Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.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.[CH2:63]([SH:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(Cl)Cl.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].O1CCOCC1>[CH2:63]([S:70][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Cc1cc2[nH]ncc2cc1Br
Reactant: SCc1ccccc1
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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2[nH]ncc2cc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-methyl-1H-indazole (4-1, 2 g, 9.48 mmol), XANTPHOS (0.548 g, 0.948 mmol), and Pd2(dba)3 (0.868 g, 0.948 mmol) were added to an oven-dried sealed tube followed by anhydrous Dioxane (31.6 ml), DIPEA (3.31 ml, 18.95 mmol) and BENZYL MERCAPTAN (1.177 ml, 9.95 mmol). Placed in 120° C. bath. After 2 h, UPLC showed >52% P1 at 1.25 min, 15% R1 at 1.07 min, 16% byproduct at 1.56 min and several minor peaks each less than 7%. After an additional 2 h, UPLC showed no change. Cooled to RT, filtered through Celite, washed with EtOAc, concentrated to give a clear, orange oil. Dissolved in 5 mL DCM, purified by normal-phase ISCO (80 g column, 0-50% EtOAc:Hex) to give 4-3 as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:31])[CH2:3][C@H:4]([C@H:15]1[CH2:19][N:18]([C@@H](C2C=CC(OC)=CC=2)C)[C:17](=[O:30])[CH2:16]1)[O:5]CC1C=CC(OC)=CC=1>C(#N)C.O>[F:31][CH:2]([F:1])[CH2:3][C@H:4]([C@H:15]1[CH2:19][NH:18][C:17](=[O:30])[CH2:16]1)[OH:5]
Reactant: COc1ccc(CO[C@H](CC(F)F)[C@@H]2CC(=O)N([C@H](C)c3ccc(OC)cc3)C2)cc1
Solvent: CC#N
Solvent: O
Product: O=C1C[C@@H]([C@H](O)CC(F)F)CN1
Reaction time: 1 h

Procedure:
To a stirred solution of 1.27 (44 mg, 0.10 mmol) in acetonitrile/water (1:1, 2 mL) was added Ceric ammonium nitrate (233 mg, 0.43 mmol) and the reaction was stirred for 1 hr. The reaction mixture was concentrated and purified by flash chromatography (10-20% MeOH in CH2Cl2) to afford (R)-4-((R)-3,3-difluoro-1-hydroxypropyl)pyrrolidin-2-one 1.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:32][Mg]Br.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH3:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (10 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.4 ml) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (490 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:5]([O:6][CH:7]1[C:12]2[CH:13]=[C:14]([CH:25]=[O:26])[O:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2occc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C=O)cc21
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of t-butyl(dimethyl)(4,5,6,7-tetrahydro-1-benzofuran-4-yloxy)silane (4.1 g, 16 mmol) that was obtained in Example 7 (7a) in tetrahydrofuran (30 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 31 ml, 49 mmol) at −78° C. with stirring, and after raising the reaction temperature to 0° C., the resulting mixture was stirred for 30 minutes. After cooling again the reaction mixture to −78° C. while stirring, N,N-dimethylformamide (13 ml, 162 mmol) was added to the reaction mixture with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.3 g) in a yield of 94% as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH2:4][CH2:3]1.