Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 50.2 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.18 mmol), 3-(tributylstannyl)pyridine (0.086 mL, 0.27 mmol), and PdCl2(PPh3)2 (25 mg, 0.036 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (50 mL) were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-5% MeOH/CH2Cl2, then 20-100% EtOAc/hexanes+2% AcOH) to give 35 mg of the title compound as an off-white solid. MS: (+) m/z 388.26 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cl)c1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), 3-chlorobenzoyl chloride (32 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 9 (16 mg, 26% yield) as a tan solid. LC-MS (M+H=403, obsd.=403).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11](Br)[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:21]=[C:22]4[N:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)n1
Reactant: Nc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(-c3ccc4c(c3)OCO4)nc3ncccn23)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 1-Benzo[1,3]dioxol-5-yl-2-bromo-2-(6-methyl-pyridin-2-yl)-ethanone of Step C (50 mg, 0.12 mmol) in dimethylformamide (1.0 mL) was added 2-aminopyrimidine (15 mg, 1.3 equiv), and sodium hydrogen carbonate (30 mg, 3 equiv). The resulting solution was shaken at 80° C. for 3 hours, diluted with ethyl acetate (2 mL) and water (3 mL). The organic extract was concentrated in vacuo and silica gel chromatography (3:1 hexane/acetone) yielded the title compound (14 mg, 35%). HPLC tR=1.75 min, LCMS 331.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:25][CH2:24][CH2:23][N:8]1[CH2:9][CH2:10][C:5]([C:3]([O:2][CH3:1])=[O:4])([N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12](=[O:15])[CH2:13][CH3:14])[CH2:6][CH2:7]1
Reactant: OCCBr
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Yield: 96.9 %

Procedure:
A mixture of 4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (7.34 g, 25 mmol), 2-bromoethanol (3.96 g, 32 mmol), sodium carbonate (20.0 g, 189 mmol), and sodium iodide (1.0 g) in acetonitrile (200ml) was heated to reflux for three days. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum yielding an oily residue. The residue was chromatographed on silica gel (250 g; ethyl acetate/hexane; 1:4) to yield 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (8.1 g, 96%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:29]=1[C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[C:29]([C:30]#[N:31])=[CH:32][C:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=4[F:22])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:34]([O:36][CH3:37])[CH:35]=1
Reactant: COc1cc(Cl)c(C#N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
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+]
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 79.7 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, Step 1; 555 mg, 1.355 mmol), 2-chloro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (INTERMEDIATE UUUU, 477 mg, 1.626 mmol), potassium carbonate (562 mg, 4.06 mmol), and Pd(Ph3P)4 (157 mg, 0.135 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (5080 μl) and water (1693 μl) were added. The flask was lowered into a 50° C. heating bath for 1 h. The reaction mixture was diluted with water and EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (583.89 mg, 1.080 mmol, 80% yield) as an off-white foam. m/z (ESI) 540.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24].[H-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CON(C)C(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON(C)C(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
A suspension of 5.01 g (16.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and 3.20 g (17.60 mmol) of 2-bromo-N-methoxy-N-methyl-acetamide (intermediate 1D) in 110 ml of THF was treated at 0° C. with 0.84 g (19.20 mmol) of NaH (55% in oil) in two portions. The reaction was warmed up to RT over night and stirred for 2.5 h at 75° C. The reaction was cooled and neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 97.5:2.5) to yield 3.49 g (53%) of the light yellow crystalline title compound. MS: 414.1 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].S(=O)(O)[O-].[Na+].S(=O)(O)[O-].[C-:17]#[N:18].[Na+]>C(Cl)Cl.O>[C:17]([CH:4]([OH:5])[CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])#[N:18]
Reactant: [C-]#N
Reactant: CCC(C=O)CC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)C(O)C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-ethyl butyraldehyde (6 g, 60 mmol) in CH2Cl2 (75 mL) was stirred vigorously with a solution of sodium bisulfite (9.4 g, 90 mmol) in water (35 mL). The thick precipitate which had formed was collected by filtration and washed with CH2Cl2 and dried in vacuo. The bisulfite adduct (10 g, 49 mmol) was dissolved in water (60 mL) and to the solution was added sodium cyanide (3.6 g, 73 mmol). The resulting solution was stirred at ambient temperature for 48 h. The mixture was extracted with ether (2×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified by flash silica gel column chromatography using a gradient elution of 10%, 12.5%, 15% EtOAc in hexanes. The product-containing fractions were combined to give 1-cyano-2-ethylbutanol as a liquid after removal of the solvents in vacuo (5.0 g; TLC Rf=0.4 (9:1 hexanes:EtOAc); 400 MHz 1H NMR, CDCl3, 4.51 ppm (dd, 1H), 2.45 ppm (d, 1H), 1.4-1.7 ppm (overlapping m, 5H), 0.98 ppm (overlapping t, 6H)).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:34](O)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:42])[C:13]1=[O:43])(C(C)(C)C)(C)C.[CH:44](O)=[O:45]>CC(=O)OCC.O.[Zn]>[CH:44]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:33])[F:32])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:42])[C:13]1=[O:43])=[O:45]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Reactant: O=CO
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Temperature: 40 °C
Yield: 80 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-(hydroxy(phenyl)methyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.162 mmol) in HCOOH (2 mL) was added Zn dust (105 mg, 1.62 mmol). The reaction was heated at 40° C. for 6 h, cooled to RT then diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4, and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate, LCMS: MH+ 514 and TR=1.790 min and 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate, LCMS: MH+ 516 and TR=1.714 min, (66.7 mg, 80% yield) as an oil. Used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:3]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([NH:32][CH3:33])=[CH:30][CH:29]=1>C(OCC)(=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([N:32]([CH3:33])[C:2]2[N:3]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]4)=[C:15]([O:25][CH3:26])[CH:14]=3)[N:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:7]=2)=[CH:30][CH:29]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(OC(C)C)nc(N(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 27 %

