Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=1)([CH3:11])[CH2:7]C(=O)C.[C:28]([C:32]1[CH:37]=[C:36]([SH:38])[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]=1[OH:43])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:5][C:6]([S:12][C:13]1[CH:14]=[C:15]([C:24]([CH3:27])([CH3:25])[CH3:26])[C:16]([OH:23])=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:18]=1)([CH3:11])[CH2:7][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)([S:38][C:36]1[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([OH:43])=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:37]=1)[CH3:5]
Reactant: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(C)(CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
0.11 Grams of BF3 -etherate is added to a solution of 2.70 grams of the product from (a) and 4.14 grams of 2,6-di-tert- butyl-4-mercaptophenol dissolved in 30 ml of toluene. The mixture is heated at 55°-65° C. for nine hours and 105°-110° C. for three additional hours. The toluene solution is washed with water and dried over sodium sulfate. The residue, isolated by evaporation of the solvent by distillation in vacuum, is purified by passing a solution in 70:30 heptane:toluene through a flash chromatographic column using silica gel. The isolated residue solidifies on cooling, and melts at 93°-115° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cccc2cc[nH]c12
Reaction time: 5 h
Yield: 76 %

Procedure:
To 30 g. (0.186 mole) of 7-acetylindoline in 415 ml. of methylene chloride was added 48.5 g. (0.56 mole) of manganese dioxide and the mixture refluxed through a soxhlet filled with 4A molecular sieves for 22 hours. The mixture was cooled and an additional 48.5 g. of manganese dioxide was added. Fresh molecular sieves were added and the refluxing continued for 5 hours. The same amount of manganese dioxide and molecular sieves were added again and the refluxing was continued for one hour. The mixture was filtered and the filtrate concentrated to dryness. The residue was triturated with hexane and filtered, 22.57 g. (76% yield), m.p. 65°-66° C.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18]/[CH:19]=[CH:20]/[CH3:21]>C(O)C>[C:2]([NH:5][C:6]([CH2:18]/[CH:19]=[CH:20]/[CH3:21])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C/C=C/CBr
Agent: [Na]
Solvent: CCO
Product: C/C=C/CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reaction time: 8 h
Yield: 87.8 %

Procedure:
3.86 g (168 mmol) of sodium metal were dissolved in 106 ml of anhydrous ethanol. 36.35 g (168 mmol) of diethyl acetamidomalonate dissolved in 225 ml of anhydrous ethanol were added and the mixture was heated under reflux for 10 minutes. 22.66 g (168 mmol) of (E)-1-bromo-2-butene were added dropwise at room temperature and the mixture was stirred overnight and then evaporated to dryness under a vacuum. The residue was partitioned between ethyl acetate and 0.1M hydrochloric acid. The organic phase was washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was evaporated to give 40 g of diethyl (E)-2-acetamido-2-(2-butenyl)malonate as a colourless oil; 1H NMR (250 MHz, CDCl3) d: 1.25 (t, 6H), 1.6 (d, 3H), 2.0 (s, 3H), 2.9 (d, 2H), 4.2 (q, 4H), 5.15 (m, 1H) 5.5 (m, 1H), 6.7 s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:20])[C:8](=[O:29])[NH:7][C:6]=1[CH2:30][O:31][CH3:32])=[O:4].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C:8](=[O:29])[NH:7][C:6]=1[CH2:30][O:31][CH3:32])=[O:4]
Reactant: CCOC(=O)CCNC(=O)N1C(=O)NC(COC)=C(C(=O)OC)[C@@H]1c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCC(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
(+)-5-Methoxycarbonyl-4-methyoxymethyl-1,2,3,6-tetrahydro-2-oxo-6(S)-(3,4-difluorophenyl)-1-[(2-ethoxycarbonylethylamino)carbonyl]pyrimidine (168 mg, 0.37 mmol) was dissolved in 5 mL of methanol. A 2.0M solution of aqueous sodium hydroxide (400 mL, 0.80 mmol) was added dropwise. The mixture was stirred at ambient temperature for 4.5 hours, then concentrated in vacuo. The resulting residue was partioned between ethyl acetate and 2.0M aqueous hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were then washed with brine. The organic phase was then dried over sodium sulfate, filtered, and the filtrate was then evaporated to dryness. The residue was reconcentrated from diethyl ether. The resulting white foamy solid was purified by “flash” chromatography (5.02, 98:2:0.2 of dichloromethane:methanol:glacial acetic acid). The product fractions were evaporated to dryness and the residue was reconcentrated from diethyl ether to give the title compound as a white foamy solid.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]1[N:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=[CH:4][CH:5]=1