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([CH:5]2[CH2:6][CH2:7][C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:1])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To tert-butyl [(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]carbamate (50 mg, 0.14 mmol) was added 4.0 M HCl in 1,4-dioxane (3 mL) at rt. After being stirred for 5 minutes, the product was precipitated out. To the mixture was added methanol (0.6 mL) and the solution became mostly clear with some gummy material present. The reaction was completed after 2% hours as judged by HPLC and LCMS. This resulting mixture was concentrated to give 4-[(3R)-3-aminopyrrolidin-1-yl]-1-pyridin-2-ylcyclohexanol HCl salt (72 mg, 99%). LC/MS: 262.1 (M+H, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35](N(CC)C1N=C(C(O)=O)C=C(C)N=1)[CH3:36].C(N)(=O)C>>[CH2:32]([N:31]([CH2:35][CH3:36])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: CC(N)=O
Product: CCN(CC)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-diethylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=1.01 min; [M+H]+=485.30. 1H NMR (D6-DMSO): δ 1.18 (t, J=6.8 Hz, 6H), 2.34 (s, 6H), 2.43 (s, 3H), 3.25 (m, 1H), 3.45 (m, 1H), 3.67 (q, J=6.8 Hz, 4H), 3.70-3.82 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.96 (m, 1H), 5.29 (d, J=5.3 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.27 (s, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.76 (s, 2H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OCC)OCC)C(=O)C)=[N-].O>CO>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1)#[CH:18]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a mixture of 4-(phenylsulfonyl)benzaldehyde (8 g, 32.5 mmol) and potassium carbonate (8.97 g, 65 mmol) in methanol (400 mL) was added diethyl (1-diazo-2-oxopropyl)phosphonate (8.6 g, 39 mmol). The reaction was stirred at room temperature for 3 days then poured into water (600 mL) and extracted with ethyl acetate (×3). The combined organic layers were dried and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5% ethyl acetate/isohexane, to give 1-ethynyl-4-(phenylsulfonyl)benzene (3.3 g, 42%). δH (500 MHz, CDCl3): 7.94–7.88 (4H, m), 7.60–7.50 (5H, m), 3.23 (1H, s).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([CH3:30])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([CH3:30])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)O)c3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.97 h
Yield: 59.4 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(methyl)amino]-2-fluorobenzoate (66 mg; 0.15 mmol) in 3 mL of anhydrous THF were added. Lithium Hydroxide monohydrate (65 mg; 1.54 mmol) and water (1 mL). The reaction mixture was stirred under micro waves at 100° C. for 3500 s. Then an aqueous solution of HCl was added; the residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated to give 37 mg of the title compound as a white solid. HPLC, Rt: 5.66 min (purity=93.20%). LC/MS, M−(ESI): 414.5. 1H NMR (CDCl3) δ: 7.40 (m, 4H), 7.31 (s, 1H), 7.20 (m, 4H), 6.92 (t, 1H), 6.75 (m, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.54 (t, J=7.7 Hz, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Na].C(O[C:5](=[O:14])[CH2:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)C.O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20]>C(O)(=O)C>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]1[C:5](=[O:14])[CH2:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:20]1
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=NN(CC(F)(F)F)C(=O)C1