Procedure:
This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methyl aniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 27% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([C:18](OC)=[O:19])[CH:15]=[CH:14][N:13]3[C:22]=2[CH3:23])=[CH:4][C:3]=1[OH:24].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][N:13]3[C:22]=2[CH3:23])=[CH:4][C:3]=1[OH:24]
Reactant: COC(=O)c1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(CCc2ccc(N)c(O)c2)nc2cc(CO)ccn12
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methoxycarbonyl-3-methylimidazo[1,2-a]pyridine (2.0 g) in tetrahydrofuran (50 ml) was dropwise added to a mixture of lithium aluminum hydride (0.7 g) in tetrahydrofuran (60 ml) at -20°~-10° C. over 30 minutes and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was dropwise added a mixture of water (10 ml) and tetrahydrofuran (20 ml), and the mixture of ethyl acetate, tetrahydrofuran and water was added thereto. The mixture was adjusted to pH 8 with 6N-hydrochloric acid and the insoluble material was removed by filtration. The separated organic layer from filtrate was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with a mixture of diethyl ether and ethyl acetate to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (1.19 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Yield: 92.7 %

Procedure:
A solution of ethyl({4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate (10) (0.290 g, 0.68 mmol) in THF/EtOH (1:1, 8 mL) was treated with 1 N NaOH (4 mL) at 70° C. for 1 h. The reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with chloroform and methanol as an eluent to afford 0.250 g (95%) of the title compound 11 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.19-7.14 (m, 2H), 7.13 (d, J=9.3 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 4.63 (s, 2H), 1.93 (s, 2H), 1.88 (s, 2H), 1.27 (s, 2H), 0.90 (s, 12H). LCMS (ESI): m/z 395 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:8]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:9][C@H:10]([OH:40])[C@@H:11]([N:25](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C@@H:10]([OH:40])[CH2:9][C@@H:8]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 60 °C

Procedure:
Method 2 A solution containing the product from Example 23P (2.7 g, 4.21 mmol) in a mixture of methanol (20 mL) and ethyl acetate (20 mL) was treated with 20% Pd(OH)2 on carbon (1 g) and an HCl solution in dioxane (2 mL, 4 N), stirred under an atmosphere of hydrogen (balloon pressure) for 16 hours at 25° C., heated to 60° C. for 6 hours. The reaction cooled and filtered through celite®, and concentrated. The residue was partitioned between dichloromethane and half-saturated NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[NH2:25])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[NH:25][CH2:13][C:8]1[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: CCOCCOc1cccnc1C=O
Product: CCOCCOc1cccnc1CNc1cc[nH]c1C(=O)OCC
Yield: 71.1 %

Procedure:
The title compound (0.17 g, 73%) was prepared in accordance with general method A using 3-(2-ethoxyethoxy)pyridine-2-carbaldehyde (0.21 g, 1.08 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.11 g, 0.717 mmol).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5cc(F)cc(F)c5OC)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Ethane sulfonyl chloride 337 (47 mg, 0.3665 mmol) was added to the reaction and stirred it for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 338. 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.52 (d, 1H), 8.17 (d, 1H), 7.84 (s, 1H), 7.72 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m, 1H), 3.96 (m, 2H), 3.68 (s, 3H), 3.06 (m, 2H), 3.00 (m, 3H), 2.29 (m, 2H), 2.14 (m, 2H), 1.40 (m, 5H), 1.25 (m, 5H) and MS ES+502.1.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>CO>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CCCS(=O)(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)c1cc(C(=O)O)cc(N[C@@H](C)CC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Add 2 N NaOH (6.0 mL, 12.0 mmol) to a solution of (S)-2-sec-butylamino-6-propanesulfonyl-isonicotinic acid methyl ester (2.47 g, 7.87 mmol) in methanol (10 mL) at 0° C. Stir the mixture at room temperature for 3 h, acidify the solution to about pH =2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (2×50 mL). Wash the combined extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17](O)[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:26][CH2:23][CH:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 143.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (250 mg), potassium carbonate (122 mg) and bromomethylyclohexane (159 mg) in N,N-dimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separator solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-4-methyl-6-cyclohexylmethoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (230 mg).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)[CH2:3][CH3:4].[C:16]([CH:20]1[CH2:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([CH:20]1[CH2:21][CH2:22][CH:23]([C:26]([NH:1][CH:2]([C:5]2[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:27])[CH2:24][CH2:25]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(C(C)(C)C)[nH]c1=O
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C(C)(C)C)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 210 mg (1.00 mmol) 6-(1-aminopropyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one, 200 mg (1.00 mmol) 4-tert-butylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)=[O:7])[CH2:9]3)[O:26][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.5 mg (0.295 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 46 mg (34% of theory).