Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.C(=O)=O.[CH3:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][C:31]([OH:35])([CH:33]=[CH2:34])[CH3:32])[CH3:27])[CH3:22])[CH3:17]>>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:34][CH2:33][C@:31]([CH2:30][CH2:29][CH2:28][C@@H:26]([CH2:25][CH2:24][CH2:23][C@@H:21]([CH2:20][CH2:19][CH2:18][CH:16]([CH3:15])[CH3:17])[CH3:22])[CH3:27])([CH3:32])[O:35][C:6]=2[C:5]=1[CH3:9]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
15.02 g (98.8 mmol) of trimethylhydroquinone and 10.59 g of the strongly acid ion exchanger Amberlyst A15 were placed in a 300 ml autoclave, and 116 g of CO2 were condensed in. Heating to 100° C. resulted in a pressure of 185 bar. 37.80 ml (29.48 g; 99.6 mmol) of isophytol were injected by means of an HPLC pump over the course of 1.5 hours (h) at 108° C. After stirring at 108° C. for a further 30 minutes (min), the autoclave was cooled to room temperature (RT), and the pressure was released. The ion exchanger was removed from the product by centrifuging the mixture. The 48.9 g of isolated pale yellow oil contained 83% tocopherol, which corresponds to an 84% yield of pure α-tocopherol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:13]=1[C:24]#[N:25])[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][CH2:58][C:59]1[C:60]([OH:67])=[N:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:13]=1[C:24]#[N:25])[C:5]([NH:57][CH2:58][C:59]1[C:60]([OH:67])=[N:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65])=[O:6]
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccncn1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccncn4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)benzoic acid (80 mg, 0.23 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (130 mg, 0.34 mmol) and triethylamine (70 mg, 0.69 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 hours. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (42 mmg, 0.28 mmol) was added. The resultant mixture was stirred at room temperature for additional 15 hours. To the reaction mixture, water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL×3). The organic layers were combined and concentrated to give a residue in vacuo. The residue was purified by preparative-HPLC to give 3-Chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide I-8 as a white solid (80 mg, 72%). LRMS (M+H+) m/z: calcd 485.13. found 485. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, d6-DMSO): δ 11.49 (s, 1H), 9.39 (s, 1H), 9.04 (d, J=5.1 Hz, 1H), 8.57-8.56 (m, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 7.83-7.73 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.87 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.CC([O:37]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:37][CH:17]1[CH:30]([C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[OH:31])([CH3:19])([CH3:18])[CH3:14]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: C#CC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C1OC1C(O)c1ccc(F)cc1
Yield: 92 %

