Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].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.CCN(C(C)C)C(C)C>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:24]([N:28]1[CH2:33][CH2:32][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)[N:8]=[C:7]4[C:6]=3[CH:23]=2)[CH2:30][CH2:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (100 mg, 0.27 mmol), 1-tert-butylpiperidine-4-thiol (120 mg, 0.69 mmol), Pd2(dba)3 (24 mg, 10 mol %), XantPhos (31 mg, 20 mol %) and DIPEA (186 μL, 1.07 mmol) in dioxane (3 mL) was purged with argon and heated at 120° C. for 40 min using microwave irradiation. The reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%). LCMS: RT 3.11 min [M+H]+ 467.4. 1H NMR (DMSO, 400 MHz): δ 8.54 (1H, d, J=2.35 Hz), 7.94 (1H, d, J=0.67 Hz), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.48 Hz), 5.92-5.91 (1H, m), 4.55-4.49 (4H, m), 3.06-3.04 (3H, m), 2.30 (2H, t, J=11.23 Hz), 2.08-1.96 (2H, m), 1.65-1.64 (2H, m), 1.58 (6H, d, J=6.65 Hz), 1.08 (9H, s)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C:13]([CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:16][O:17][S:35]([CH3:34])(=[O:37])=[O:36])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[O:27][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of nucleoside 5 (1100 mg, 2.91 mmol) in anhydrous tetrahydrofuran (20 cm3) was added anhydrous pyridine (5 cm3) followed by methanesulfonyl chloride (1.2 ml, 15.5 mmol). The mixture was stirred under a nitrogen atmosphere for 18 h at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and dissolved in ethyl acetate. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate (3×10 cm3) and dried (Na2SO4). The organic phase was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2% methanol, v/v) as elutxnt to afford nucleoside 11 (908 mg, 51%). δC (CDCl3) 163.3, 150.6, 135.6, 134.6, 128.7, 128.3, 112.2, 87.9, 85.0, 83.1, 80.9, 77.2, 76.9, 76.6, 73.3, 66.6, 66.2, 38.6, 37.6, 37.6, 12.2.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-iodo-benzo[1,3]dioxol-5-ylmethyl)adenine (6 mg, 0.0145 mmol), Cs2CO3 (5 mg, 0.0145 mmol) and pent-4-ynyl tosylate (4.5 mg, 0.189 mmol) in anhydrous DMF (200 L) was stirred at 60° C. for 1.5 h. Following solvent removal, product (5.9 mg, 84.9%) was collected through silica gel column purification (EtOAc:hexanes:CHCl3:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDCl3) 7.29 (s, 1H), 6.59 (s, 1H), 5.94 (s, 2H), 5.83 (bs, 2H), 4.26 (s, 2H), 4.11 (t, J=7.4 Hz, 2H), 2.26-2.19 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.98-1.94 (m, 2H); 13C NMR (100 MHz, CDCl3) 150.9, 148.9, 147.8, 131.5, 118.8, 109.4, 101.9, 88.1, 82.3, 69.9, 42.3, 39.2, 28.2, 15.9; MS m/z 480.0 (M+H)+. HPLC: (a) 95.5% (60% water-40% acetonitrile); (b) 95.0% (35% to 55% acetonitrile).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc(N3CCNCC3)nc3ccccc23)cc1
Yield: 91.1 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (4.0 g) and anhydrous piperazine (8.0 g) in toluene (4 ml) is heated under reflux for 5 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (40 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (4.4 g), m.p. 133°-134° C.
