Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.[C:47]([O:51][C:52](=[O:59])[C:53]([CH3:58])([CH3:57])[C:54]([OH:56])=[O:55])([CH3:50])([CH3:49])[CH3:48].[I-].[Na+].C(=O)([O-])O.[K+].[Cl-].[Na+]>C(OCC)(=O)C.O.CC(N(C)C)=O>[C:47]([O:51][C:52](=[O:59])[C:53]([CH3:58])([CH3:57])[C:54]([O:56][CH2:35][O:34][C:32]1[N:31]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C@H:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH2:43])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])=[CH:9][CH:10]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[N:33]=1)=[O:55])([CH3:50])([CH3:48])[CH3:49]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (170 mg), 2,2-dimethylmalonic acid mono-t-butyl ester [CAS No. 143688-40-8] (490 mg), sodium iodide (390 mg), potassium hydrogen carbonate (182 mg), and DMA (25 mL) was stirred at 50° C. overnight. After cooling the mixture to room temperature, 1:1 mixture of water and saturated aqueous sodium chloride and ethyl acetate were added thereto, and the resulting mixture was extracted. The aqueous layer was reextracted with ethyl acetate twice. All the organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain a racemate of the captioned compound.
Reaction SMILES: [C:1](=[O:57])([O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([O:33]CC1C=CC=CC=1)[C@@H:10]([O:41]CC1C=CC=CC=1)[C@@H:9]2[O:49]CC1C=CC=CC=1)[CH3:7])[O:2][CH2:3][CH3:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[C:1](=[O:57])([O:2][CH2:3][CH3:4])[O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([OH:33])[C@@H:10]([OH:41])[C@@H:9]2[OH:49])[CH3:7]
Reactant: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of ethyl 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl carbonate 12a (76.3 g, 0.09 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.05 mL, 0.48 mmol) and 10% Pd/C (12 mg, 0.01 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/4 to give the title compound 12 as a light yellow solid (38 mg, 60%, HPLC: 89.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 523.2 [M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (m, 1H), 7.09 (s, 2H), 6.83 (m, 2H), 5.59 (d, 1H), 5.13 (d, 1H), 5.02 (d, 1H), 4.93 (m, 1H), 4.14-4.02 (m, 3H), 4.02-3.92 (m, 4H), 3.55 (d, 2H), 3.47-3.37 (m, 2H), 1.31 (m, 6H), 1.19 (t, 3H).
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[S:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)sc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzothiazole-7-yl)-acetonitrile (40 mg 0.23 mmol) (Starting Material 8) was suspended in concentrated H2SO4 /H2O (1/1, 2 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. Subsequently, to a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (88.4 mg, 1.36 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one. (Yield 12 mg, 33%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](Cl)=[O:26])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2].[N+:29](=[CH2:31])=[N-:30]>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:26])[CH:31]=[N+:29]=[N-:30])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 13, compound (19) is reacted with diazomethane at room temperature without being separated from the reaction solution, so that the 4-chlorocarbonyl group of compound (19) is converted into diazoacetyl group, affording 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-4-diazoacetyl-5-(dimethylaminomethyleneamino)-imidazole [compound (20)].
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]3[N:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:14][C:15]=3[CH3:16])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (549 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetate (618 mg, yield: 74%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([O:38][CH3:39])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (500 mg, 1.76 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methoxypyrimidin-5-yl)ethanamine (800 mg, 2.82 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to afford a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1Cl)=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].ClCCl.CO.[CH3:30][NH:31][CH3:32]>C(O)C.O>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[N:31]([CH3:32])[CH3:30])=[C:12]([CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: CNC
Reactant: Cc1cccc2c1c(Cl)c(C(=O)N(C)c1ccccc1)c(=O)n2C
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1c(N(C)C)c(C(=O)N(C)c1ccccc1)c(=O)n2C

Procedure:
N-Methyl-N-phenyl-4-chloro-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (0.52 g) in a mixture of dimethylamine and ethanol was heated in a thick-walled glass flask stoppered by a screw cap. The reaction was monitored by TLC (mixtures of dichloromethane/methanol were used as elutents). After 8 hours of heating the flask was cooled, opened, and diluted with water. The resulting precipitate was filtered, washed with water and dried in vacuum to afford the title compound (0.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][C:11]2([S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][CH:3]=1>[Pd].CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(CCCc3ccc(Cl)cc3)SC(=O)NC2=O)cc1