Reactant: On1nccc1-c1cccs1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1nccc1-c1cccs1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (51%, crystals).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:33])[CH2:31][NH2:32])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][NH:32][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:33])[CH3:28]
Reactant: CCOC(=O)CN
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(NCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 57 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.86 g), glycine ethyl ester hydrochloride (0.65 g) and triethylamine (0.47 g) in dichloromethane (15 ml) yielded the title compound, 0.38 g, m.p. 174.5-176° C. (recrystallized from ethanol:water).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]#[N:40]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]#[N:40])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(O)cc3)c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC#N)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenol (0.260 g, 0.668 mmol) was reacted with K2CO3 (0.111 g, 0.802 mmol) and bromoacetonitrile (0.096 g, 0.802 mmol) in acetone (5 ml) to give the product (0.271 g, 0.633 mmol, 95%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 5.22 (s, 2H), 5.33 (s, 2H), 6.85-6.89 (m, 3H), 7.11-7.14 (m, 3H), 7.17 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.33-7.35 (m, 3H), 7.39-7.47 (m, 5H); [ESI(+)], m/z 429 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.[N+]([NH:13][C:14](N)=[O:15])([O-])=O>>[NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:14]([NH2:13])=[O:15])[CH2:6]1
Reactant: NCCOC1CCNC1
Reactant: NC(=O)N[N+](=O)[O-]
Product: NCCOC1CCN(C(N)=O)C1

Procedure:
Generally speaking, the reaction of a 3-aminoethoxypyrrolidine II with nitrourea to give a 3-aminoethoxypyrrolidine-1-carboxamide I is run in a lower alkanol solvent, e.g., ethanol, usually at or below reflux temperature for a period of time of from about 4 hours to about 18 hours. The reaction of a 3-aminoethoxypyrrolidine II with an isocyanate to give an N-substituted-3-aminoethoxypyrrolidine-1-carboxamide I is run in a dry aprotic solvent such as benzene at room temperature for a period of time up to about 18 hours. The reaction of a 3-aminoethoxypyrrolidine II with a compound having an active halide radical is generally run in a solvent such as dimethylformamide or a lower alkanol at a temperature of from about 70°-90° C. in the presence of an inorganic acid acceptor such as sodium carbonate for a period of from about 8 to 18 hours. The products of Formula I are isolated by methods known to the art such as concentration of the reaction mixture under reduced pressure followed by crystallization of the product from a suitable solvent, distillation of the product in vacuo, or acid base extraction of the reaction mixture.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:36])=[CH:30]5)=[N:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:26][C:20]1[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:17][CH:18]=3)[N:23]=[CH:22][N:21]=1)=[CH:35][CH:34]=2
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCN(C(=O)OC(C)(C)C)CC5)ccc34)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A suspension of 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.31 mmol), (prepared as described in Example 90), in methylene chloride (2 ml) and TFA (1.5 ml) was stirred for 1 hour at ambient temperature. After removal of the volatiles under vacuum the residue was azeotroped with toluene. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH11. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (80 mg, 67%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>ClCCl>[N:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:12][CH:13]=1
Reactant: Cc1ccncc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
30.2 g of benzoyl chloride dissolved in 30 cc of dichloromethane was added dropwise over 1 hour to 10 g of 4-methylpyridine dissolved in 60 cc dichloromethane and maintained at 10° C. during the addition. The reaction was brought to room temperature and stirred 16 hours. The reaction was brought to reflux for 1 hour, then cooled and quenched into saturated sodium carbonate solution. The organic layer was separated, solvent removed under reduced pressure and alcohol added. The mixture was refluxed 16 hours, then the solvent removed under reduced pressure. The residue was taken up in dichloromethane and washed two times with 3N HCl. The organic layer was separated and the aqueous acid layer first neutralized, then saturated with sodium carbonate. Dichloromethane extraction of the product, solvent removal and azeotropic removal of excess unreacted 4-methylpyridine using toluene gave 4.85 g of desired product.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].[C:24](OC(=O)C)(=[O:26])[CH3:25].S(=O)(=O)(O)O>>[C:24]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(N)s2)ccn1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(NC(C)=O)s2)ccn1
