Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a solution of 2.78 g (7.2 mmol) of 4-((S)-2-benzoyloxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 80 ml of CH2Cl2 was added 5.83 ml of TFA (90% in water) drop by drop. After 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography [CH2Cl2 (sat. with NH3) and MeOH 1:0 to 9:1] to give 1.96 g (95%) of the title compound as yellow oil. MS: 289.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3[N:50]([CH2:65][CH2:66][N:67]([CH:69](C)C)[CH3:68])[CH:51]=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][N:50]([CH2:65][CH2:66][N:67]([CH3:69])[CH3:68])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CN(C)CCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.Cl[Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]1[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:18]1([CH3:26])[CH3:25]
Reactant: NCc1cccc(Br)c1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si]1(C)CC[Si](C)(C)N1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The conversion of Polymer 1 into Polymer 2 was preceded by the preparation of 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine. 3-Bromobenzylamine hydrochloride (25.0 g, 112.3 mmol) was converted to the free base by neutralization with sodium hydroxide and extraction into methylene chloride. Drying and solvent removal resulted in 20.3 g of a brown liquid which was used as such. To the above 3-bromobenzylamine (20.3 g, 109 mmol), in a round bottom flask equipped with a condenser and under argon atmosphere, was added 150 mL of methylene chloride and 30.3 mL (217 mmol) of triethylamine. To this stirred mixture cooled with an ice bath was added slowly 109 mL (109 mmol) of 1 M 1,2-bis(chlorodimethylsilyl)ethane dissolved in methylene chloride. During the addition, considerable precipitate formed. The ice-bath was removed and the mixture was stirred for another 6.5 h at room temperature. The white solid was removed by filtration and washed with methylene chloride (2×30 mL). The filtrate was evaporated using a rotary evaporator resulting in further precipitate formation. Hexanes (100 mL) were added to this mixture. The solid was removed by filtration and washed with hexanes (2×20 mL). After hexane removal from the filtrate, a yellowish liquid was obtained which was distilled to yield 29.0 g (82% yield) of light yellowish liquid (bp. 93-5° C./0.05 mm Hg).
Reaction SMILES: C[C:2]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[C:23](C)[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:22].Br[C:38]1[CH:43]=[CH:42][N:41]([CH:44]2[CH2:46][CH2:45]2)[C:40](=[O:47])[CH:39]=1>>[CH:44]1([N:41]2[CH:42]=[CH:43][C:38]([C:25]3[CH:24]=[CH:23][C:3]([CH2:4][N:5]4[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[O:7][C:6]4=[O:22])=[CH:2][CH:26]=3)=[CH:39][C:40]2=[O:47])[CH2:46][CH2:45]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1CN1CCC(CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(Br)ccn1C1CC1
Product: CC(C)(O)CC1(c2ccccc2)CCN(Cc2ccc(-c3ccn(C4CC4)c(=O)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from 3-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedure analogous to that described in Step 5 of Example 96. LC-MS (Method 5): tR=3.53 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+].Cl>>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)Cl
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)N1CCC(C(=O)O)CC1
Yield: 61.5 %

Procedure:
The procedure of Example A is used with 43 g (0.3 mol) of isonipecotic acid, 31 g (0.3 mol) of acryloyl chloride, 26.6 g (0.66 mol) of sodium hydroxide at 0° C. (ice-salt bath). The reaction mixture is acidified with 2N HCl to pH 3.0 and extracted with ethyl acetate. The organic layer is washed with a sodium chloride solution, dried over magnesium sulfate to dryness to leave a crystalline material which is crystallized from ethyl acetate n-hexane to yield 33.8 g (60%) product. Melting point 109°-110° C. NMR (CDCl3), 5.4-6.9 gamma (br m, 3H, CH2 =CH), 4.0 gamma (br, 2H), 2.1-3.4 gamma (br m, 3H), 1.2-2.1 gamma m, 4H).
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23].C(O)(C)C>O>[C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10]([NH:22][NH2:23])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OOC(C)(CCC(=O)NN)OOC(C)(C)C
Reaction time: 20 h

