Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.N1C=CC=CC=1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C(Cl)Cl.CCOC(C)=O>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][C@H:5]2[CH2:10][CH2:9][CH2:8][O:7][CH2:6]2)(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
The above crude product tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was dissolved in anhydrous DCM (22 mL). To this solution was added pyridine (2 mL) and TsCl (1.230 g, 6.45 mmol). After stirred at rt for 4 hr, another batch of pyridine (3 mL) and TsCl (0.700 g, 3.67 mmol) was added and stirred for another 12 hr. The reaction mixture was diluted with EtOAc (80 mL), washed with 1 N HCl (75 mL), followed by H2O (2×30 mL), saturated aq. NaHCO3, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated under reduced pressure. The resulted slurry was purified through flash chromatography on silica gel (eluted with gradient system: 0-35% EtOAc in hexane) to afford (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl 4-methylbenzenesulfonate, 670 mg, yield 75% for two steps. MS ESI +ve m/z 436 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6]([CH:26]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:32]1([C:2]2[CH:3]=[CH:4][C:5]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[C:6]([CH:26]=2)[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)=[O:8])[CH2:34][CH2:33]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(C2CC2)ccc1-n1nccn1

Procedure:
A solution of 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 52; 100 mg, 0.22 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 29 mg, 0.33 mmol), bis(triphenylphosphine)palladium(II) dichloride (3 mg, 4.43 μmol) and potassium carbonate (31 mg, 0.22 mmol) in 1,4-dioxane (1.3 ml) and water (0.13 ml) was sealed and degassed with nitrogen. The reaction was subjected to microwave irradiation at 130° C. for 30 minutes. To this was then added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (157 mg, 0.22 mmol) and the reaction was subjected to microwave irradiation at 130° C. for a further 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with water and brine, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:50]([O:52][C:53](=[O:60])[N:54]([CH2:58][CH3:59])[CH:55]([CH3:57])[CH3:56])[CH3:51]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:50]([O:52][C:53](=[O:60])[N:54]([CH2:58][CH3:59])[CH:55]([CH3:56])[CH3:57])[CH3:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CCN(C(=O)OC(C)Cl)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)OC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1)C(C)C
Yield: 54.3 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 150 mg, 0.243 mmol) in dimethylformamide (6 mL) was added cesium carbonate (243 mg, 0.746 mmol). After stirring for a few minutes, a solution of the above freshly made ethyl-isopropyl-carbamic acid 1-chloro-ethyl ester (190 mg, 0.491 mmol) in dry dimethylformamide (1 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was diluted with ethyl acetate and washed with water, brine and concentrated to dryness. The crude material was purified by chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 1-(ethyl(isopropyl)-carbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (102 mg, 54% yield). LCMS (ES+) m/z calcd. for C39H45Cl2F2N4O6 [(M+H)−]: 773, found: 773.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=[CH:3][N:2]=1.O.NN>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][NH2:14])[CH:4]=[CH:3][N:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc2ccncc12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1cccc2ccncc12
Yield: 100.5 %

Procedure:
To a refluxing solution of 0.174 g of [3-(8-isoquinolinyl) propyl]-1H-isoindole-1,3-(2H)-dione in 8 mL of ethanol was added 0.12 mL of hydrazine hydrate and the reaction was stirred at reflux for 5.5 hours. The solvent was removed under reduced pressure and the residue was triturated with chloroform. The chloroform extract was concentrated to an oil which was passed through a short column of silica gel (chloroform-methanoltriethylamine; 1:4:15) to yield 0.103 g of 8-isoquinolinepropanamine as an oil.
Reaction SMILES: B.CSC.[CH:5]1([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N)CN>C1COCC1>[NH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc(CSC2CCCC2)cn1
Agent: B
Solvent: NCCN
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1ccc(CSC2CCCC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Add borane-dimethylsulfide complex (6.9 mL, 13.7 mmol, 2M solution in THF) to a solution of 5-cyclopentylthiomethyl-pyridine-2-carbonitrile (1 g, 4 mmol) in THF (12 mL) at room temperature under a nitrogen atmosphere. Stir the solution at room temperature for 16 h. Concentrate the solution in vacuo, dissolve the residue in chloroform (50 mL), add ethylenediamine (0.72 g, 12 mmol) and stir at 50° C. for 1 h. Wash the mixture with water (10 mL), dry the organic phase over Na2SO4 and concentrate in vacuo. Purify the residue by SCX chromatography followed by chromatography on silica gel (10 g) eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient) to obtain the title compound (0.24 g, 27%). MS (ES+) m/z: 223.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([F:29])[C:3]=1[F:30].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[F:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([OH:22])[C@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([F:29])[C:3]=1[F:30]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2c(F)c(F)c(F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(C)Nc1nc2c(F)c(F)c(F)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 73.8 %