Procedure:
1 Mole (221 g) of the sodium salt of oxalacetic diethyl ester and 1 mole (224 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred for 1 hour in 1 l of boiling acetic acid. The mixture was poured out on water and stirred. The product melting at 171° C. was filtered with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)CNc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (138 mg, 63%). MS (ESI): m/z=527.057 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH2:30])=[N:27][C:26]=2[CH:31]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH:30][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)=[N:27][C:26]=2[CH:31]=1
Reactant: Nc1nc2cc(Cl)ccc2o1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2nc3cc(Cl)ccc3o2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 5-chloro-1,3-benzoxazol-2-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1). Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:26])=[O:1])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: COC(=O)C1CC(Oc2ccc3c(c2)Cc2ccccc2-3)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2c(c1)Cc1ccccc1-2)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3.3 h

Procedure:
A mixture of lithium hydroxide (0.117 g) in water (1.5 ml) and tetrahydrofuran (4.7 ml) was treated with methyl 3-(2-fluorenoxy)-2-pyrrolidone-5-carboxylate (0.526 g), and heated to 60° C. After about 3.3 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (976 ml). The resulting colloidal suspension was sonicated for ten minutes. The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN.NN>CO>[NH2:3][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reaction time: 12 h
Yield: 85.3 %

Procedure:
A solution of 1,1-dimethylethyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate (2 g, 5.46 mmol) and either MeNH2 (40 wt % in H2O, 10 eq.) or NH2NH2 (10 eq.) in MeOH (0.5M, 10 mL) was heated to 60° C. in a sealed tube. After 12 h, the solution was concentrated and purified via column chromatography (silica-dry load, 2% MeOH in DCM (1% NH4OH)) affording the title compound (1.1 g, 85%) as a white solid: LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24]>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCCC1c2ccccc2-c2ccccc21
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
A solution of fluorene (5.04 g; 30.32 mmol) in THF (50 mL) was cooled to 0° C. and treated with n-butyllithium (12.13 mL of a 2.5M solution in hexanes; 30.32 mmol). After stirring the red anion mixture for 15 minutes, 4-bromobutyronitrile (4.86 g; 31.84 mmol) in 20 mL of THF was added via syringe, and the mixture was stirred overnight. It was quenched with 100 mL of saturated ammonium chloride and extracted into ethyl acetate (2×75 mL); the organic portions were washed with brine, dried and concentrated. The crude product was purified on a silica gel column, eluted with 20% ethyl acetate in hexane, to afford 4.91 g (70%) of the product as an orange oil. 1H NMR (CDCl3): δ 1.38 (m, 4H); 2.18, 2.29 (m, 2H each); 4.10 (m, 1H); 7.37 (m, 4H); 7.45 (d, 2H); 7.75 (d, 2H).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)c1ccc(C=CC(=O)O)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 3.7 g of the crude 6-isopropyl-3-pyridinecarbaldehyde, 3.9 g of malonic acid, 0.5 ml of piperidine, and 18 ml of pyridine is stirred at 110° C. for 2 hours. The reaction mixture is concentrated, and 5 ml of water is added. The resulting precipitate is collected to give 4.0 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:65]([Sn](CCCC)(CCCC)CCCC)#[N:66].CCOC(C)=O>C1(C(N)C2CCCCC2)CCCCC1.CN1C(=O)CCC1.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].O>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:65]#[N:66])[CH:3]=4)[C:8]([CH3:30])([CH3:29])[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C#N)cc21

Procedure:
A stirred solution of 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (95 mg, 0.20 mmol), Pd2dba3 (56 mg, 0.06 mmol), XPhos (58 mg, 0.6 mmol) and cyanotributyltin (65 mg, 0.20 mmol) in dicyclohexylmethylamine (1.5 mL) and NMP (1.0 mL) was heated in the microwave at 150° C. After this time the reaction was treated with EtOAc (100 mL) and water (50 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10% to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile. Mass Spectrum (ESI) m/e=410 (M+1).
Reaction SMILES: C[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.BrC1C=NC=C([F:31])C=1.CC1(C)C(C)(C)OB(C2C=CC([C@@H]3C[C@H]3NS(C(C)C)(=O)=O)=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.[Pd].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>[F:31][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:10][CH:9]=2)[CH:6]=[N:7][CH:2]=1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1ccc(-c2ccc([C@@H]3C[C@H]3NS(=O)(=O)C(C)C)cc2)cn1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(-c2cncc(F)c2)cc1

Procedure:
A similar procedure was followed as set out above for trans-N-{-2-[4-(6-methyl-3-pyridinyl)phenyl]cyclopropyl}-2-propanesulfonamide racemic (Example 2) using 3-bromo-5-fluoropyridine (66.5 mg, 0.378 mmol), trans-N-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}-2-propanesulfonamide (Intermediate 8) (69 mg, 0.189 mmol) in dry 1,4-dioxane (1.0 ml), polymer supported Tetrakis palladium catalyst (Pol-Pd(PPh3)4) (51 mg, 0.00567 mmol) and Na2CO3 2M (0.236 ml, 0.472 mmol) to give a crude product which was purified by reverse phase HPLC to give the title compound. The HPLC conditions were as given in “Preparative Chromatography” above.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]=1[C:27](=[O:37])[N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[C:45]([C:46]#[N:47])=[CH:44][C:43]([C:48]([F:51])([F:50])[F:49])=[N:42][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:40]2[CH:41]=[N:42][C:43]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:45]=2[C:46]#[N:47])=[CH:13][C:12]=1[C:27](=[O:37])[N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: Cc1ccccc1N(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 99.6 %

Procedure:
4-[5-Chloro-2-(methyl-o-tolyl-carbamoyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric acid tert-butyl ester (444.0 mg, 0.8 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (171.0 mg, 0.7 mmol), Pd(Ph3P)4 (78.6 mg, 0.07 mmol), Na2CO3 (432.0 mg, 4.1 mmol) in dioxane (9 mL) and water (1 mL) was degassed with N2 for 5 min, sealed, and heated at 100° C. for 12 hrs. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and filtered. Concentration and purification by TLC plates eluting with ethyl acetate in hexanes (2/3) and again with TLC plates eluting with acetonitrile/dichloromethane (1/9) gave 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid tert-butyl ester (410 mg). MS: 588.7 (M+H)+; tR=11.05 min (method 3).