little sulpholane) was dissolved in hot ethanol (165 ml) and the solution was treated with a solution of potassium hydroxide (4.5 g) in water (13.5 ml). The mixture was cooled and the white crystalline solid which separated was filtered off to give potassium 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylate (4.3 g), m.p. 271°-273° C. (with decomposition). [The pure salt, obtained as a hemihydrate after recrystallisation from water, had a melting point of 273°-274° C. (with decomposition)].
Reaction SMILES: [OH-].[K+].[I-].[K+].[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19].[CH3:20]Cl>C(O)(C)(C)C>[CH3:5][C:6]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]1=[O:19]
Reactant: CCl
Reactant: CC1CCCC(=Cc2ccccc2)C1=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC1(C)CCCC(=Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
66 g of 85% strength potassium hydroxide solution and 750 ml of tert-butanol were placed in a 1 l 4-necked flask, and the mixture was heated briefly at reflux with stirring. Then 8.3 g of potassium iodide were added, the mixture was cooled to room temperature and 200 g of 2-methyl-6-benzylidene-cyclohexanone were added. 101 g of methyl chloride were passed in at room temperature over 8 hours. The mixture was subsequently stirred at room temperature for 8 hours, and then 450 ml of tert-butanol were distilled off. 500 ml of water were added to the residue, the mixture was stirred thoroughly, and the product which separates out was filtered off with suction. Recrystallization from methanol gave 161 g (75% of theory) of pure product with a melting point of 79°-81° C.,
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[C:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])([CH3:27])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:20]([CH3:27])[CH:21]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1ccccc1C(C)(O)Cn1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(C(C)c2ccccc2OC)n2ccnc2)cc1
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
5.2 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 363 mg of methyl 4-mercaptobenzoate and 334 mg of 1-[2-hydroxy-2-(2-methoxyphenyl)propyl]imidazole, and the resulting mixture was stirred at 0°-5° C. for 2.5 hours. The reaction mixture was then treated and purified by the same method as described in Example 13, to give 482 mg of the title compound as a colorless oily substance.