Procedure:
4,5,6-Trifluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.42 g, 1.02 mmol), ethanol (10 mL), sodium carbonate (0.19 g, 1.79 mmol), water (2 mL) and methanol (5 mL) were used according to general procedure III. The title compound was purified by silica gel chromatography using 10:1 dichloromethane-methanol as eluant to provide a white solid (0.26 g, 75%); m.p. 148-151° C.; 1H NMR (DMSO-d6) δ: 7.10 (m, 1H, Ar—H), 6.68 (d, J=7.5 Hz, NH), 5.70 (d, J=6.7 Hz, 1H, CH), 5.27 (m, 2H, overlapping OH), 4.35 (dd, J=6.6 Hz, 1H, CH), 4.12 (m, 1H, CH), 3.91 (m, 1H, CH), 3.85 (m, 1H, CH), 1.40 (d, J=6.5 Hz, 3H, CH3), 1.24 (d, J=6.4 Hz, 6H, overlapping CH3).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)=O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)OC
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 100 °C
Yield: 56.6 %

Procedure:
In a three-neck flask (capicity 100 ml) equipped with a mechanical stirrer and reflux condenser, 20 ml of dimethylformamide, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 100° C. To this mixture was added 8.00 ml (0.094 mol) of dimethyl sulfite. The mixture was maintained at about 100° C. for eight hours and then cooled to 25° C. and quenched with 500 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to give 4.0 g of 3, 4, 5-trimethoxybenzaldehyde.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([C@@H:10]([NH2:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:20]([C:22]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1)=O.Cl>C(O)C.O>[C:1]([CH:20]([NH:19][C@H:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:22]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1)#[N:2]
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Reactant: [C-]#N
Reactant: CCOC(=O)C1(C=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(C#N)N[C@@H](Cc2ccc(C)cc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
An eggplant type flask was charged with 133 mg of potassium cyanide, 1.0 g of (S)-1-phenyl-2-p-tolylethylamine and 1 ml of water. After adding 146 mg of ethyl 1-formylcyclopropane-1-carboxylate dissolved in 2.5 ml of ethanol, dropwise at room temperature, the resulting mixture was further mixed with 0.2 ml of concentrated hydrochloric acid, and stirred for 1 hour at the same temperature and then for 2 hours at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate and, after removing insoluble matter by filtration, the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 251 mg (67%) of a diastereomer mixture in the form of colorless oil. Formation ratio of the two diastereomers was found to be 4:1 based on the integral ratio of NMR.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1cccc(CC(=O)O)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1F
Reaction time: 8 h
Yield: 82.8 %

Procedure:
In a 20 mL vial with cap, to 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-fluoro-3-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), and HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred overnight. The reaction was poured into water, off-white solid formed. The solid was filtered to give 3-{1-[(2-fluoro-3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (71 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J=1.52 Hz, 3H), 3.24-3.32 (m, 2H), 3.92 (s, 2H), 3.94 (s, 3H), 4.30 (t, J=8.46 Hz, 2H), 7.04-7.11 (m, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.53 (s, 1H), 8.16 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]1[C:2]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(F)c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 100.4 %

Procedure:
A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with 3-bromo-4-fluorobenzonitrile (2.507 g, 1.23×10−2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23×10−2 mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85×10−6 mol, 0.02 mol %), and sodium bicarbonate (1.577 g, 1.82×10−2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80° C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm×150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1% H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35° C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+; 282.0542, found 282.0536; 1H NMR (CDCl3) δ 7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) δ 161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR(KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B<30 ppm, Na<1 ppm; mp˜63.5-64.2° C.
Reaction SMILES: O=[C:2]([CH2:13][CH3:14])[CH2:3][C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5].[NH2:15]/[C:16](/[CH3:30])=[CH:17]\[C:18]([O:20][CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>CC(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:35]2[C:17]([C:18]([O:20][CH2:21][CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:19])=[C:16]([CH3:30])[NH:15][C:2]([CH2:13][CH3:14])=[C:3]2[C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5])[CH:37]=[CH:38][CH:39]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccccc1
Reactant: CCC(=O)CC(=O)OCC[Si](C)(C)C
Solvent: CC(C)O
Product: CCC1=C(C(=O)OCC[Si](C)(C)C)C(c2cccc(Cl)c2)C(C(=O)OCC=Cc2ccccc2)=C(C)N1