Procedure:
4,4-Di-(t-butylperoxy)pentanohydrazide was prepared by reacting ethyl 4,4-di-(t-butylperoxy)pentanoate with 9 molar excess of 54% aqueous hydrazine. A 3-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 125 mL of isopropanol (IPA), 15.3 g (0.05 mole) of 99% ethyl 4,4-di-(t-butylperoxy)pentanoate and 30 g (about 0.50 mole) of 54% aqueous hydrazine at 25° C. The solution was stirred for about 20 hours at 20°-25° C. Then the reaction mass was poured into 1000 mL of water and extracted once with 300 mL of methylene chloride. After drying over 10% by weight of anhydrous magnesium sulfate and separation of the spent desiccant by filtration, the methylene chloride was removed in vacuo leaving 14.4 g of liquid product. 30 mL of pentane were added and a solid was precipitated. The solid was separated by filtration and air dried, leaving 12.2 g (83.6% of theory, uncorrected) of a white solid having a melting point (mp) of 76°-78° C. An infrared (IR) spectrum of the product showed strong carbonyl absorption bands at 1640 cm-1 and at 1680 cm-1 and a strong NH band at 3300 cm-1. A DSC scan run on the product showed a peroxide decomposition exotherm at 170° C. These product data confirm that the product was 4,4-Di-(t-butylperoxy)pentanohydrazide (I-1).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22]>O.C1(C)C=CC=CC=1>[C:19]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
18.19 g of tyrosine was suspended in a solution of 9.8 g of concentrated sulfuric acid, 40 mL water, 40 mL of butanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was cooled in an ice bath, which caused the solution to separate into two phases. The upper phase was discarded and the lower phase, an oily syrup, was retained. The syrup was mixed with sufficient 5% aqueous sodium bicarbonate solution to neutralize acidic impurities to provide a solid that was collected by filtration and washed with cold water. The resulting solid was re-crystallized in ethyl acetate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][NH:4][C:3]1=O.CSC>C1COCC1>[NH2:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: NC1CN(C(=O)OCc2ccccc2)CCNC1=O
Solvent: C1CCOC1
Solvent: CSC
Product: NC1CNCCN(C(=O)OCc2ccccc2)C1
Reaction time: 15 h

Procedure:
A solution of benzyl 6-amino-5-oxo-1,4-diazepane-1-carboxylate (12.86 g, 47.4 mmol) in THF (158 mL) was treated dropwise with BH3.DMS (22.5 mL, 237 mmol). The mixture was warmed to reflux and stirred for 15 hours. The mixture was then cooled to 0 OC, quenched by the slow addition of MeOH (50 mL; vigorous H2 evolution observed) and treated over 10 min with concentrated HCl (12 mL). The reaction vessel was then heated to reflux for 8 hours. The volatiles were partially removed under reduced pressure and the mixture was basified to pH 11 with solid Na2CO3. The aqueous layer was extracted with CH2Cl2 (2×), the organic phase was dried (Na2SO4), and concentrated in vacuo to afford benzyl 6-amino-1,4-diazepane-1-carboxylate (I-54a). MS calculated for C13H20N3O2 (M+H+) 250.15. found 250.1. The crude was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1.C(O)(=[O:25])C.Br>CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:25])=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(F)ccc1S2
Reactant: CC(=O)O
Agent: Br
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(F)ccc1S2
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a mixture of 150 mg of 2-(10,11-dihydro-8-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 1.5 ml of acetic acid was added 1.5 ml of hydrobromic acid, and the mixture was refluxed with stirring for 1 hour. To this was added ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown crystals, which were chromatographed over 10 g of silica gel and eluted with chloroform/methanol (50/1). The thus obtained product was recrystallized from ethyl acetate--n-hexane to give 105 mg (yield: 70%) of 2-(10,11-dihydro-8-fluoro-11-oxodibenzo[b,f]-thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 213°-214° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[O:10][N:9]=2)=[C:4]([CH3:27])[CH:3]=1.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.[F-].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:28]=[CH2:29])=[CH:3][C:4]=3[CH3:27])[N:12]=2)=[CH:14][C:15]=1[C:23]([F:26])([F:25])[F:24])([CH3:22])[CH3:21]
Reactant: Cc1cc(Br)ccc1-c1noc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2noc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)n2)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 1.12 g (2.54 mmol) of 3-(4-bromo-2-methylphenyl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (EXAMPLE 12), 816 μL (2.79 mmol) of tributyl(vinyl)tin, and 848 mg (5.58 mmol) of cesium fluoride in 20 mL of 1,4-dioxane was added 32 mg (0.06 mmol) of bis(tri-tert-butylphosphine)palladium(0). After stirring at 100° C. for 2 h, the mixture was filtered through a cake of Celite and concentrated. Chromatography on Biotage 40M cartridge using 1:19 v/v EtOAc/hexanes as the eluant afforded 873 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Cl[CH:13](C)[CH2:14][NH2:15].Cl>O.CO>[NH2:15][CH2:14][CH2:13][CH2:2][S:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: CC(Cl)CN
Reactant: c1ccc2scnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCCSc1ccccc1N
Temperature: 70 °C
Reaction time: 3 h

Procedure:
270 parts of benzothiazole and 160 parts of sodium hydroxide are boiled under reflux for 3 hours in 400 parts of water. After cooling to 70° C., 250 parts of methanol are added, followed by the dropwise addition over a period of 2 hours at 70° C. of a solution of 260 parts of 2-chloropropylamine·HCl in 500 parts of water. After stirring for another 3 hours at 100° C., the mixture is cooled and a solution of 100 parts of sodium hydroxide in 200 parts of water is added to it. The organic phase is separated off, the aqueous phase is washed twice with 200 parts of toluene and the combined organic phases are concentrated by evaporation, leaving 346 parts of 2-(3-aminopropylthio)-aniline in the form of a yellowish liquid boiling at 130° C./0.04 mm.
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([O:19]C)=[CH:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([OH:19])=[CH:9][CH:8]=1
Reactant: COCc1cc2c(Br)ccc(OC)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COCc1cc2c(Br)ccc(O)c2o1
Temperature: 160 °C
Yield: 62.5 %

