Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: Cc1ccc2nc(C#N)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1nc2ccc(CBr)cc2o1

Procedure:
To a stirred solution of 2-cyano-6-methylbenzoxazole (2.0 g, 12.66 mmol) in carbon tetrachloride (50 ml) at room temperature are added successively N-bromosuccinimide (2.37 g, 13.3 mmol) and benzoyl peroxide (30.7 mg, 0.13 mmol). The solution is irradiated with a sun-lamp for 2 hours and concentrated. The residue is dissolved in 500 ml of ether and the solution filtered. The filtrate is concentrated and subjected to HPLC (2% ethyl acetate in hexane) to afford 2-cyano-6-bromomethylbenzoxazole which is used directly in the next step.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:10]1([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([CH2:23][NH2:24])[CH2:20][C@H:19]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[N:10]1([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20][C@H:19]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: BrCc1ccccc1
Reactant: NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](CNCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
Benzyl bromide (0.067 mL, 0.56 mmol) was added to a mixture of (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-aminomethyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride salt (0.247 g, 0.564 mmol), DMF (10 mL) and K2CO3 (0.312 g, 2.26 mmol), prepared as in Reference 12. The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with 1N hydrochloric acid (30 mL). The dilution was washed with ethyl acetate (30 mL). The aqueous layer was basified with 2N sodium hydroxide (40 mL) and extracted with methylene chloride (40 mL). The extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 262, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((benzylamino)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (23 mg, 0.044 mmol, 8%), as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.03 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.58 (d, J=7.6 Hz, 2H), 7.37-7.30 (m, 3H), 7.25-7.17 (m, 3H), 7.03-6.94 (m, 5H), 5.30, 5.19 (m, 2H), 4.49-4.46 (m, 2H), 3.89-3.84 (m, 1H), 3.74 (s, 2H), 2.69-2.52 (m, 2H), 2.16-1.87 (m, 2H). MS (EI) for C29H29FN6O3. found 529.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][C@@H:31]([OH:35])[C@H:32]([OH:34])[CH3:33]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH2:30][CH:31]([OH:35])[CH:32]([OH:34])[CH3:33])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: C[C@@H](O)[C@H](O)CN
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCC(O)C(C)O)nc21
Yield: 90.9 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-(2,3-dihydroxy-butylamino)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 7 using 0.40 g (0.97 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.245 g (2.33 mmol) of (2R,3R)-1-amino-butane-2,3-diol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.40 g (91%) of title compound: mp 171° C.–173° C. MS (APCI) (m+1)/z 454.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12](OCC)[CH3:13]>C(OC(=O)C)(=O)C>[CH3:12][C:13]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Nc1ccncc1S(N)(=O)=O
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC1=NS(=O)(=O)c2cnccc2N1