Procedure:
The product was prepared by General procedure T using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.78 mL (1.55 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, 54 μL (0.50 mmol) p-fluorobenzaldehyde, 100 μL (0.10 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 21 μL (0.10 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 92% yield (103 mg, 0.46 mmol). threo-diastereomer: Colorless solid. m.p.: 83-85° C.; [α]D20=−14.8 (c=0.23, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.82 (s, 9H), 2.31 (br s, 1H), 2.78 (d, 1H, J=2.1 Hz), 2.95 (dd, 1H, J=5.5, 2.2 Hz), 4.42 (d, 1H, J=5.2 Hz), 6.99 (t, 2H, J=8.6 Hz), and 7.31 (dd, 2H, J=8.3, 5.5 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 30.6, 59.2, 65.1, 73.6, 115.4, 115.6, 127.68, 127.74, 136.2, and 163.5 ppm; IR (neat): 3403, 3002, 2963, 2919, 2872, 1725, 1661, 1637, 1603, 1511, 1461, 1390, 1361, and 1226 cm−1; HRMS-CI m/z 224.1206 [M+; calcd for C13H17FO2: 224.1213]. erythro-diastereomer: Colorless solid. m.p.: 56-59° C.; [α]D20=−34.3 (c=0.40, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.85 (s, 9H), 2.28 (br s, 1H), 2.96 (d, 1H, J=2.1 Hz), 3.01 (t, 1H, J=2.7 Hz), 4.84 (br d, 1H, J=2.8 Hz), 7.04 (t, 2H, J=8.5 Hz), and 7.34 (dd, 2H, J=8.3, 5.5 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.8, 30.4, 58.2, 62.7, 70.5, 115.4, 115.6, 128.08, 128.15, 135.6, and 163.6 ppm; IR (KBr): 3409, 3015, 2964, 2871, 1606, 1510, 1463, 1392, 1369, 1331, and 1316 cm−1; HRMS-CI m/z 224.1206 [M+; calcd for C13H17FO2: 224.1213].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:17]([O:16][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[S:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=1)=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[F:13])=[O:15])[CH3:18]
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Sc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
The reaction mixture of 100.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline, 80.3 mg (0.44 mmol) of 3-trifluoromethylthiophenol and 80 μL of diisopropylethylamine in 2.0 mL of N,N-dimethylformamide was stirred at room temperature for 2 h and cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:3) to give 30.0 mg (20%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](OC(C)(C)C)=O)[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:17])[S:51]([CH3:50])(=[O:53])=[O:52])[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)S(C)(=O)=O
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A suspension of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline (148 mg, 0.31 mmol), (prepared as described in Example 149), in methylene chloride (4 ml) containing TFA (1 ml) was stirred for 1 hour. After removing the volatiles under vacuum, the residue was azeotroped with toluene. The residue was dissolved in methylene chloride (3 ml) and triethylamine (215 μl, 1.5 mmol) was added followed by methanesulphonyl chloride (48 μl, 0.62 mmol). After stirring for 1 hour at ambient temperature, the mixture was partitioned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/methanol (99/1 followed by 97/3). After evaporation of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline (54 mg, 38%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[NH:7][C:8]3[C:9]([N:16]=2)=[N:10][C:11]([CH3:15])=[CH:12][C:13]=3[CH3:14])[CH2:5][CH2:4]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][N:19]=1>CS(C)=O.O>[CH:3]1([C:6]2[N:16]([CH2:24][C:21]3[CH:20]=[N:19][C:18]([Br:17])=[CH:23][CH:22]=3)[C:9]3=[N:10][C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: BrCc1ccc(Br)nc1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(Br)nc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
255 mg (6.4 mmol) of sodium hydride and 994 mg (5.3 mmol) of 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine are stirred at 0° C. for 2 h in 15 ml of dimethyl sulphoxide. After adding 2 g (7.97 mmol) of 2-bromo-5-bromomethylpyridine, the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and washed twice with ethyl acetate; the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and then chromatographed on 150 g of silica gel using ethyl acetate/petroleum ether mixtures 1:2→1:0 to yield 1.32 g of the title compound.
Reaction SMILES: CC(C[CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=C.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH3:19][C:18](=[CH:17][CH2:16][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:20]
Reactant: CC(C)=CCBr
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Product: CC(C)=CCCc1cc2ccccc2[nH]1

Procedure:
Refer to 28a) using 4-bromo-2-methyl-2-butene as the alkylating reagent.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:6]1.F[B-](F)(F)F.[CH3:24][S:25][C:26](=[S+]C)[S:27][CH3:28].O1CCOCC1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:24][S:25][C:26]([S:27][CH3:28])=[C:9]1[C:8](=[O:12])[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:6][N:5]([CH2:4][CH2:3][CH:2]([CH3:18])[CH3:1])[C:10]1=[O:11]
Reactant: CC(C)CCN1N=C(c2cccs2)C(=O)CC1=O
Reactant: CSC(SC)=[S+]C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)C(c2cccs2)=NN(CCC(C)C)C1=O
Temperature: 100 °C
Yield: 20 %

Procedure:
2-(3-Methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.215 g, 0.814 mmol) and (bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoro borate salt (prepared as described in WO 2008/011337; 0.79 g, 3.26 mmol) were combined. 1,4-Dioxane (1.06 mL) and pyridine (0.15 mL) were added. The mixture was heated at 100° C. for 1 h while stirring. Upon cooling, the mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL), saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; eluting with 25% ethyl acetate in hexanes). Upon concentrating, 4-(bis-methylsulfanyl-methylene)-2-(3-methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.06 g, 0.163 mmol) was obtained as an orange solid. The solid was combined with 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide (0.07 g, 0.245 mmol). Toluene (5 mL) and 1,4-dioxane (10 mL) were added and the mixture stirred at 100° C. in a sealed vial for 2 h. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes) afford the desired product, N-{3-[5-hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazin-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.018 g, 0.032 mmol, 10%) as a light orange powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.95 (6H, d, J=6.2 Hz), 1.57-1.69 (3H, m), 2.97 (3H, s), 4.13 (2H, t, J=7.1 Hz), 4.27 (2H, d, J=5.5 Hz), 7.13-7.16 (1H, m), 7.31 (1H, s), 7.64-7.69 (2H, m), 7.89 (1H, d, J=4.0 Hz). LC-MS (ESI) calculated for C20H23N5O6S4 557.05. found 558.0 [M+H+].
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1.O.CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([OH:15])[CH2:12][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of (3R,5R)-5-(tert-butyldimethylsilyloxy)piperidin-3-ol (1 eq) in 20 mL of 1,4-dioxane and 8 mL of water was added benzyl chloroformate (1.5 eq). The mixture was stirred at room temperature for 4 hours. The crude mixture was diluted with 100 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (74%). LC/MS (m/z): 366.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2Cc1cccc(OC)c1
Reaction time: 4 h

