Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1>C1COCC1>[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[OH:36])[CH2:31][CH2:30]1
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=CC1CCOCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A round bottom flask at −78° C. was charged with 4-bromo-4′-(trifluoromethyl)-1,1′-biphenyl (192 mg, 0.638 mmol) and THF (2.1 mL). nBuLi 2.5M in Hexane (281 μL, 702 mmol) was then added dropwise. The mixture stirred for one hour at −78° C. after which time, tetrahydro-2H-pyran-4-carbaldehyde (86 μL, 0.83 mmol) was added in one portion and mixture stirred for 30 minutes. Reaction mixture warmed up to 0° C. and stirred for an additional hour. Reaction quenched with ammonium chloride solution (aq. sat.) and extracted twice with ethyl acetate. Combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to provide the crude oil. Purification by silica gel flash chromatography (MeOH/DCM) to give the title compound as a colorless oil (118 mg, 55.0%). MS (M): 336.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH2:25][CH3:26])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1.O1CCCC1.B>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][C:10]3[N:16]([CH2:25][CH3:26])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1
Reactant: CCn1nc(-c2ccccn2)c2c1NC(=O)CCC2c1ccc(Br)cc1C
Agent: B
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccn2)c2c1NCCCC2c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one (0.045 g, 0.11 mmol, Example #AA.1) in THF (2 mL) was added borane tetrahydrofuran complex (1M in THF, 0.74 mL, 0.74 mmol) and the reaction was stirred at rt for about 2 h. The reaction was cooled to 0° C. and carefully quenched with 5M HCl (1 mL) and then stirred about 30 min at rt. The organic solvents were removed in vacuo and the aqueous layer was neutralized with solid Na2CO3 and extracted with EtOAc (2×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was further purified by silica gel column chromatography using a gradient of 65-85% EtOAc in heptane. Product fractions were combined and concentrated in vacuo. The residue was dissolved in ACN (2 mL) and the product was precipitated by addition of water. The product was filtered off and dried in the vacuum oven at about 50° C. to yield 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepine as an off-white solid (0.030 g, 0.073 mmol, 69%); LC-MS (Table 1, Method g) Rt=2.72 min, m/z 411/413 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.39 (m, 1H), 7.77-7.72 (m, 1H), 7.68-7.61 (m, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.16-7.09 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 5.70 (t, J=3.9 Hz, 1H), 5.66-5.58 (m, 1H), 4.13-3.97 (m, 2H), 3.40-3.30 (m, 1H), 2.84-2.74 (m, 1H), 2.45 (s, 3H), 1.92-1.82 (m, 1H), 1.81-1.70 (m, 1H), 1.68-1.57 (m, 1H), 1.57-1.45 (m, 1H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]([CH2:14][C:15](O)=[O:16])[C:11]([OH:13])=[O:12]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:15](=[O:16])[CH2:14][CH:10]([C:11]([OH:13])=[O:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1

Procedure:
4-Fluoroaniline (0.7 ml, 7.6 mmol) was added to 2-methylenebutanedioic acid (1.0 g, 7.6 mmol) in a sealed tube. The mixture was heated to 110 degrees for 3 hours after which a precipitate formed. The reaction was filtered and the solid was dissolved in ethyl acetate and concetrated to yield 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (M+1=223.8). The product was taken to next step without determining mass.
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]([O:9]C)=O.[CH3:15][N:16]([CH3:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][N:16]([CH3:24])[C:17]1[CH:23]=[CH:22][C:20]([N:21]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: COC=C(C=CC(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(-c2ccc(N(C)C)cc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
After 1.24 g (6.1 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioate obtained in Example 1-1 was dissolved in 10 mL of DMF, 830 g (6.1 mmol) of 4-dimethylaminoaniline was added to the solution. Afterward, the resulting reaction solution was stirred under reflex at about 50° C. for about 3 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then washed using brine, followed by drying using magnesium sulfate and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain a target compound (Actual yield: 357 mg, Yield ratio: 21%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cccc([N+](=O)[O-])c1)OCC

Procedure:
Analogously to the process described under Example 6A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 804 mg (3.98 mmol) of 1-bromo-3-nitrobenzene gave 1.26 g (87% of theory) of the title compound. In this case, chromatographic isolation of the product was by MPLC (mobile phase cyclohexane/ethyl acetate 1:2); subsequent trituration with diisopropyl ether was dispensed with.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.BrC1[O:17][C:18]([CH2:21]C2C=CC(F)=CC=2)=[CH:19][CH:20]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:4]2[S:3][C:2]([C:20]#[C:19][CH:18]([OH:17])[CH3:21])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Cc2ccc(Br)s2)cc1
Reactant: Fc1ccc(Cc2ccc(Br)o2)cc1
Product: CC(O)C#Cc1ccc(Cc2ccc(F)cc2)s1
Yield: 71 %