Procedure:
1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) is maintained for 4-6 hours at reflux in 10 cm3 of acetic anhydride. After cooling, the reaction mixture is treated with 60 cm3 of diethyl ether. The precipitate obtained is filtered, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:33])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:28]([F:31])([F:30])[F:29])[C:8]=1[CH3:32]>C1COCC1.CO>[Cl:16][C:12]1[N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=3[C:28]([F:29])([F:31])[F:30])[C:8]([CH3:32])=[C:7]([CH2:6][C:5]([OH:33])=[O:4])[C:15]2=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1M Aqueous NaOH (0.25 ml) is added to a stirring suspension of [6-chloro-1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (0.01 g, 0.021 mmol) in 1:1 THF/MeOH (0.5 ml). The resulting suspension is sonicated and allowed to stir at room temperature overnight. The solvent is removed in vacuo and the crude solid is dissolved in water (0.5 ml) and acidified to pH 2-3 using 1 N HCl. The suspension which forms is filtered, washed with water (0.5 ml) and dried under high vacuum to yield the titled compound. (MH+461)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26](=O)[C:27](OC)=[O:28])=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: CCc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 30 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (370 mg, 1.97 mmol) and methyl 2-(6-ethyl-1H-indol-3-yl)oxoacetate (446 mg, 1.93 mmol) in DMF (8.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (6.0 mL, 6.0 mmol) dropwise over 20 min. The reaction was heated to 50° C. and stirred for 7 h at this temperature. The reaction mixture was then cooled to room temp and quenched with 1.0 N hydrochloric acid (5.0 mL), extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% EtOAc/hexanes containing 1% TEA) gave the title compound (214 mg, 30%) as a red solid, mp 98–100° C. 1H NMR (DMSO-d6) δ 11.69 (s, 1H), 11.06 (s, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 7.28 (m, 1H), 7.16 (s, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 6.50 (m, 1H), 6.32 (m, 1H), 6.20 (m, 1H), 3.69 (s, 3H), 3.32 (m, 2H), 1.11 (m, 3H). MS (ESI, negative mode): m/z=368 [C23H19N3O2−H]−
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:19])[C:6]([CH3:18])=[C:7]([OH:17])[C:8]=2[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[O:3]1.C(OCC)(=[O:23])C>[Pd]>[OH:3][C:2]([CH3:20])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:23])[C:5]([CH3:19])=[C:6]([CH3:18])[C:7](=[O:17])[C:8]=1[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Agent: [Pd]
Product: CC1=C(C)C(=O)C(CCC(C)(C)O)=C(CCC(C)C)C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (68 mg) in ethyl acetate (2.4 mL) was added Pd/C (26 mg, 5% w/w). The resulting suspension was flushed with hydrogen gas, the container sealed, and the contents stirred under 1 atm of hydrogen gas for 30 min. The mixture was then filtered and concentrated in vacuo. The resulting residue was dissolved in acetonitrile-water (5:1, 2.6 mL) and the solution cooled to 5° C. in an ice-water bath. Into the reaction mixture was added a solution of cerium(IV) ammonium nitrate (287 mg) in acetonitrile-water (1:4, 1.6 mL) over a period of 5 minutes. The reaction mixture was allowed to stir for an additional 5 minutes, after which it was poured into a separatory funnel containing dichloromethane (30 mL) and water (30 mL). The aqueous layer was removed and the remaining organics were washed once with 1.0 M sodium chloride solution (30 mL). The organics were subsequently dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (18% ethyl acetate-82% hexanes) provided 29 mg of 2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-butyl)-[1,4]benzoquinone. 1H NMR (CDCl3, 400 MHz) 2.53 (m, 2H), 2.43 (m, 2H), 1.99 (s, 3H), 1.62 (m, 1H), 1.53 (m, 2H), 1.24 (m, 8H), 0.94 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Cl)cc1NC(=O)C1CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-(piperidine-4-carboxamido)anisole (10.4 g) was dissolved in a mixture of acetic acid (100 ml) and concentrated sulphuric acid (5 ml). Fuming nitric acid (2.1 ml) was added dropwise, keeping the temperature below 30°. The solution was stirred at room temperature for 2 hr, poured onto crushed ice (ca 500 ml) and basified with 40% sodium hydroxide. The mixture was extracted with ethyl acetate (2×250 ml), the extracts dried (K2CO3) and solvent removed at the pump. The brown residue was crystallised from ethyl acetate and petroleum ether (b.p. 60°-80°), giving 4-chloro-5-nitro-2-(piperidine-4-carboxamido)anisole as brown plates (e17) (9.9 g, 82%), m.p. 167°-170°.
Reaction SMILES: [NH:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36](Cl)=[O:37].P(O)(O)([O-])=O.[K+]>C(Cl)Cl>[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36]([N:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3])=[O:37]
Reactant: NC(=O)NC[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1
Reactant: COC=C(C)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC=C(C)C(=O)N(C[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In 32.2 ml of methylene chloride was dissolved 2.3 g of 1-ureido-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol followed by addit ion of 9.2 ml of pyridine. Then, 1.67 g of 2-methyl-3-methoxypropenoyl chloride was added and the mixture was stirred at room temperature overnight. This reaction mixture was poured in 5% aqueous solution of monopotassium phosphate followed by extraction with ethyl acetate. The organic layer was washed with 5% aqueous monopotassium phosphate solut ion thrice, saturated aqueous sodium hydrogen carbonate solution once, and saturated aqueous sodium chloride solution once in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (chloroform→1% methanol/chloroform) to provide 2.3 g of the desirable compound as pale-yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8](=[O:10])[CH3:9])=[N:4][N:3]=1.Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2([C:8](=[O:10])[CH3:9])[CH2:13][CH2:12]2)=[N:4][N:3]=1
Reactant: BrCCBr
Reactant: CC(=O)Cc1nnc(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C1(c2nnc(C)o2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
A mixture of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-propan-2-one (312 mg, 2.2 mmol), 1,2-dibromo-ethane (0.25 mL, 2.85 mmol), and potassium carbonate (770 mg, 5.6 mmol) in acetone (5 mL) was stirred at 60° C. for 16 h. Insoluble material was filtered off and the filtrate was diluted with ethyl acetate (30 mL). The solution was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-100% ethyl acetate as eluent to afford the title compound (75 mg, 20%) as pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=1.Cl>CO.[Pt]=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: Clc1cccc(C2=CCNCC2)c1Cl
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Clc1cccc(C2CCNCC2)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridine (0.49 g, 2.15 mmol), platinum oxide (0.11 g) and hydrochloric acid (0.1 ml, conc) in methanol (30 ml) was hydrogenated at 50 psi for 1 h under hydrogen gas. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethylacetate (3×30 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Yield: 0.17 g. MS m/z (rel. intensity, 70 eV) 230 (M+, 22), 229 (24), 228 (35), 196 (30), 194 (bp).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][C:13]1([CH3:20])[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[O:14]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[S:1]1[C:2]([CH:10]=[CH:19][C:15]2[O:14][C:13]([CH3:20])([CH3:12])[C:17](=[O:18])[CH:16]=2)=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1cc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cc3ccccc3s2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 2-benzothiophenecarboxaldehyde (1.5 g, 9.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.6 g, 9.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred at room temperature for one day, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The residue was purified by chromatography (silica gel, hexane-ethyl acetate) to afford a yellow solid (2.2 g, 58% yield), m.p. 103.5°-104° C.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[C:17]1([Si:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][Si:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Yield: 60.3 %

