Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=O)[O:6]1)(=O)C.[H][H]>[Pd].CO>[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][O:6]1)=[O:4]
Reactant: [H][H]
Reactant: CC(=O)OC1OC(=O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C1OCc2ccccc21
Temperature: 35 °C
Reaction time: 3 h

Procedure:
In the manner described in Example 1, the autoclave is filled with 86.4 g of 3-acetoxyphthalide, 400 ml of methanol and 10 g of palladium-on-charcoal catalyst (Pd content 5 wt%), raised to 10 bars with hydrogen, and slowly heated to 35° C. The consumed hydrogen is first replaced by addition in the range up to 10 bars, and then again in the range up to 20 bars and after the reaction rate has decreased. After 3 hours the pressure remains constant. The catalyst is filtered off and the remaining solution is concentrated at 70° C. and 20 Torr in a rotary thin film evaporator. The residue, still smelling slightly of acetic acid, is fractionally distilled between 99° and 103° C. at 0.5 Torr, and the distillate is recrystallized from water. 54 g (90.05% of the theory) of phthalide of a melting point of 72.5° C. is obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1.[H-].[Na+].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH:20]([C:19]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:13][N+:14]([O-:16])=[O:15])=[O:23])([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])N=C1NCCCN1CC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)C(=O)N1CCCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of 2.2 g of 1-[(tetrahydro-3-furanyl) methyl]-2-(nitroimino)hexahydropyrimidine, 0.58 g of sodium hydride (60%) and 100 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 1.58 g of isobutanoyl chloride was added dropwise thereto over 30 minutes, and the mixture was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and concentration was then carried out under a reduced pressure. The resultant residue was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 1.30 g of 1-(isopropylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl)methyl]hexahydropyrimidine
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[CH:11]=[C:12]([NH2:26])[C:13]([O:24][CH3:25])=[C:14]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:3](=[O:4])[CH2:2][Cl:1])[C:13]([O:24][CH3:25])=[C:14]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:18])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: COc1c(N)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)CCl)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride (4.4 ml) in dichloromethane (40 ml) was added dropwise to a cooled and stirred solution of 5-t-butyl-2-methoxy-3-aminophenyl N-t-butyl-sulfonamide (15.6 g) and diisopropylethylamine (9.5 ml) in dichloromethane (100 ml). The solution was left standing at ambient temperature for 2 hours and then washed with a 2% solution of citric acid. The organic phase was dried and evaporated. Recrytallization from aqueous ethanol gave the title compound (16.4 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:12])[C:9](Cl)=[O:10].Cl.[CH2:14]([S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[Cl:30])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:7][N:8]([CH3:12])[C:9]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:24]([Cl:30])[CH:25]=1)=[O:10]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(SCCc2ccccc2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(SCCc2ccccc2)c(Cl)c1
Temperature: 60 °C

Procedure:
Anhydrous potassium carbonate (10 g) and dimethylcarbamyl chloride (4.0 g; 0.037 mol) are added to a solution of 2-chloro-4-aminophenyl phenethyl sulfide hydrochloride (3.0 g; 0.01 mol) in dry DMF (75 ml) at 25° C. The reaction mixture is heated at 60° C. for 15 hours and then poured into ice water (500 ml). The precipitate (74%) of title product, a white solid, m.p. 133°-134° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/N(C)C)=[C:11]([N+:20]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[Pd]>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]2[C:12]([CH:15]=[CH:16][NH:20]2)=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)/C=C/c1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.9 %

Procedure:
A suspension of N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide (5.41 g, 16.5 mmol) and 7.5% palladium/carbon (500 mg) in tetrahydrofuran (50 ml) and ethanol (50 ml) was stirred at room temperature for 3.5 hr under a hydrogen atmosphere of 3.5 atm. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give N-tert-butyl-1H-indole-6-sulfonamide (3.62 g, yield 87.1%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CC[O:13][C:14]([CH2:16][C:17]([C:19]([F:22])([F:21])[F:20])=O)=O>O>[OH:13][C:14]1[N:6]2[N:5]=[CH:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]2[N:1]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: COC(=O)c1cn[nH]c1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cnn2c(O)cc(C(F)(F)F)nc12
Reaction time: 16 h

