Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23])(=[O:7])[CH3:6].[F:24][C:25]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:26]=1[C:27]([NH:29][CH:30](OC)[CH2:31][Cl:32])=[O:28]>ClCCl>[F:24][C:25]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:26]=1[C:27]([NH:29][CH:30]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5](=[O:7])[CH3:6])=[C:10]([CH2:21][CH2:22][CH3:23])[CH:11]=2)=[CH:16][CH:17]=1)[CH2:31][Cl:32])=[O:28]
Reactant: CCCc1cc(-c2ccccc2)ccc1OC(C)=O
Reactant: COC(CCl)NC(=O)c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1cc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)ccc1OC(C)=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
At 0° C., 28.5 g (0.215 mol) of aluminium chloride are added a little at a time with stirring to a solution of 14.9 g (59 mmol) of 4-acetoxy-3-n-propylbiphenyl and 16.2 g (65 mmol) of 2,6-difluoro-N-[2-chloro-1-methoxyethyl]-benzamide in 100 ml of dichloromethane. The mixture is stirred for 30 minutes, a further 4 g (30 mmol) of aluminium chloride are added and the mixture is stirred for a further 2 hours at 0° C. The reaction mixture is poured onto ice, the product is extracted with dichloromethane and the organic phase is concentrated under reduced pressure. 27 g of a resinous crude product (log p=3.92, pH 2.3) are obtained and used for further reactions without any further purification (˜100% crude yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)[CH:9]=2)=[CH:6][C:5]([NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][N:10]1[C:11](=[O:20])[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([NH:31][C:32](=[O:43])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:6]=2)=[CH:9]1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)c(=O)n(CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)c(=O)n(CCN)c1

Procedure:
A 0.1 M solution of tert-butyl (2-(2′-methyl-5-morpholino-6-oxo-5′-(3-(trifluoromethyl)benzamido)-[3,3′-bipyridin]-1(6H)-yl)ethyl)carbamate (1.00 equiv.) in 1:1 DCM:TFA was stirred for 15 min at ambient temperature. The reaction mixture was concentrated. The residue was basified with aqueous sodium carbonate and extracted with DCM. The combined extracts were dried over sodium sulfate, filtered, and concentrated to give crude N-(1′-(2-aminoethyl)-2-methyl-5′-morpholino-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide which was used without further purification. LCMS (m/z) (M+H)=502.2, Rt=0.58 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=[C:7]3[C:6]2=[O:18])[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=[C:7]3[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CC1CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)N(CC1CC1)C2=O
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 48.6 %

Procedure:
N-Cyclopropylmethyl-4-nitrophthalimide (6.0 g, 24 mmol) in methanol (200 mL) was added dropwise over 30 min to a solution of sodium dithionite (27.0 g, 156 mmol) and sodium carbonate (13.0 g, 125 mmol) in water (200 mL) while the temperature was maintained at 70° C. The mixture was stirred at 70° C. for an additional 50 min before it was allowed to cool to room temperature. The reaction volume was then reduced to one-third by rotary evaporation. Water (400 mL) was added, and the suspension extracted with ethyl acetate (2×450 mL). The combined organic solutions were dried with anhydrous MgSO4. Solvent was then removed by rotary evaporation to afford 2.52 g (49%) of pure N-cyclopropylmethyl-4-aminophthalimide as a powder.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[F:52][C:53]([F:67])([F:66])[C:54]1[C:55]([NH2:65])=[C:56]([NH2:64])[CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1>>[F:52][C:53]([F:66])([F:67])[C:54]1[C:55]2[N:65]=[C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)[NH:64][C:56]=2[CH:57]=[C:58]([C:60]([F:61])([F:62])[F:63])[CH:59]=1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1)c1c(F)cccc1F

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 3,5-bis(trifluoromethyl)-1,2-diaminobenzene to give N-[3-(4,6-bis-trifluoromethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (51 mg) as a pink solid. (LC/MS: Rt 3.64, [M+H]+ 476.07).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([NH:11][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1ccc(Nc2ccccc2)nc1
Yield: 48.4 %