Reaction SMILES: CI.[CH2:3](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.[C:19]1([S:25]([CH:27]2[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:27]2([CH3:3])[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1S(=O)c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)S(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride and 27b is substituted for 2, the title compound is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15]([CH3:16])=[N:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[C:8]=3[N:9]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c12

Procedure:
In analogy to Example 1 step (c) the title compound was synthesized starting from 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester and 4-benzyloxy-phenylboronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31][NH2:32]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31][NH:32][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: NCCc1cccs1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4cccs4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and thiophene-2-ethylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 443 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:32]([OH:34])=[O:33])[CH:7]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
3.00 g (0.0086 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 5.9 ml of a 1.6M-hexane solution of BuLi (0.0086×1.1 mol) was added thereto, followed by stirring the obtained solution for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: O.O.O.[F-].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[C:23]([O:24]COCC[Si](C)(C)C)=[C:22]([Si](C)(C)C)[CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:37]=1)#[N:6]>O1CCCC1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:37]=1)#[N:6]
Reactant: CC1(C)N=C(c2nccc([Si](C)(C)C)c2OCOCC[Si](C)(C)C)c2cc(C#N)ccc2O1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)N=C(c2ncccc2O)c2cc(C#N)ccc2O1
Yield: 13.1 %

Procedure:
Molecular sieves 5A (5 g) and tertrabutylammonium fluoride trihydrate (3.2 g) were added to a solution of 6-cyano-2,2-dimethyl-4-[4-trimethylsilyl-3-(2-trimethylsilylethoxymethyloxy)pyridin-2-yl]-2H-1,3-benzoxazine (2.5 g) in tetrahydrofuran (20 ml), and the mixture was heated under reflux for 30 minutes. After air-cooling, the mixture was extracted by addition of ethyl acetate. The organic layer was washed with saturated saline solution, the solvent was distilled off under reduced pressure and the residue was crystallized from ethyl acetate to obtain 6-cyano-2,2-dimethyl-4-(3-hydroxypyridin-2-yl)-2H-1,3-benzoxazine (0.19 g) (Compound 12).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC.O[C:50]1[CH:51]=[C:52]([S:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:53]=[CH:54][CH:55]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][O:16][C:54]3[CH:53]=[C:52]([S:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:51]=[CH:50][CH:55]=3)[CH:13]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCO
Reactant: CCOC(=O)CCCSc1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCSc1cccc(OCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of 5-(diphenylmethyl)-1-(2-hydroxyethyl)pyridin-2(1H)-one (300 mg) in toluene (4.0 mL) were added 1,1′-azobis(N,N-dimethylformamide) (203 mg) and tributylphosphine (291 μL) at ambient temperature. And then to the mixture was added a solution of ethyl 4-[(3-hydroxyphenyl)sulfanyl]butanoate (378 mg) in toluene (2.0 mL) at 0° C. After stirring at ambient temperature for an hour, the reaction mixture was diluted with EtOAc (10 mL). The mixture was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The oil was purified by silica gel column chromatography(n-hexane:EtOAc=4:1-1:1) to give ethyl 4-[(3-{2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethoxy}phenyl)sulfanyl]butanoate (436 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:21])=O>>[Br:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)[nH]1
Product: FC(F)(F)c1cc(Br)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-trifluoromethyl-1H-pyridin-2-one (example A.16 step 2) (7.38 g, 27 mmol) and phosphoryl bromide (25 g, 87 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a brown solid (8.92 g, 98%). MS (EI) 334.8 [(M)+], 336.7 [(M+2)+], 338.8 [(M+4)+] and 339.8 [(M+6)+]; mp 51-53° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#N)=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1.C[OH:15].O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:11]2
Reactant: CO
Reactant: N#CCc1c(F)cccc1[N+](=O)[O-]
Solvent: O
Product: O=C1Cc2c(F)cccc2N1
Temperature: 25 °C

Procedure:
6-Fluoro-2-nitrobenzyl cyanide (23.10 g, 0.12 mole) (prepared according to A. Kalir, Synthesis (1987) 514-515) was dissolved in 10:1 MeOH/H2O (250 mL) and the solution was chilled in an ice water bath. HBr gas was bubbled into the cold mixture for 75 min. The solution was allowed to warm up to r.t. and then concentrated to half its volume under reduced pressure. THF (100 mL), water (100 mL) and conc. HCl (6 mL) were successively added at r.t. and stirring was maintained for 75 min. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, sat. aq. NaHCO3 and brine, then dried over sodium sulfate and concentrated under educed pressure. This material (20.9 g) was dissolved in acetic acid (200 mL) and hydrogenated for 2 h in a Parr apparatus at 50 Psi, in the presence of 10% Pd/C (4.33 g). The reaction mixture was filtered through a cake of Celite®, and the cake was washed with acetic acid. The solution was concentrated under reduced pressure and dissolved in MeOH (300 mL) containing 1N NaOH (15 mL). This mixture was poured into 2:1 sat aq. NaCl/H2O (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was triturated with ether to afford 5.8 g (first crop) of pure 1,3-dihydro-4-fluoro-2H-indol-2-one. The mother liquor was chromatographed on Silica Gel (230-400 mesh, eluted with 40% ethyl acetate in hexanes) to yield 16 g of product (overall yield from cyanide: 41%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-piperidin-1-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (39 mg, 0.10 mmole) and glycine (573 mg, 7.63 mmole) in 0.5 M sodium methoxide/methanol (10.2 ml) was refluxed for 25 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 ml) and extracted three times with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 ml). The suspension was extracted with ethyl acetate (2×40 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (40 mg). MS: (+) m/z 413.30 (M+1), MS: (−) m/z 411.33 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([NH2:30])[CH2:28][CH3:29])=[N:25][CH:26]=1>>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][N:25]=3)[CH2:28][CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: CC[C@H](N)c1ccc(F)cn1
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Product: CCOc1cc(Nc2nc(N[C@@H](CC)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 28 using 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26) and [(1S)-1-(5-fluoropyridin-2-yl)propyl]amine (Intermediate 35) as the starting materials. LCMS: 402 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.00 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.10 (d, 1H), 7.60 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 5.80 (s, 1H), 5.00 (m, 1H), 4.10 (q, 2H), 2.00 (m, 2H), 1.40 (d, 3H), 1.10 (t, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=O)C.[CH2:16]([CH2:18][NH2:19])[OH:17].CN.Cl>O.C(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]([NH:19][CH2:18][CH2:16][OH:17])=[O:12])=[CH:14][CH:15]=1
Reactant: NCCO
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(C=Cc1ccc(O)cc1)NCCO
Temperature: 40 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
43.6 g (194 mmol) of p-acetoxycinnamoyl chloride was added to 200 ml of methylene chloride and heated at 40° C. to make a homogeneous solution. The solution was cooled down to 15°-20° C., into which 35.5 g (582 mmol) of monoethanolamine was dropped. Since the system generated heat during the dropping, it was cooled and the dropping rate was so controlled that the liquid temperature was maintained at 15°-20° C. After completion of the dropping, the system was stirred at room temperature for 1 hour, and was then heated under reflux and stirred for further 1 hour to complete the reaction. After distillation of the methylene chloride under reduced pressure, 50 ml of ethanol was added so as to obtain a substantially homogeneous solution. Thereafter, 30.1 g (388 mmol) of a 40% methylamine aqueous solution was added to the system at one time, followed by heating to 40°-50° C. and stirring for 1 hour. The reaction solution was poured into 800 ml of water, to which a 12% hydrochloric acid aqueous solution was added to a pH of about 3. The resultant crystals were filtered off and recrystallized from acetone to obtain 24.9 g of p-hydroxy-N-(2-hydroxyethyl)cinnamamide as colorless or slightly yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[NH:13]1[CH2:14][CH2:15][CH:10]([O:9][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:12]1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCNCC1
Product: Brc1ccc(OC2CCNCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 4-hydroxypiperidine by the method of Example 10 (b).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:46][C:41]=2[O:40][CH2:39]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:9]([OH:20])[CH2:10][N:11]([S:47]([C:45]1[CH:44]=[CH:43][C:42]2[O:38][CH2:39][O:40][C:41]=2[CH:46]=1)(=[O:48])=[O:49])[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 57.9 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.099 g, 0.25 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.066 ml, 0.38 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.067 g, 0.31 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% MeOH in CH2Cl2) gave 0.083 g of a white solid. MS (ES): 574 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:24])[N:35]([CH3:36])[CH3:33])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Acid compound 33 (0.7 g, 1.58 mmol) was dissolved in DCM (20 mL) and stirred at room temp under an atmosphere of argon. Triethylamine (0.26 mL, 1.9 mmol) and BOP reagent (0.77 g, 1.74 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 4.0 mL, 7.9 mmol) was added and the resulting solution was stirred at room temp for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 40 (0.7 g, 94.5%). 1H NMR (400 MHz, DMSO-d6): 7.33 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.93 (overlapped d, J=8.4 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 5.50 (d, J=7.6 Hz, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 2.84 (s, 3H), 2.82 (s, 3H), 2.79 (t, J=8.0 Hz, 2H), 2.59 (t, J=8.0 Hz, 2H), 1.37 (s, 9H).