Procedure:
A mixture of 11.5 g of methyl 5-aminopyrazole-4-carboxylate, 16 ml of ethyl ω,ω,ω-trifluoroacetoacetate and 150 g of polyphosphoric acid was heated to 100° while stirring for 16 hours. After cooling to 20°, cold water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N aqueous hydrochloric acid and aqueous saturated sodium chloride solution and then dried over Na2SO4. The solvent was evaporated in a vacuum and the residue was taken up in ether. The solid product was filtered off under suction and recrystallized from 2-propanol. There was obtained an isomer of the product, namely methyl 7-hydroxy-5-(trifluoromethyl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate of m.p. 216°-217°. The product enriched in the mother liquors was crystallized from ethyl acetate. There was obtained methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate of m.p. 149°-150°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:42]([OH:44])[CH3:43])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41])[CH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O>Cl>[CH2:1]([O:8][C@@H:9]([C@@H:42]([OH:44])[CH3:43])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41])[CH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H](OCc1ccccc1)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)Cc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H](OCc1ccccc1)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)Cc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 250 mL round bottom flask was charged with (2S,6R,7R,8S)-benzyl 7-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-(2,4-difluorobenzyl)-8-hydroxynonanoate (2.10 g, 3.43 mmol), THF (24 mL) and H2O (6 mL). LiO.H2O (153 mg, 3.64 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After stirring for 2.5 h, the reaction mixture was heated to 50° C. and was stirred for an additional 17 h at that temperature. Additional portions of water (3 mL) and LiO.H2O (152 mg, 3.62 mmol) were added and the reaction was stirred at room temperature for 4.5 h. The reaction mixture was diluted with 1.0 M aqueous HCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (NaCl, brine; 50 mL), dried over anhydrous MgSO4, filtered, concentrated, and dried under high vacuum to obtain the title compound as a colorless oil contaminated with 10% BnOH (1.55 g, 87%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 7.15-7.05 (m, 1H), 6.82-6.69 (m, 2H), 5.03 (d, J=8.3 Hz, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.20 (q, J=7.4 Hz, 1H), 4.03 (p, J=6.2 Hz, 1H), 3.37-3.24 (m, 1H), 2.99 (dd, J=14.0, 4.6 Hz, 1H), 2.51 (dd, J=14.0, 9.9 Hz, 1H), 2.01-1.90 (m, 1H), 1.75-1.60 (m, 1H), 1.56-1.15 (m, 17H); 13C NMR (101 MHz, CDCl3) δ 176.51, 161.26 (dd, J=246.7, 12.7 Hz), 161.07 (dd, J=247.1, 12.0 Hz), 155.60, 138.35, 131.98 (dd, J=9.3, 6.9 Hz), 128.37, 127.77, 126.97, 124.00 (dd, J=15.8, 3.8 Hz), 110.83 (dd, J=20.8, 3.6 Hz), 104.38 102.95 (m), 83.36, 80.11, 73.75, 68.11, 53.17, 39.82, 32.49, 29.71, 28.85, 28.25, 22.55, 19.22; 19F NMR (376 MHz, CDCl3) δ −113.45 (d, J=7.0 Hz), −113.63 (d, J=6.7 Hz); ESIMS: m/z 522 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.Cl[CH2:41][C:42]1[N:46]([CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:45]2[CH:52]=[CH:53][C:54]([C:56]#[N:57])=[CH:55][C:44]=2[N:43]=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:41][C:42]2[N:46]([CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:45]3[CH:52]=[CH:53][C:54]([C:56]#[N:57])=[CH:55][C:44]=3[N:43]=2)[C:9]1=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reaction time: 0.42 h
Yield: 209.8 %

Procedure:
(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid tert-butyl Ester (399 mg, 1.61 mmol) in CH2Cl2 (15 ml) was trreated with BTPP and then treated with 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (400 mg, 1.53 mmol). The reaction was stirred for 25 min then the mixture was diluted with ether and washed with water. The organic layer was dried over MgSO4, concentrated and the residue purified by column chromatography with gradient elution using first 1:1 EtOAc in hexanes then 2:1 EtOAc in hexanes to give 1.52 g (99%) of {3-[5-Cyano-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[S:23][C:22]=2[CH:31]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])=[CH:14][CH:13]=3)=[O:12])=[C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[S:23][C:22]=2[CH:31]=1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc2cc(C3CCCC3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN(C)C)cc3)c(C3CCCC3)sc2c1
Yield: 42.7 %

Procedure:
The same operations as in Preparation example 6 were carried out using 200 mg of 4-[2-(dimethylamino)ethoxy]benzoic acid in place of 4-(2-chloroethoxy)benzoic acid and 45 mg of 6-methoxy-2-cyclopentylbenzo[b]thiophene in place of 6-methoxy-2-cyclohexylbenzo[b]thiophene, and then purification was carried out by TLC (developing solvent, chloroform:methanol=19:1) to obtain 35 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])#[N:26]
Reactant: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccccc3C#N)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in example 23; 172 mg, 0.42 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (96 mg, 0.46 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.84 ml, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (29.2 mg, 0.025 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 58 mg.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Temperature: 120 °C
Yield: 71 %