Procedure:
To a stirred solution of sodium hydride (334 mg, 60% in mineral oil) in dry N, N-dimethylformamide (25 ml) under an atmosphere of dry nitrogen at room temperature was added dropwise ethane thiol (0.586 ml). After stirring for 20 minutes a solution of 4-bromo-7-methoxy-2-methoxymethylbenzofuran (2.04 g) in N,N-dimethyl-formamide (7 ml) was added dropwise and the reaction mixture was heated at 160° C. for 2 hours. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (70 ml) and washed with ammonium chloride solution (70 ml). The organic extract was dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane afforded the title compound as a white solid (1.21 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2cccs2)cc1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27, 0.3 g (2.3 mmol) of thiophene-2-boronic acid and 0.3 g (2.3 mmol) of potassium carbonate in 7 mL of dioxane and 2 mL of water was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to 100° C. for 16 hours cooled to ambient temperature, diluted with 5 mL of water and extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from ethyl ether, filtered and dried in vacuo to afford 0.2 g (47%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[CH2:15][O:16][CH3:17])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.O>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH2:15][O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: COCc1cc(C(=O)OC)ccc1OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A solution of methyl 4-isopropoxy-3-(methoxymethyl)benzoate (11.30 g; 47.42 mmol; 1 eq.) in EtOH (339 mL) at RT was treated with NaOH (47.42 mL; 5 M; 237.11 mmol; 5 eq.). The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated to give a yellow solid. It was taken up in water and the aqueous phase was washed with EtOAc and then acidified with HCl cc to pH 2. The aqueous layer was extracted with EtOAc (twice). The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (9.71 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 12.39 (br s, 1H), 7.89-7.82 (m, 2H), 7.11-7.07 (d, J=8.75 Hz, 1H), 4.79-4.67 (sept, J=5.92 Hz, 1H), 4.39 (s, 2H), 3.35 (s, 3H), 1.31-1.28 (d, J=6.06 Hz, 6H). LC/MS (Method B): 223.2 (M−H)−. HPLC (Method A) Rt 3.71 min (Purity: 92.8%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])O.C(O)C>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:21]1[O:22][C@H:13]([CH2:12][OH:11])[C@@H:15]([OH:16])[C@H:17]([OH:18])[C@H:19]1[OH:20]
Reactant: Fc1cccc2c1CCN2
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@@H](N2CCc3c(F)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A mixture of 4-fluoroindoline (185 mg) and D-glucose (267 mg) in H2O (0.74 ml)-ethyl alcohol (9 ml) was refluxed under argon atmosphere for 24 hours. The solvent was evaporated under reduced pressure to give crude 4-fluoro-1-(β-D-glucopyranosyl)indoline, which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH2:27][CH3:28])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH2:27][CH3:28])[N:9]=1
Reactant: C1COCCN1
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(CCC(=O)O)sc2-n2c(C)nnc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC1N=C(c2ccccc2Cl)c2cc(CCC(=O)N3CCOCC3)sc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1 g of 3-[4-(2-chlorophenyl)-6-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.23 ml of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.6 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 100 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from a mixture of isopropyl ether-ethyl acetate (1:1) to give 0.8 g of 3-[4-(2-chlorophenyl)-6 -ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-2-yl]propionic acid morpholide as colorless crystals, melting at 145°-147° C.
Reaction SMILES: OO.[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11]CC)[CH:7]=[C:6]([CH3:14])[C:5]=1OB(O)O.S([O-])(O)=O.[Na+]>C1COCC1>[F:10][C:9]1[C:4]([F:3])=[CH:5][C:6]([CH3:14])=[CH:7][C:8]=1[OH:11]
Reactant: CCOc1cc(C)c(OB(O)O)c(F)c1F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under cooling with an ice bath, 6.57 g of aqueous hydrogen peroxide was slowly added dropwise to the compound (10) having been dissolved in 37 mL of THF, followed by stirring at room temperature for 3 hours. Under cooling with an ice bath, 20 mL of a saturated sodium hydrogen sulfite aqueous solution was added thereto to terminate the reaction, and an aqueous layer was extracted with diethyl ether, which was added to the organic layer. The organic layer was washed with a saturated sodium hydrogensufite aqueous solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.84 g of 2,3-difluoro-5-methylphenol (11).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:39]([CH2:38][CH2:37][O:36][CH3:35])[CH3:40])=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCOC
Reactant: O=C(Nc1nc2c(OCc3ccccc3)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OCc4ccccc4)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide and (2-methoxy-ethyl)-methyl-amine the title compound was prepared using the general procedure C as white solid (69%), MS: m/e=547 (M+H+).