Procedure:
A sample of 5-[3-(4-Chlorophenyl)prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione (U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.) was hydrogenated in the presence of palladium on charcoal (10%) in methanol plus 2% water to give the title compound as a colorless glass, NMR (CDCl3) δ 1.57 (m, 1H); 1.97 (m, 1H); 2.20 (triplet of doublet), 1H); 2.45 (m, 1H); 2.61 (q, 2H); 3.92 (s, 3H); 7.0 (dd, 4H); 7.26 (d, 2H) 7.98 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:28][CH:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([OH:32])=[O:31].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:28][CH:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([OH:32])=[O:31].[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][CH:24]=1)=[O:4]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCCCCCC(C)C(=O)Cl
Agent: CCCCCCC(C)C(=O)O
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 48.9 %

Procedure:
Next, 2.02 g (11.4 mmol) of the above (+)-2-methyloctanoic acid chloride and 3 ml of nitrobenzene were charged into a flask, and cooled to 0° C., to which was added 3.06 g (22.9 mmol) of anhydrous aluminum chloride with stirring and then the resulting mixture was stirred at room temperature for 30 minutes. This mixture was added with a solution of 2.89 g (7 mmol) of (+)-2-methyloctanoic acid biphenyl dissolved in 3 ml of nitrobenzene, which was reacted at room temperature for 140 hours with stirring. After the completion of the reaction, 2N hydrochloric acid and ice were added, and the extraction with chloroform was carried out, and the extract was washed with water, dried on anhydrous magnesium sulfate, distilled to remove the solvent, and purified by a column chromatography of silica gel to obtain 1.55 g (yield 49%) of an oily (+)-2-methyloctanoic acid-4-(2-methyloctanoyl) biphenyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:38]=[O:39].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:38][OH:39])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1C(CO)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.100 g, 0.25 mmol) in THF (3 mL) at −78° C. was added LDA (0.15 mL, 0.3 mmol, 2 M in THF). After stirring for 10 min at −78° C., dry paraformaldehyde (0.025 g, 0.82 mmol, suspended in THF) was added. The mixture was then warmed to rt for 8 min, followed by the addition of sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to yield the desired product (0.056 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.42 (m, 2H), 7.18 (dd, J=8.4, 8.4 Hz, 2H), 6.36 (s, 1H), 5.41 (t, J=5.6 Hz, 1H), 4.36 (m, 1H), 4.20 (m, 1H), 3.69 (m, 1H), 3.26 (m, 1H), 2.76 (m, 2H), 2.31 (s, 3H), 1.92 (m, 2H); MS: (ES) m/z calculated for C20H19F4N5O2 [M+H]+ 438.1, found 438.1.
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: O=C(O)c1cccnc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ccncc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3cccnc3)C1)c1ccncc21
Yield: 88.9 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,8-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (145 mg, 0.31 mmol) with nicotinic acid (45 mg, 0.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol), 1-hydroxy-7-azabenzo-triazole (49 mg, 0.36 mmol), and N,N-diisopropylethyl amine (0.20 mL, 1.15 mmol), in N,N-dimethylformamide (4 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Eluted over silica gel using methanol/dichloromethane to give 115 mg (83%) of the desired amide as a solid. MS(ES): (M+1)+ 418.0,419.0 m/z.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][CH2:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:37][O:36][CH2:35]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(C)C=CC=CC=1>[Si:19]([O:26][CH2:27][CH:28]1[N:29]([CH:34]2[CH2:37][O:36][CH2:35]2)[CH2:30][CH2:31][N:32]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:33]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCN1C1COC1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Temperature: 105 °C
Yield: 62.4 %