Procedure:
The title compound was synthesised following a similar procedure as described for Example 11. 3′-Fluoro-2′,3′-dideoxyuridine (0.214 g, 0.93 mmol) was reacted with triphenylsilyl chloride (0.332 g, 1.12 mmol) in dry pyridine (7 mL) for 3 h. to yield the title compound as a white solid (0.274 g, 60%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[O:29]=[C:25]1[CH2:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCCN1CCCC1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCCC3=O)s2)c(C)[nH]c1=O
Yield: 69 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(3-aminopropyl)pyrrolidin-2-one as described in Step 5, Example 24 to give the title compound as a white solid (69% yield). LC/MS: RT 2.42 min; m/e 424.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and propionyl chloride. m.p.: 152-155° C. 1H-NMR (CDCl3) δ: 10.02 (1H, br s), 8.36-8.20 (2H, m), 7.63-7.51 (2H, m), 7.48-7.38 (2H, m), 7.28 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.50 (2H, q, J=7.7 Hz), 2.46 (3H, s), 1.29 (3H, t, J=7.7 Hz)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[OH:13].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([NH2:10])[C:3]=1[OH:13]
Reactant: Cc1cc([N+](=O)[O-])c(O)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1F
Yield: 98.9 %

Procedure:
A solution of 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol) (D44) in ethanol (120 mL) was hydrogenated using a 10% Pd/C cartridge in the H-cube™ hydrogenator at 1 mL/min and full hydrogen at 25° C. Evaporation gave 2,3-difluoro-4-methyl-6-aminophenol (1.0 g, 6.28 mmol, 99% yield) as a fawn solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCNC
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: Fc1cccc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzyl chloride gave the title compound. ES-MS m/e (%): 567.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: O=C1Nc2cccc(F)c2C1=CO
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4cccc(F)c43)cc2)C1
Yield: 67.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (576 mg, 68%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([F:20])[CH:5]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1>>[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:15][CH2:16][N:17]([C:36](=[O:37])[CH2:35][N:28]3[C:29]4=[N:30][CH:31]=[CH:32][CH:33]=[C:34]4[C:26]([C:22]4[NH:21][CH:25]=[CH:24][N:23]=4)=[N:27]3)[CH2:18][CH2:19]2)=[C:6]([F:20])[CH:5]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FCCOc1cc(N2CCNCC2)c(F)cc1Cl
Agent: Cl
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2cc(OCCF)c(Cl)cc2F)CC1

Procedure:
The title compound was prepared following Protocol A. 1-[4-Chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]-piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3.5% MeOH in CH2Cl2) to provide 1-{4-[4-chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]piperazin-1-yl}-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H, J=8.0, 1.8 Hz), 8.67 (d, 0.4H, J=6.4 Hz), 8.57-8.55 (m, 1H), 7.30-7.25 (m, 1H), 7.11-7.06 (m, 2H), 6.63 (d, 0.6H, J=7.6 Hz), 6.57 (d, 0.4H, J=7.6 Hz), 6.54 (d, 1H, J=7.6 Hz), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.83-4.80 (m, 1H), 4.71-4.68 (m, 1H), 4.31-4.18 (m, 2H), 3.82-3.76 (m, 3H), 3.50 (t, 1H, J=5.2 Hz), 3.23-3.04 (m, 4H); LC/MS m/z (M+H)+ 502.4.