Procedure:
6-Chloro-3-pyridinecarboxylic acid (15.76 g, 0.1 mole) and aniline (9.3 g, 0.1 mole) were heated together in 50 mL xylene at 180°-185° C. (oil bath) for 3 hours. After cooling, the solid that formed was filtered and washed with Et2O. The solid was triturated with NaHCO3 solution (pH 8), then filtered to give 7.0 g (24%) of N-phenyl-6-(phenylamino)-3-pyridinecarboxamide. The aqueous NaHCO3 solution was carefully neutralized with glacial HOAc (pH 6), and the solid that precipitated was filtered and washed (H2O and with Et2O); yield 12.13 g (57%), mp 264°-266° C. MS (EI) m/e 214 (M+), 213 (M-1, base), 169 (M-45), 167 (M-47).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[N:17]S(C(C)(C)C)=O)[C:6]=2[CH:24]=1.Cl.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7](=[NH:17])[C:6]=2[CH:24]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of N-(5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide (Example 29 Step 1, 2 g, 4.83 mmol) in anhydrous 1,4-dioxane (40 mL) was added 4M HCl in 1,4-dioxane (12.07 mL, 48.27 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt overnight. Et2O (30 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated, yielding 1.37 g of the crude title compound which was used immediately in the next step: MS (EI) m/z 309 M.
Reaction SMILES: Cl.[C:2]([CH:7]([NH:16][CH:17]([CH3:32])[C:18]([N:20]1[CH2:28][CH:27]2[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]1[C:29]([OH:31])=[O:30])=[O:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:4]CC)=[O:3].[OH-].[K+]>C(O)C>[C:2]([CH:7]([NH:16][CH:17]([CH3:32])[C:18]([N:20]1[CH2:28][CH:27]2[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]1[C:29]([OH:31])=[O:30])=[O:19])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:4])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC(C)C(=O)N1CC2CCCCC2C1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CC2CCCCC2C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.7 g of 2-[2-([1-carbethoxy-3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-isoindole-1-carboxylic acid hydrochloride in 15 ml of absolute ethanol is treated with 0.5 g of potassium hydroxide pellets. The mixture is stirred at room temperature overnight, then filtered and the solvent is evaporated at reduced pressure. The residue is taken up in 50 ml of water and acidified to pH 3 with 4N hydrochloric acid. The product precipitates out and is recrystallized from absolute ethanol; mp 193°-197° C. [α]D23 =-39.9°.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl-].[Na+]>O.CN(C=O)C>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[C:23]([F:22])([F:32])[F:33])=[O:21])[N:9]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: Cc1csc(-c2nn(CC(=O)O)c(=O)n2CC(C)C)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(-c2nn(CC(=O)NCc3ccccc3C(F)(F)F)c(=O)n2CC(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.121 mmol) of 2-[3-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 249A and 23.4 mg (0.133 mmol) of 2-trifluoromethyl-benzylamine are placed 1.5 ml of DMF and treated with 19.7 mg (0.146 mmol) of HOBt. 30.2 mg (0.158 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with about 15 ml of water, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is separated and concentrated, and the residue is dissolved in methanol and purified by preparative HPLC [Method 12]. 26 mg (44% of theory) of the target compound are thus obtained.
Reaction SMILES: O.[Li+].CC([N-]C(C)C)C.[OH:10][C@H:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:12]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH3:13].Br[CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]([CH:36]=1)=[N:33][S:34][N:35]=2.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:35]1[S:34][N:33]=[C:32]2[CH:36]=[C:28]([CH2:27][C@H:16]([CH3:17])[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:18])[CH:29]=[CH:30][C:31]=12
Reactant: CCC(=O)N(C)[C@H](C)[C@H](O)c1ccccc1
Reactant: BrCc1ccc2nsnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@@H](C)Cc1ccc2nsnc2c1
Reaction time: 1 h

Procedure:
Water free LiCl (59.4 g, 1.4 mol) is carefully dried in vacuo at 600° for 10 minutes and then the vessel purged with Ar. THF (460 ml) is added and cooled to 0°. A solution of LDA (2M in THF/heptane/Et2O, 200 ml, 0.4 mol) is added and cooled to −75°. A solution of N-[(1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl]-N-methyl-propionamide (44.4 g, 0.2 mol) in 460 ml THF is added dropwise over 170 minutes while maintaining the internal temperature at −62° to −69°. After stirring for 1 h at −75°, the cooling bath is removed for 30 minutes, during which time the temperature rises to −30°. The mixture is recooled to −75° and then treated with a solution of 5-bromomethyl-benzo[1,2,5]thiadiazole (34.8 g, 0.152 mol) in 260 ml THF during 85 min at −70° to −78°. The mixture is then stirred for 40 h at −78°. A 15% NH4Cl solution (1000 ml) is added and the mixture stirred well. Extraction with EtOAc (2×500 ml), drying (Na2SO4) and evaporation afford crude product. MPLC purification (2 kg silicagel, EtOAc/hexanes 2/1) afford pure product as a orange oil. Diastereomeric ration 92:8 (NMR, 120°). TLC (silicagel, EtOAc/hexanes2:1): rf 0.38.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19](O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1.Cl>CCOCC.C(Cl)Cl.CCOCC.CO>[CH2:19]([C:14]1[CH:13]=[C:12]([Br:11])[CH:17]=[CH:16][C:15]=1[OH:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc(Br)cc1C(O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc(Br)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 13.24 g (99.3 mmol, 4.1 eqv) AlCl3 in 85 ml dry Et2O was added cautiously under stirring to a suspension of 3.91 g (102.9 mmol, 4.2 eqv) LiAlH4 in 100 ml dry Et2O. After complete addition the resulting mixture was stirred for 30 min at rt and then a solution of 6.85 g (24.5 mmol) 4-Bromo-2-(hydroxy-phenyl-methyl)-phenol (19) in 80 ml dry Et2O was added dropwise. The mixture was refluxed for 12 h and after that cooled to 0° C. After adding cautiously 60 ml of a mixture of Et2O/MeOH (1:1), 170 ml 1 N HCl-solution was added and the mixture was extracted with Et2O. The comb. org. fractions were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2) yielded 4.00 g (15.2 mmol, 62%) 20 as a colorless liquid: Rf (CH2Cl2) 0.41; 1H NMR (500 MHz, CDCl3) δ 3.95 (s, 2H), 4.64 (s, 1H), 6.67 (dd, 1H, J1=8.04 Hz, J2=0.79 Hz), 7.23 (m, 5H), 7.31 (m, 2H); LRMS (EI) m/z 265 (17), 264 (98), 263 (21), 262 (100), 186 (53), 184 (49), 183 (78), 182 (18), 181 (27), 165 (49), 153 (23), 152 (26), 91 (29), 84 (14), 78 (25), 77 (31), 76 (16), 63 (15); HRMS (EI) Calcd. for C13H11BrO: 261.999326. Found: 261.998568.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])[N:28]=[CH:29][C:22]=12>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([O:18][C:21]2[N:26]=[CH:25][N:24]=[C:23]3[N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[Cl:37])[N:28]=[CH:29][C:22]=23)[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4]
Reactant: Clc1cccc(-n2ncc3c(Cl)ncnc32)c1Cl
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 125 %

Procedure:
Sodium hydride (60% in oil) (80 mg, 2.00 mmol) was added to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (314 mg, 1.34 mmol) in THF (10 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 minutes. 4-chloro-1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AR4) (400 mg, 1.34 mmol) in THF (2 mL) was then added dropwise and stirred at 0° C. for a further 10 mins. The reaction was then allowed to warm to r.t. and stirred for 3½ hours. The reaction mixture was quenched with 1M citric acid, extracted with EtOAc and washed with water ×2. The organic layer was dried (MgSO4), filtered and evaporated to afford yellow gum (835 mg). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (285 mg, 42.8%, 96% ee). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 3.58-3.74 (2H, m), 4.04-4.17 (2H, m), 6.04 (1H, t), 7.37-7.48 (2H, m), 7.64-7.69 (1H, m), 7.93-7.99 (1H, m), 8.36-8.41 (1H, m), 8.43 (1H, s), 8.56-8.58 (1H, m), 8.58 (1H, s), 9.02 (1H, s); m/z (ES−) (M−H)−=496.33; HPLC tR=2.70 min.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:31][S:41]([CH3:44])(=[O:43])=[O:42])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][O:11][S:41]([CH3:44])(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](COCc1ccccc1)OS(C)(=O)=O
Reaction time: 8 h

Procedure:
2,3,4,6-Tetra-O-benzyl-D-galactitol (7.6 g) was stirred at 0° C. in pyridine (20 ml) and a solution of mesyl chloride (2.5 ml) in pyridine (20 ml) was added. The solution was stored at 4° C. overnight. TLC analysis showed completion of the reaction. The reaction mixture was partitioned between ethyl acetate and water/ice. The organic fractions were washed with 5% hydrochloric acid then saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and concentrated to give a colourless oil which was used directly in the next stage.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.O[C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:42]=[C:39]1[NH:38][C:37]2[CH:43]=[C:33]([C:31]([NH:30][CH:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:17]4[CH:16]=[N:15][C:14]5[C:19]([N:18]=4)=[CH:20][C:11]([O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:12][CH:13]=5)[CH2:29][CH2:28]3)=[O:32])[CH:34]=[CH:35][C:36]=2[S:41][CH2:40]1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (519 mg, 2.92 mmol, 20.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (610.4 μL, 4.38 mmol, 30.0 eq). After 30 minutes stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford methanesulfonic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as an off-white powder (25 mg, 26% yield).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[C:10]([C:12](N(OC)C)=[O:13])[N:11]=1)=[O:5].C[Mg+].[Br-].O.[CH2:37]1COC[CH2:38]1>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)=[C:10]([C:12](=[O:13])[CH2:37][CH3:38])[N:11]=1)=[O:5]
Reactant: CON(C)C(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Product: CCC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To the solution of Compound 93 (220 mg, 0.47 mmol) in 10 mL of anhydrous THF was added MeMgBr (3.0 M in Et2O, 0.5 mL) at −78° C. The solution was slowly warmed to room temperature over 2 hours. The reaction mixture was treated with 10 mL of water. The mixture was extracted with Et2O, the combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with 10-100% ethyl acetate in hexanes) to give Compound 94 (184 mg, 83%) as a white solid.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].Br[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH:18]([F:20])[F:19])=[C:12]([Cl:21])[CH:11]=1>O1CCCC1.CN(C)C=O>[Cl:21][C:12]1[CH:11]=[C:10]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:15]=[C:14]([Cl:16])[C:13]=1[O:17][CH:18]([F:20])[F:19]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(c1cc(Cl)c(OC(F)F)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (21 mL) was added a solution of 4-bromo-2,6-dichloro-1-(difluoromethoxy)benzene (2.4 g) in N,N-dimethylformamide (12 mL), then the bulk of the tetrahydrofuran was removed in vacuo. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g) was added to the residual N,N-dimethylformamide solution, which was stirred at 100° C. for 3 hours under nitrogen atmosphere and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with diethyl ether (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a brown oil (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(OC)nc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3OC)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 64.1 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(2,6-dimethoxypyridin-3-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (120 mg, 0.245 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (16 mg, 0.736 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 36 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (70 mg, 0.157 mmol, 64%) as a pale blue solid.