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a stirred solution of N-{4-[5-amino-4-(2-chlorophenyl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.020 g, 0.058 mmol) in anhydrous acetic anhydride (1.00 mL, 10.60 mmol) was added dropwise concentrated sulfuric acid (0.002 mL, 0.030 mmol) and stirred for 18 h. The reaction was quenched by the dropwise addition of a triethylamine (0.200 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexanes) to provide 0.014 g of product as a yellow oil (62%). LC/MS (AA) ES+ 387, 389. 1H NMR (400 MHz, d1 CDCl3) δ: 9.10 (br s, 1H), 8.63 (br s, 1H), 8.31-8.30 (m, 0.5H), 7.64-7.24 (m, 6.5H), 2.18 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:28][C:27]1[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and p-fluoroaniline (0.39 g), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(4-fluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride (0.15 g) as in Reference Example 9 to give ethyl 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylate (0.64 g), as white crystals (recrystallized from ethanol), m.p. 256°-259° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=1.C1C=C[C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.C(Cl)CCl.C1(N)CC1>ClCCl>[CH:20]1([NH:22][C:13]([C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[O:12][N:11]=2)=[O:15])[CH2:21][CH2:19]1
Reactant: O=C(O)c1cc(-c2ccccc2O)on1
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a 20 mL flask was added the crude acid from step 3 (20 mg, 0.1 mmol), HOBt (16 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol). To this was added dichloromethane (3 mL) and the resulting heterogeneous mixture was stirred for 30 minutes at room temperature. To the resulting solution was added cyclopropylamine (9.0 mg, 0.15 mmol) and the reaction was monitored by HPLC for product formation. After 2 hours, the reaction was complete and concentrated to a thick oil. This oil was partitioned between EtOAc (3 mL) and water (2 mL) with stiffing for 10 minutes. The layers were then allowed to separate and the aqueous layer was discarded. The organic layer was then washed with water (2 mL), brine (2 ml) and dried over Na2SO4. Concentration gave an oil that was purified by column chromatography (30% EtOAc in hexanes) to give 6.1 mg (25% yield) of the desired isoxazole 6; 1H NMR (400 MHz, d6-DMSO) S 8.85 (d, 1H), 7.78 (d, 1H), 7.32 (t, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 6.94 (t, 1H), 2.82 (m, 1H), 0.67 (m, 2H), 0.59 (m, 2H). LC/MS (electrospray ionization, positive mode) M+H=245.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[C:28]6[C:33](=[CH:32][CH:31]=5)[N:25]([CH3:24])[CH2:26][CH2:27]6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc5c(c4)CCN5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 1-methylindoline-5-boronic acid pinacol ester (Maybridge, Basel, Switzerland, 34 mg, 0.127 mmol) to give the title compound as a yellow solid. (HPLC: tR 2.52 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.87 (s, 1H), 8.16 (s, 1H), 8.00-7.97 (m, 1H), 7.83-7.81 (m, 1H), 7.41-7.40 (m, 1H), 7.20-7.17 (m, 1H), 7.14-7.13 (m, 1H), 6.57-6.55 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 3.33-3.29 (m, 2H), 2.92 (t, 2H), 2.73 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([S:25]([CH3:27])=[O:26])[CH:19]=1)[OH:17].C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([S:25]([CH3:27])=[O:26])[CH:19]=1)[OH:17])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)c1cc(C(O)CN)ccc1O
Reactant: CC(=O)CCOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCOCc1ccccc1)NCC(O)c1ccc(O)c(S(C)=O)c1
Reaction time: 16 h

Procedure:
Combine 4-benzyloxy-2-butanone (1.78 g, 10 mmol) with 2-amino-1-(4-hydroxy-3-methylsulfinylphenyl)ethanol (10 mmol) in methanol (50 ml) and add sodium cyanoborohydride (0.63 g, 10 mmol). Let stand 16 hours, concentrate the solution and purify the crude product by chromatography on silica gel using chloroform: methanol: ammonium hydroxide (70:27:3) as eluent to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH3:8].C([Li])CCC.CN([CH:17]=[O:18])C.Cl>C1COCC1.O>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:17]=[O:18])[CH3:8]