Procedure:
A mixture of Boc-homopiperazine (900 mg, (4.63 mmol), 2-bromobenzonitrile (766 mg, 4.211 mmol), Pd2(dba)3 (193 mg, 0.21 mmol), xantphos (366 mg, 0.63 mmol), sodium t-butoxide (1.19 g, 12.6 mmol) in degassed anhydrous dioxane (10 mL) was heated at 120° C. in a sealed tube for 2 h. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (905 mg, 71%). m/z (M+1) 301.27.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>C(Cl)Cl.CO>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: C1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCCCC2)c1
Yield: 84 %

Procedure:
Piperidine (3 g) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide (0.19 g) in a mixture of methylene chloride (3 ml) and methanol (3 ml). The resultant solution was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.19 g); NMR Spectrum: (DMSOd6) 1.6 (m, 6H), 2.18 (s, 3H), 2.92 (m, 12H), 4.02 (m, 2H), 4.22 (m, 1H), 6.9 (m, 1H), 7.2 (m, 4H), 7.29 (t, 1H), 7.43 (t, 1H), 7.57 (m, 3H), 7.8 (d, 1H), 9.92 (br s, 1H), 10.12 (br s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]=[C:14]3[CH3:38])[CH:8]=2)[O:3]1.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.O1CCCC1>[OH:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]=[C:14]3[CH3:38])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:39])[CH2:11]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
4′-{[1-(2,2-Dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (7.0 g) was dissolved in methanol (35 mL) and tetrahydrofuran (35 mL), and sodium borohydride (0.61 g) was added at 0° C. After stirring for 30 min, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (7.0 g, 100%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].S(Cl)(Cl)(=O)=O>O.CO.C1COCC1>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](=[O:21])(=[O:20])[NH:8][OH:9]
Reactant: NO
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1ccccc1S(=O)(=O)NO
Yield: 44 %

Procedure:
A solution of potassium carbonate (3.53 g, 25.57 mmol) in water (3.6 ml) was added dropwise to a solution of hydroxylamine hydrochloride (1.76 g, 25.57 mmol) in water (2.4 ml) at 0° C. maintaining an internal reaction temperature between 5° C. and 15° C. THF (12 ml) and methanol (3 ml) were added, followed by 2-chlorosulfonyl-benzoic acid methyl ester (3 g, 12.78 mmol) portionwise maintaining a temperature below 15° C. and the reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by tlc. The resulting suspension was concentrated to remove any volatiles and the aqueous suspension was extracted with diethyl ether (2×100 ml). The organic portion was dried over sodium sulphate, filtered and concentrated in vacuo to yield the crude N-hydroxy sulfonamide. Purification was achieved by chromatography on silica gel eluting with heptane:ethyl acetate (8:2 v:v) to give the parent compound as a white solid (1.3 g, 44% yield); δH (400 MHz, DMSO) 9.87 (1H, d, 3.4 Hz), 9.39 (1H, d, 3.2 Hz), 7.97 (1H, m), 7.77 (2H, m), 7.68-7.72 (1H, m), 3.83 (3H, s); TR=1.43 min.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1>CO>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1ccn(CCO)c(C(O)c2cccnc2)c1OCc1ccccc1
Solvent: CO
Product: O=c1ccn(CCO)c(C(O)c2cccnc2)c1O

Procedure:
At room temperature and under normal pressure, 0.6 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-pyridin-3-yl-methyl)-1H-pyridin-4-one are hydrogenated in 20 ml of methanol until 1 mol of H2 per mol of starting material has been taken up. The catalyst is removed by filtration and the flitrate is concentrated to dryness by evaporation. The residue is recrystallised from methanol, yielding 3-hydroxy-1-(2-hydroxy-ethyl)-2-(hydroxy-pyridin-3-yl-methyl)-1H-pyridin-4-one in the form of colourless crystals, m.p.: 189°-190.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:41]2[S:40][C:39]3[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=3[CH:42]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)c1cc2cc(F)ccc2s1
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3cc(F)ccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (300 mg, 0.601 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (236 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (695 mg, 0.601 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 mL) was heated to 120° C. via microwave irradiation for 30 minutes. After the solvent was removed, the crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The fractions were collected to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was first dissolved in DCM (3 mL) then TFA/DCM (1:1, 10 mL) and the mixture was stirred at 60° C. for 1 hour. After solvent was removed, the resulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) and purified via preparative mass trigger LCMS, eluting with gradient of 30-40 ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The mixture was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×300 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (77 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-2.09 (m, 8H), 3.82 (br s, 1H), 4.31 (d, J=1.95 Hz, 1H), 4.42-4.53 (m, 2H), 7.13 (d, J=5.86 Hz, 1H), 7.27 (td, J=8.91, 2.69 Hz, 1H), 7.56-7.82 (m, 3H), 7.94-8.04 (m, 1H), 8.64 (s, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.