Procedure:
4-[5-(4-fluorophenylmethyl)-2-thienyl]-3-butyn-2-ol (9.16 g, 71%) was prepared according to the method of Example 1, step 3, except substituting 2-bromo-5-(4-fluorophenylmethyl)thiophene (13.3 g, 49.0 mmol), prepared as in step 2, for 2-bromo-5-(4-fluorophenylmethyl)furan.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27]C(=O)C)=[CH:14][C@H:13]3[O:35]C(OC)=O)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=C[C@H]4OC(OC)=O)CC2)C)OC1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[OH:27])=[CH:14][C@H:13]3[OH:35])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Yield: 88.3 %

Procedure:
The reaction and workup procedures of Example 140 were repeated except that 90 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7α-tris (methoxycarbonyloxy)pregn-5-ene to give 65 mg of 20-(1,3-dioxolan-2-yl)-3β-(methoxymethyl)oxypregn-5-ene-1α,7α-diol showing the following properties.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: [H][H]
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 12 h

Procedure:
A solution of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields 30.8 g. (100%) of product as a viscous oil.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: c1ccc2c(c1)CNc1ccccc1S2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
To a solution of 1.6 g of 10,11-dihydrodibenz[b,f][1,4]thiazepine in 30 ml of dichloromethane is added 0.1 g of 4-(N,N-dimethylamino)pyridine, 4 ml of triethylamine and 1.0 g of 4-nitrobenzoyl chloride and the mixture is stirred for 16 hours. The mixture is poured into ice-water and extracted with 3×150 ml of dichloromethane. The combined organic extract is washed with water, 2N HCl, 2N Na2CO3, water and dried (MgSO4). The solvent is removed in vacuo and the product (2.6 g) purified by chromatography on silica gel with hexane-ethyl acetate (4:1) as eluent to give 2.2 g of crystals, m.p. 147°-149° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][CH2:9][CH2:8]1>C(O)C>[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8]1
Reactant: O=C1CCC=Cc2ccccc21
Reactant: C1CCNC1
Solvent: CCO
Product: O=C1CC(N2CCCC2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 7.1 g of pyrrolidine in 30 ml of ethanol was added to a solution of 7.9 g of 5-oxo-6,7-dihydro [5H] benzocycloheptene in 30 ml of ethanol and the mixture was stirred at room temperature for 30 minutes and was evaporated to dryness to obtain 11.5 g of 5-oxo-7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:22]1[S:26][C:25]([S:27]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[C:24](B(O)O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:15]([C:11]1[N:10]([CH2:9][C:8]([C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[C:22]([CH2:18][CH:19]([CH3:20])[CH3:21])[S:26][C:25]=3[S:27]([NH:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=2)=[O:17])[CH:14]=[CH:13][N:12]=1)[CH3:16]
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCc1nccn1CC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1nccn1CC(=O)c1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(2-ethylimidazol-1-yl)ethanone (54.6 mg, 0.186 mmol; see step (a)) in toluene (10 mL) and ethanol (1 mL) was added 5-isobutyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (101 mg, 0.317 mmol; see Example 1(c)), Pd(PPh3)4 (12.9 mg, 0.0112 mmol), Na2CO3 (373 μL, 0.745 mmol, 2.0 M aq) and the reaction mixture was stirred for 4 h at 80° C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic phase was dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound as a colourless syrup in 94% yield (85.5 mg, 0.175 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[NH:14]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:14]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]2)=[O:9])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C1CCNCCN1
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Product: O=C1CCN(C(=O)/C=C/c2ccc(F)c(Cl)c2)CCN1

Procedure:
In analogy to the procedure described for intermediate 1A, (E)-3-chloro-4-fluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid. MS: 297.2 (MH+, 1Cl).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:18]([C:20]1(O)[CH2:22][CH2:21]1)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:10]([N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:18]([C:20]1([F:7])[CH2:22][CH2:21]1)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)C1(O)CC1
Solvent: ClCCl
Product: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)C1(F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
DAST (2.99 ml, 22.60 mmol) was added dropwise to a stirred solution of (R)-1-(1-(dibenzylamino)ethyl)cyclopropanol (5.3 g, 18.83 mmol) in dichloromethane (94 ml) at −78° C. under a nitrogen atmosphere. The reaction was allowed to stir for about 2 hrs before quenching with sat. sodium bicarbonate solution (100 mL) via dropwise addition. The quenched reaction was allowed to warm slowly to rt overnight. The organic layer was separated, dried (MgSO4) and evaporated in vacuo before purifying by column chromatography using hexane to 2% ethyl acetate in hexane as eluent to give the title compound (1.16 g, 4.09 mmol, 21.73% yield). HPLC (condition B): retention time=3.69 min. LCMS (condition B): m/z 284.2. 1H NMR (400 MHz, MeOD) δ ppm 7.11-7.52 (10 H, m), 4.98-5.32 (1 H, m), 3.76-4.08 (4 H, m), 1.08-1.42 (3 H, m), 0.47-0.82 (4 H, m).
Reaction SMILES: [CH2:1](OC(=O)C1C=CN=C(C)C=1Cl)C.[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23](Cl)[CH:24]=2)[O:19][CH2:18]1>>[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23]([CH3:1])[CH:24]=2)[O:19][CH2:18]1
Reactant: CON=C1COc2cnc(Cl)cc21
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Product: CON=C1COc2cnc(C)cc21