Procedure:
649 mg (3.0 mmol) of (2-trimethylsilylethyl) 3-oxovalerate, 652 mg (3.0 mmol) of (3-phenyl-2-propene-1-yl) 3-aminocrotonate and 0.340 ml (3.0 mmol) of 3-chlorobenzaldehyde were heated at 70° C. under stirring in 15 ml of 2-propanol three nights. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([Cl:24])[CH:23]=2)[C:20](=[O:25])[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:22]1[CH:23]=[C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]=[C:17]2[C:21]=1[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 109.2 %

Procedure:
4-[7-Chloro-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (54.90 mg, 0.102 mmol) was stirred in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) overnight. The reaction mixture was quenched with sodium carbonate to pH=8-9 and the free base was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (48.9 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.39 (d, 2H), 7.18 (d, 3H), 7.06 (s, 1H), 4.77 (s, 2H), 4.61 (broad s, 1H), 4.23 (s, 2H), 3.16 (d, 2H), 2.62 (m, 4H), 1.61 (d, 3H), 1.29 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([O-:16])=O)[C:11]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[K+].[CH3:23][O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH2:33][NH2:34])[N:26]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:33][NH:34][C:14]([C:12]2[C:11]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:10][N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=2)=[O:16])=[N:26][C:25]=1[O:24][CH3:23]
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cc(C(=O)[O-])c(-c3nccs3)cn2)c1
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)ncc2-c2nccs2)nc1OC
Temperature: 65 °C
Yield: 74.7 %

Procedure:
Potassium 5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate (7-4, 980 mg, 2.9 mmol, 1 equiv), 1-(5,6-dimethoxypyridin-2-yl)methanamine (3-6, 490 mg, 2.9 mmol, 1 equiv), EDC (670 mg, 3.5 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (480 mg, 3.5 mmol, 1.2 equiv) and diisopropylethylamine (2.0 mL, 12 mmol, 4 equiv) were suspended in DMF (14.6 mL) and the reaction mixture was heated for 2 hours at 65° C. The reaction mixture was then partitioned between DCM (50 mL) and water (50 mL). The layers were separated and the organic layer was dried over MgSO4 and concentrated. The residue was purified by normal phase column chromatography (0-20% MeOH in EtOAc) to afford a white solid that was recrystallized from chloroform/hexanes to give the title compound (7-5) as a crystalline solid (970 mg, 75% yield). 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 2H), 8.53 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.81 (dd, J=3.1 and 1.1 Hz, 1H), 7.78 (t, J=4.8 Hz, 1H), 7.43 (dd, J=3.3 and 1.1 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 4.58 (d, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 2.45 (s, 3H). HRMS (M+H)C23H21N5O3S calc'd 448.1438. found 448.1443
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=O.[CH3:24][C:25](C)=[O:26].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br-:13].[C:25]([O:17][C:15]1[N+:6]2[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][S:3][C:2]=2[S:1][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])[CH3:24]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CC(C)=O
Reactant: CCOC(=O)Cc1csc(S)n1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Cc1csc2sc(-c3ccccc3)c(OC(C)=O)[n+]12
Product: [Br-]

Procedure:
A mixture of 10.0 g (0.05 m.) 2-mercapto-thiazole-4-acetic acid, ethyl ester (prepared according to U.S. Pat. No. 2,766,238) and 10.75 g. (0.05 m.) α-bromophenylacetic acid in 200 ml. of acetone and 20 ml. each of glacial acetic acid and acetic anhydride is heated in an open flask for two hours. The solvents are removed and the residual solid triturated with acetone. 12 g. of title product is obtained, m.p. 160°-170° C. (dec.).
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[NH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[S:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:17])(=[O:14])=[O:13]>C(O)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([C:15]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:10]=[CH:9][S:8][C:7]=3[NH:6][N:1]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: O=N[O-]
Reactant: Nc1sccc1S(=O)(=O)CC(=O)NCc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)C1=NNc2sccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution containing sodium nitrite (0.06 g) and water (1 mL) is cooled to 0° C. before adding a solution of 2-((2-amino-3-thienyl)sulfonyl)-N-(4-chlorobenzyl)-acetamide (Preparation 54, 0.255 g) in hot acetic acid (10 mL) dropwise. The solution is warmed to room temperature and stirred for 30 minutes. The reaction mixture is poured into a beaker containing ice. The crude product is collected by filtration and dried under high vacuum to provide 0.18 g (66%) of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]#[N:27])[CH:4]=3)[NH:8][N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 8.9 %

Procedure:
To a solution of 1.0 g of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 5 ml dimethyl sulfoxide was added 204 mg of sodium cyanide, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 50 ml of ethyl acetate, and after washing with water, the aqueous layer was re-extracted with diethyl ether. The collected organic layer was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9), and suspended in diethyl ether-diisopropyl ether, to give 62 mg of the title compound as yellow crystals.