Procedure:
(+/−) Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (545 mg, 1.644 mmol), 2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxetan-3-yl)piperazine (518 mg, 1.808 mmol), Pd2(dba)3 (151 mg, 0.164 mmol), BINAP (102 mg, 0.164 mmol), Cs2CO3 (1071 mg, 3.29 mmol), and Toluene (16 mL) were combined in a 2 dram vial. The vial was evacuated and backfilled with Ar 3×, and the reaction was heated at 105° C. for 18 h. The reaction was cooled to rt and diluted with MeOH. The solution was filtered through celite and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography (0-50% EtOAc/Hex). (+/−) tert-butyl (3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)carbamate (551 mg) was obtained as an orange glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:23][CH3:24])[C:11]=1[O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:23][CH3:24])[C:11]([O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC/C=C(\C)CCC=C(C)C)c(OC)c1
Yield: 95.9 %

Procedure:
In a manner identical to Example 15, 3,5-dimethoxy-4-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 1.02 g (95%) of the aimed compound.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]#[C:4][Si](C(C)C)(C(C)C)C(C)C.[CH:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]([F:15])([F:16])[C:3]#[C:4][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC=O
Reactant: CC(C)[Si](C#CC(F)(F)Br)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCC(O)C#CC(F)(F)Br
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of (3-bromo-3,3-difluoro-prop-1-ynyl)-triisopropyl-silane (156 mg, 0.5 mmol) and hexanal (60 mg, 0.6 mmol) in THF (5 mL), TBAF (1M, 0.75 mL) was added dropwise at −90° C. After the addition was completed, the reaction mixture was stirred for 0.5 h and quenched with saturated aq. NH4Cl. The mixture was extracted with ether (20 mL×3) and washed with water (20 mL×2). After drying over Na2SO4 the solvent was removed and the product was purified by silica gel chromatography (AcOEt:hexane=1:20) to afford the title compound (82 mg, 65%) as colorless liquid. Colorless liquid, yield: 78%. IR (neat): 3320, 2934, 2261, 1223, 1096 cm−1 . 1H NMR (500 MHz, CDCl3) δ 4.49-4.52 (m, 1H), 2.14 (bs, 1H), 1.74-1.77 (m, 2H), 1.45-1.47 (m, 2H), 1.33-1.38 (m, 4H), 0.91 (t, J=6.5 Hz, 3H); 19F NMR (470 MHz, CDCl3) δ −32.9 (s, 2F); 13C NMR (125 MHz, CDCl3) δ 101.5 (t, J=288 Hz), 91.5 (t, J=5.8 Hz), 77.3 (t, J=38 Hz), 62.2, 36.8, 31.4, 24.6, 22.6, 14.1; GCMS: 157, 137, 115, 104, 91.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([NH:32][CH2:33][CH:34]([F:36])[F:35])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1.C(O)(=O)C.C=O>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:33][CH:34]([F:36])[F:35])[CH3:1])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(N2CC[C@@H](NCC(F)F)C2)nc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(F)F)[C@@H]1CCN(c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)C1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Add sodium cyanoborohydride (716 μmol, 45 mg) to a room temperature mixture of 2-(4-chloro-phenyl)-6-{6-[(R)-3-(2,2-difluoro-ethylamino)-pyrrolidin-1-yl]-pyridin-3-yl}-6H-thieno[2,3-c]pyridin-7-one, hydrochloride (150 mg, 287 μmol), acetic acid (49 μL, 360 μmol,) and formaldehyde (115 μL, 1.53 mmol, 37% aqueous solution) in methanol (9 mL) and stir the mixture for 18 h. Concentrate the mixture and partition between CH2Cl2 (5 mL) and 1N NaOH (5 mL). Separate the organic portion and extract the aqueous portion with CH2Cl2 (3×). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography 0% to 5% MeOH (2M NH3)/CH2Cl2 to afford 116 mg (80%) of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one. Add 1M hydrogen chloride in ethanol (232 μL, 232 μmol) to a solution of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one (232 μmol, 116 mg) in dichloromethane (2 mL) and stir the mixture at room temperature for 5 min. Dilute the mixture with of Et2O (8 mL) and filter. Rinse the solid with Et2O (2×) and dry under vacuum at 80° C. to afford 100 mg (80%) of the title compound. LC-MS/ES m/z (35Cl) 501.0 [M+H]+.