Procedure:
366.5.0 mg (0.929 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 15 mL DMF. Sequentially 192.6 mg (1.394 mmol) K2CO3 and 156.1 μl (1.394 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 300 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) (separation of isomers) to give 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:14]([SH:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:14]([S:22][S:13][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCCCc1ccc2c(c1)OCO2
Reactant: SCCc1ccccc1
Product: c1ccc(CCSSCCCc2ccc3c(c2)OCO3)cc1
Yield: 17.7 %

Procedure:
1.5 g of the title compound was prepared from 5 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of phenethyl mercaptan as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:25]2[S:29][C:28]([C:30](O)=[O:31])=[CH:27][C:26]=2[CH3:33])=[CH:11][CH:10]=1.[CH3:34][N:35]([CH:37]=O)[CH3:36].C(N(CC)CC)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>ClCCl>[CH3:37][N:35]([CH:34]=[N:22][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=[C:12]([C:25]3[S:29][C:28]([C:30]([N:48]([O:49][CH3:50])[CH3:47])=[O:31])=[CH:27][C:26]=3[CH3:33])[CH:13]=2)=[CH:16][CH:17]=1)(=[O:24])=[O:23])[CH3:36]
Reactant: COc1ccc(-c2sc(C(=O)O)cc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNOC
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc(C(=O)N(C)OC)cc2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
Oxalyl chloride (0.87 g, 0.58 ml, 6.94 mmol) was added drop wise to a solution of 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-4-methylthiophene-2-carboxylic acid (1c, 1.4 g, 3.47 mmol) in dichloromethane (28 ml) and DMF (0.53 ml, 6.94 mmol) at 0° C. The reaction mixture was then allowed to come to room temperature and stirred for 1.5 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure and used directly for further reaction. Residue obtained after concentration was dissolved in dry dichloromethane (20 ml) and to this was added triethylamine (2.1 g, 2.89 ml, 20.8 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (1.34 g, 13.88 mmol) under stirring. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with dichloromethane (100 ml). The mixture obtained was washed with water (2×20 ml), followed by washing with brine (1×20 ml). The separated organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography over silica gel using 80% ethyl acetate in hexane as an eluent to obtain the title compound (1.1 g, 63.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=2)[CH:19]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:19][C:18]=3[CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Reaction time: 3 h

Procedure:
520 mg of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde are added at 20° under nitrogen with stirring to 5 ml of NMP, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added to the solution. The mixture is stirred at 105° for 3 hours and then cooled to 25°. The batch is added to 30 ml of water (10°) with stirring, the aqueous phase is extracted at 10° with 3 times 30 ml of ethyl acetate, and the combined organic phases are washed with 30 ml of saturated NaCl solution and with 30 ml of water and then freed from solvent under reduced pressure (0.6 g of orange oil with crystal components). After chromatography on 30 g of silica gel (MTB ether/heptane 5:1), 0.45 g of pale-yellow crystals can be isolated (70%), m.p. 116-117°; MS 374 (M+), 318 (100%), 244, 232.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2
Reactant: CCOC(=O)c1cc2c(C)ccc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.7 %

Procedure:
To a mixed solution of ethyl 7-amino-4-methyl-1H-indole-2-carboxylate (0.71 g) and pyridine (20 mL) was added 2-thiophenesulfonyl chloride (0.78 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (957 mg, yield 81%) as colorless needle crystals. melting point 180-181° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16](=[O:17])[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.C(N(CC)CC)C.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:25]([OH:28])(=[O:27])[CH3:26].[OH:1][CH2:2][C:3]1[C:16](=[O:17])[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=c1c(CO)cnc2c3ccccc3ccn12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O
Temperature: 25 °C

Procedure:
To 3.0 g of 3-(hydroxymethyl)-4H-pyrimido [2,1-a]isoquinolin-4-one (13.3 mmole) suspended in 100 ml chloroform with 10 ml of triethylamine and a trace of 4-dimethylaminopyridine was added 5.0 g of acetic anhydride (50.0 mmole). The reaction mixture was refluxed for 2 hours, then cooled to room temperature and washed twice with water. The organic layer was dried and concentrated in vacuo to give a crude solid which was crystallized from methylene chloride/hexane to yield 3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one acetate as yellow crystals (2.09 g, 59% yield) of the formula: ##STR22## having a melting point of 173.3° C. and the following elemental analysis: