Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][CH:22]([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH:22]([F:21])[F:33])=[CH:25][CH:26]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(OC(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-difluoromethoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:50]=1[CH2:51][O:52][C:53]2=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:57]=[CH:56][CH:55]=[C:54]3[C:50]=2[CH2:51][O:52][C:53]3=[O:58])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1OCc2c(O)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc3c2COC3=O)cc1

Procedure:
Analogously to Method G, 0.210 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.094 g of 4-hydroxy-3H-isobenzofuran-1-one are reacted. The title compound is obtained as a white solid. Rf=0.32 (1:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:27][CH:28]1[C:38](=[O:39])[N:30]2[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[C:10]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:12])[N:8]=1)=[O:2]
Reactant: Cc1nc(CON=C(C(=O)O)c2csc(NC=O)n2)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cs1
Yield: 61.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-methylthiazol-4-yl-methoxyimino)acetic acid (syn isomer, 0.50 g.), N,N-dimethylformamide (0.123 g.), phosphoryl chloride (0.259 g.) and ethyl acetate (6 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. The solution and a solution of 7-amino-3-cephem-4-carboxylic acid (0.306 g.), trimethylsilylacetamide (1.03 g.), and bis(trimethylsilyl)acetamide (0.90 ml.) in ethyl acetate (3 ml.) were treated in a similar manner to that of Example 1-(1). Water (10 ml.) was added to the resultant mixture, and the ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-methylthiazol-4-yl-methoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.48 g.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH2:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)(O)[O-].[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:7]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Temperature: 85 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine [1 g, 5.1 mmol, Intermediate (29)], 3,4-dimethoxy-phenylethylamine [0.98 g, 5.4 mmol, Intermediate (30)], and sodium bicarbonate (0.86 g, 10 mmol) in EtOH (5 mL) is heated to reflux. After stirring at 85° C. for 4 hours the mixture is diluted with water and filtered. The solid is washed with water, and dried to afford (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [1.8 g, Intermediate (31)]. LCMS: RT=3.25 minutes, MS: 340 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].[CH3:18][O-:19].[Na+]>ClCCl.CO.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:19][CH3:18])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(C(C)=O)cnc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-acetyl-4-chloro-8-nitroquinoline (339 mg) in dichloromethane was added 28% solution of sodium methoxide in methanol (0.52 mg) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 2:3, v/v) to give 3-acetyl-4-methoxy-8-nitroquinoline (239.3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](OC)=[O:13])[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[AlH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1cc(Br)c2cccnc2c1-c1cccc(F)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Br)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a mixture of methyl 5-bromo-8-(3-fluorophenyl)quinoline-7-carboxylate (0.360 g, 1.00 mmol, from Example 10, Step 4) in tetrahydrofuran (1 mL) was added 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (1.00 mL, 1.00 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes then quenched by successive addition of 0.038 mL of water, 0.038 mL of 15% NaOH, 0.11 mL of water. After stirred for 30 minutes, the mixture was filtered. The filtrate was dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 80% ethyl acetate in hexane, to give the desired product (150 mg, 45%). LCMS calculated for C16H12BrFNO (M+H)+: m/z=332.0; Found: 332.0.
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][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH2:10][N+:9]=1[O-].[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:30][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]12)(=[O:29])[CH3:28]
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C[N+]([O-])=C2c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC(C)=O)N=C2c1ccccc1Cl

Procedure:
A mixture of 1.2 g. of 6--(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide-5-oxide and 20 ml. of acetic anhydride is heated at 90° to 95° C. for 50 minutes, and then the solvent is evaporated. The residue is washed with ether to give 4-acetoxy-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide as crystals. Recrystallization from ethyl acetate gives colorless prisms melting at 168° to 170° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=[O:42])[C:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(CC(O)=O)=CC=1.S(=O)(=O)(O)O.[H-].[Na+].CI.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Li+].[OH-]>CC(C)=O.CO.C1COCC1.C(Cl)(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:31]([CH3:33])([CH3:32])[C:30]([OH:42])=[O:29])=[CH:39][CH:38]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)c1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Agent: Cc1ccc(CC(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)cc1

Procedure:
This compound was prepared similarly to that of Example 525 by treating 3-(2-benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (23 mg, 1 eq) with 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid methyl ester (17 mg, 1 eq) and potassium carbonate (26 mg, 3 eq) in acetone (2 mL). The latter reagent was obtained by heating p-tolyl-acetic acid in methanol and a catalytic amount of sulphuric acid. Subsequent methylation was accomplished by treating the obtained ester (50 mg, 1 eq) with sodium hydride (26 mg, 2.2 eq) and methyl iodide (41 μL, 2.2 eq) in THF (1 mL). Then α-bromination was accomplished by refluxing the ester (16 mg, 1 eq) with NBS (15 mg, 1 eq) and benzoyl peroxide (1 mg, 3%) in carbon tetrachloride (1.5 mL) overnight. The reaction mixture was cooled, water was added and product extracted with dichloromethane. The residue was purified by flash chromatography (ethyl acetate/n-heptane, 1:9, as an eluent). Then the resulting compound was then hydrolyzed with aq LiOH (1M, 40 eq)/THF, 1:1, and purified by preparative HPLC, affording the desired product in 26% yleld.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:23])OC1C=CC([N+]([O-])=O)=CC=1)[CH2:8]2.[NH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[NH:11][C:12]([N:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:25]1)=[O:23])[CH2:9]2
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 45.3 %

Procedure:
To a stirred solution of 4-nitrophenyl (2-adamantyl)carbamate (40 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added tert-butyl azetidin-3-ylcarbamate (40 mg, 0.23 mmol), followed by i-Pr2NEt (0.05 mL, 0.28 mmol). The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was applied to 2-g silica SPE cartridge which was eluted sequentially with 0, 25, 50, 75, 100 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fraction 4 was concentrated to provide tert-butyl 1-(2-adamantylcarbamoyl)azetidin-3-ylcarbamate (19 mg, 43%). LC-MS Method 1, tR=1.74 min, m/z=350, 294; 1H NMR (CDCl3) 1.45 (s, 9H), 1.60-1.95 (14H), 3.75 (m, 2H), 3.89 (m, 1H), 4.22 (m, 2H), 4.39 (d, 1H), 4.46 (1H), 5.06 (1H).
Reaction SMILES: Cl.N1(CC2C=C(C=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][O:28][C:27]5=[O:31])[CH:22]=4)[NH:17][C:16]3=[O:32])NC=2)CCOCC1.[OH:33]S(O)(=O)=O>>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:32])[C:15]3=[O:33])[CH2:30][CH2:29][O:28]1
Reactant: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=Cc1cc(CN2CCOCC2)c[nH]1
Reactant: O=S(=O)(O)O
Agent: Cl
Product: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Concentrated H2SO4 (20 ml) is heated to 50° C. The compound obtained in Step D (25.24 mmoles) is added slowly in solid form, maintaining the temperature between 60 and 70° C. The reaction mixture is then stirred for one hour at 80° C. The mixture is brought to ambient temperature and then poured onto 200 g of crushed ice. After 30 minutes, the red solid formed is filtered off and washed intensively with ice-cold water; it is then dried in vacuo in the presence of P2O5 and at 40° C. overnight to yield the title product, which is used directly in the next Step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br>O1CCOCC1>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccc(F)c1
Solvent: C1COCCO1
Product: O=C(CBr)c1cccc(F)c1
Reaction time: 0.25 h

Procedure:
A solution of 1-(3-fluorophenyl)ethanone (14.0 g, 100 mmol) (Aldrich) in dioxane (250 mL) at 12-15° C. was treated with a solution of bromine (17 g, 105 mmol) in dioxane (120 mL) drop wise over 0.5 h. This was stirred for 15 min and most of the solvent removed. The residue was taken up in hexane (200 mL), washed 2× water, and dried (MgSO4). Solvent was removed to give 2-bromo-1-(3-fluorophenyl)ethanone. 1H NMR (CDCl3), 300 MHz) δ3.71 (s, 2H, CH2), 7.30-7.77(m, 4H, Aromatic).
Reaction SMILES: [OH-].[Na+].[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](/[C:16]1[CH2:17][O:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=2)\[CH3:15])=[CH:5]\[C:6]([O:8]CC)=[O:7].Cl>C(O)C.O>[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](/[C:16]1[CH2:17][O:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:21][CH:20]=2)\[CH3:15])=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)C1=Cc2cc(-c3ccccc3)ccc2OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(/C=C/C=C(\C)C1=Cc2cc(-c3ccccc3)ccc2OC1)=C\C(=O)O
Reaction time: 1 h
Yield: 67.5 %

Procedure:
44 ml of 35% sodium hydroxide are added to a solution of 7.34 g (19 mmol) of the ester obtained in Example 25 in a mixture of 310 ml of ethanol and 140 ml of distilled water. The reaction mixture is then refluxed for 2 hours. The solution, cooled to +10° C., is acidified to pH 4 by means of a 4N hydrochloric acid solution. After the addition of 80 ml of water, the mixture is stirred at +10° C. for one hour. After filtration, the solid is rinsed with water and dried in a vacuum oven at 70° C. over phosphoric acid. Recrystallisation from ethanol yields 4.6 g of a yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product from step (v) (1.84 g) and Lawesson's reagent (1.65 g) in 1,4-dioxane (30 ml) was heated at reflux for 24 hours. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.38 g.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[O:35]([C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccccc1
Reactant: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1Oc1ccccc1
Yield: 69.3 %

Procedure:
A solution of 100 mg of 4-fluoro-N-indan-1-yl-3-(3-methyl-butylsulfamoyl)benzamide (Example 41), 26 mg of phenol, and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated to 100° C. for 6 h. After water had been added and the precipitated product filtered off with suction, 82 mg of 4-phenoxy-N-indan-1-yl-3-(3-methyl-butylsulfamoyl)benzamide were obtained; m.p. 73° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCOC(C)=O>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:21]3[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc3ncc(C=O)n3c2)cc2ccccc21
Yield: 51 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (step 1 of Intermediate 1, 150 mg, 0.6729 mmol), 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (228 mg, 0.8742 mmol), dichlorobis(triphenylphosphine) palladium (II) (30 mg, 20% mmol) and 2M aqueous Na2CO3 (1 mL) were added to DMF (5 mL) and refluxed for 2 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The solvent was evaporated to obtain solid residue, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 51%; 1H NMR (DMSO-d6; 300 MHz): δ 11.91 (s, 1H), 9.99 (s, 1H), 9.81 (s, 1H), 8.55 (s, 1H), 8.17 (dd, 1H, J=9.3, 1.8 Hz), 7.95 (d, 1H, J=9.3 Hz), 7.56 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.142 (t, 1H, J=7.2 Hz), 7.03 (m, 2H); MS: m/z 260 (M−1)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C(Cl)=O.CN1C2C=C(C(Cl)=O)C=CC=2OC1=O.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[C:38]([Cl:44])[CH:37]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.COCCOC.[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])=[C:38]([Cl:44])[CH:37]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Agent: [Pd]
Agent: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: COCCOC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (2.20 g) in CH2Cl2 (30 mL) were added five drops of DMF and oxalylchloride (1.57 mL). The mixture was stirred at room temperature for 1.5 hours and was then concentrated to dryness. 1,2-Dimethoxyethane (150 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (1.49 g) in 1,2-dimethoxyethane (15 mL) was added tetrakis(triphenylphosphine) palladium(0) (132 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (20 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (3.25 g, [CAS Reg. No. 89720-77-4]) in 1,2-dimethoxyethane (15 mL) was slowly added over a period of 30 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Ethyl acetate (50 mL) was added to the resulting precipitate and the suspension was stirred for 30 minutes at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as a light yellow solid (1.95 g, 40%). MS (neg. ion, m/e)=378.0 [(M−H)−].
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[C@H:26]2[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[Si:33]([O:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][CH2:30]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.5 mg), and the mixture was stirred at room temperature for 1 hr. cis-4-((tert-Butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (351 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (31.1 mg).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1N=C(CN)C=CC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cccc(CN)n1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1cccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)n1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(6-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.18 (m, 5H), 1.56-1.59 (m, 5H), 1.87 (s, 3H), 2.21 (s, 3H), 2.49 (s, 3H), 3.63 (d, J=6.72 Hz, 1H), 4.62 (d, J=4.30 Hz, 2H), 7.21-7.23 (m, 2H), 7.56 (d, J=5.64 Hz, 1H), 7.76-7.80 (m, 1H), 8.24 (s, 1H), 12.39 (s, 1H); MS (ESI) m/z 326.5 (M+1)+.