Reactant: CCc1ccsc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccsc1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of 3-ethyl-thiophene (12.14 g, 54.4 mmol) in acetonitrile (60 mL) is cooled to 10° C. before a solution of N-bromo-succinimide (9.31 g, 52.3 mmol) in acetonitrile (90 mL) is added dropwise. The reaction is slightly exothermic. The mixture is stirred and warmed to rt. Another portion of N-bromo-succinimide (2.0 g, 11.2 mmol) dissolved in acetonitrile (40 mL) is added dropwise. Stirring is continued for 2 h before a third portion of N-bromo-succinimide (0.5 g, 2.81 mmol) dissolved in acetonitrile (10 mL) is added. After additional 1 and 2 h, a further portion of N-bromo-succinimide (0.75 g, 4.21 mmol, and 500 mg, 2.81 mmol, respectively) is added. Stirring is continued for another hour before the solvent is evaporated. The residue is dissolved in DCM, washed twice with 2 M aq. NaOH followed by brine, dried over MgSO4, filtered and concentrated. The crude product is purified by distillation at 180° C./50 mbar to give 2-bromo-3-ethyl-thiophene (11.0 g) as a colourless liquid; LC-MS*: tR=0.92 min. 1H NMR (CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.62 (q, J=7.8 Hz, 2H), 6.85 (d, J=5.5 Hz, 1H), 7.22 (d, J=5.8 Hz, 1H) b) A solution of 2-bromo-3-ethyl-thiophene (1.00 g, 5.23 mmol) in THF (25 mL) is cooled to −75° C. before n-butyl lithium (3.6 mL of a 1.6 M solution in THF) is added. The mixture is stirred at −75° C. for 1 h. DMF (765 mg, 10.5 mmol) is added and stirring is continued at −75° C. for 2 h. The mixture is warmed to 10° C., treated with 1 N aq. HCl (5 mL), diluted with water and extracted with EA (3×50 mL). The organic extracts are washed with water (30 mL) followed by brine (30 mL), combined, dried over MgSO4, filtered and concentrated to give crude 3-ethyl-thiophene-2-carbaldehyde (650 mg) as a yellow oil; LC-MS*: tR=0.78 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.5 Hz, 3H), 3.03 (q, J=7.5 Hz, 2H), 7.06 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 10.08 (s, 1H). c) The title compound is prepared in analogy to the procedures described in the literature (G. Constantino et al., II Farmaco 59 (2004), 93-99; A. J. Carpenter et al., Tetrahedron 41 (1985) 3803-3812) starting from the above 3-ethyl-thiophene-2-carbaldehyde; LC-MS*: tR=0.15 min, [M−1]−=183.16; 1H NMR (D6-DMSO): δ1.24 (t, J=7.5 Hz, 3H), 3.00 (q, J=7.5 Hz, 2H), 7.72 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][O:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:13]([O:28][CH:29]2[O:38][CH:37]3[CH:32]([O:33][CH:34]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:35][CH2:36]3)[CH:31]([OH:45])[CH:30]2[OH:46])[CH:12]([OH:47])[CH:11]1[OH:48])(=[O:3])[CH3:2].[K+].[Br-]>O>[C:14]([O:47][CH:12]1[CH:11]([O:48][C:18](=[O:17])[CH3:19])[CH:10]([O:9][CH2:8][C:7]2[CH:49]=[CH:50][C:51]([Cl:52])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[O:15][CH:14]([CH2:16][O:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:13]1[O:28][CH:29]1[O:38][CH:37]2[CH:32]([O:33][CH:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:35][CH2:36]2)[CH:31]([O:45][C:8](=[O:9])[CH3:7])[CH:30]1[O:46][C:1](=[O:3])[CH3:2])(=[O:15])[CH3:13]
Reactant: COc1ccc(C(=O)OCC2OC(OCc3ccc(Cl)c(NC(C)=O)c3)C(O)C(O)C2OC2OC3COC(c4ccccc4)OC3C(O)C2O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C(=O)OCC2OC(OCc3ccc(Cl)c(NC(C)=O)c3)C(OC(C)=O)C(OC(C)=O)C2OC2OC3COC(c4ccccc4)OC3C(OC(C)=O)C2OC(C)=O)cc1

Procedure:
The title compound was prepared as a white foam (0.142 g, 81%) from 4-methoxy-benzoic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl ester using a procedure similar to Example 25, mp >110° C. (decomp.); 1H NMR (DMSO-d6) δ1.94 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 1.99 (s, 3H), 2.06 (s, 3H), 3.61 (t, J=9.7 Hz, 1H), 3.68-3.75 (m, 1H), 3.80 (dd, J=4.6, 9.4 Hz, 1H), 3.82 (s, 3H), 3.82-3.89 (m, 1H), 4.11-4.16 (m, 1H), 4.17 (q, 9.7 Hz, 1H), 4.40 (dd, J=3.3, 12.3 Hz, 1H), 4.63 (ABq, J=12.7 Hz, Δδ=0.15, 2H), 4.64 (d, J=10.8 Hz, 1H), 4.77 (dd, J=7.9, 9.4 Hz, 1H), 4.86-4.91 (m, 2H), 5.26 (t, J=9.9 Hz, 1H), 5.32-5.38 (m, 2H), 5.54 (s, 1H), 7.06 (dt, J=2.9, 9.7 Hz, 3H), 7.29-7.37 (m, 5H), 7.42 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.99 (dt, J=2.9, 9.9 Hz, 2H), 9.4 (s, 1H); IR (KBr) 3400, 2950, 2840, 1755, 1700, 1600, 1580, 1535, 1515, 1450, 1420, 1375, 1240, 1165, 1110, 1070, 1055, and 1030 cm−1; mass spectrum [(+) FAB], m/z 914/916 (M+H)+, 936/938 (M+Na)+; Anal. Calcd. for C44H48ClNO18.1.0 H2O: C, 56.68; H, 5.41; N, 1.50, Found: C, 56.37; H, 5.08; N, 1.48.