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), 5-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing 2,3-dichloroisonicotinic acid ethyl ester. Purification by prep HPLC, xbridge very polar method acidic gives the desired product as brown solid;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6](=[O:14])[C:5]2([CH2:17][CH3:18])[CH2:15][CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:15]([C:5]1([CH2:17][CH3:18])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=2)[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]1=[O:14])[CH3:16]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2ccc(N)cc21
Reactant: CC(=O)OC(C)=O
Product: CCC1(CC)C(=O)N(C(C)C)c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of 5-amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (9.7 g, 39.37 mmol) in acetic anhydride (57 ml) was stirred at room temperature for 4 h. The mixture was poured into ice water, allowed to warm to room temperature and was stirred again for 2 h. After extraction with ethyl acetate, the combined organic layers were washed with aqueous NaOH solution (1M) and brine and dried over sodium sulfate. After removal of the solvent the crude product was triturated with iso-hexane to yield 10.4 g N-(3,3-Diethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (36.06 mmol, 91%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[O:58]1CCO[CH:59]1[CH:63]1[CH2:68][CH2:67][CH2:66][CH:65](O)[CH2:64]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[NH2:26][C:24]1[C:25]2[C:17]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[CH:18][N:19]([CH:65]3[CH2:66][CH2:67][CH2:68][CH:63]([CH:59]=[O:58])[CH2:64]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: OC1CCCC(C2OCCO2)C1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(OCc3cccc(F)c3)c(Cl)c1)cn2C1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3—CHloro-4-(3-fluorobenzyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (prepared according to a similar procedure as described in Example 1) (1 equivalent) is placed in THF. Triphenyl phosphine (1.5 equivalents) is added, followed by dropwise addition of DEAD (3 equivalents). 3-(1,3-dioxolan-2-yl)cyclohexanol (1 equivalent) is added and the mixture is stirred at room temperature overnight. The reaction mixture is partitioned between EtOAc and water, the organic layer is separated, washed with water, brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and suspended in acetone. p-Toluensulfonic acid (0.6 equivalent) is added and the mixture is refluxed for 4 h. The mixture is filtered, the filtrate is concentrated in vacuo and purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:25])CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]2([F:25])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Solvent: ClCCl
Product: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a −78° C. solution of the product of Example 1A (7.13 g, 26.4 mmol) in CH2Cl2 (120 mL) was added diethylaminosulfur trifluoride (DAST, 6.0 g, 4.89 mL, 37.0 mmol). The reaction mixture was allowed to warm to ambient temperature, quenched with water, diluted with ethyl acetate, and washed with water. The organic layer was separated and concentrated. The resulting residue was chromatographed on silica gel, eluting with 0%-30% ethyl acetate-hexane to obtain the title compound (3.0 g, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.69-1.77 (m, 2H), 1.86 (td, J=12.89, 4.75 Hz, 2H), 2.15-2.40 (m, 4H), 3.91 (s, 4H), 7.44 (ddd, J=8.14, 4.75, 0.68 Hz, 1H), 7.96 (dd, J=7.97, 1.53 Hz, 1H), 8.52 (dt, J=4.75, 1.19 Hz, 1H). MS (DCI) m/z 272.05 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(=O)C(F)(F)F)[CH:19]=1)[C:3]1[N:8]=[C:7]2[S:9][C:10]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])=[N:11][C:6]2=[CH:5][CH:4]=1.[Cl-].[NH4+]>O1CCCC1.CO.[OH-].[Na+]>[NH2:24][C:20]1[CH:19]=[C:18]([N:2]([CH3:1])[C:3]2[N:8]=[C:7]3[S:9][C:10]([NH:12][C:13]([CH:15]4[CH2:16][CH2:17]4)=[O:14])=[N:11][C:6]3=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92.8 %

Procedure:
N-[5-(Methyl{3-[(trifluoroacetyl)amino]phenyl}amino)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (748 mg, 1.72 mmol) was dissolved in tetrahydrofuran (22.5 mL)/methanol (7.5 mL), 2N aqueous sodium hydroxide solution (7.5 mL) was added, and the mixture was stirred at room temperature for 19 hr. Aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (542 mg, 93%) as a colorless powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[Br-].C[O:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[S:25](=[O:40])(=[O:39])[NH:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=1)=O.[Cl-].[NH4+]>CCOCC.C1COCC1>[CH3:38][O:37][C:29]1[CH:28]=[C:27]([NH:26][S:25]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]2[C:17](=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:40])=[O:39])[CH:32]=[C:31]([O:33][CH3:34])[C:30]=1[O:35][CH3:36]
Reactant: COC(=O)[C@@H]1CCCCN1S(=O)(=O)Nc1cc(OC)c(OC)c(OC)c1
Reactant: BrCCCCCc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCCC[C@H]2C(=O)CCCCCc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 1 %

Procedure:
At 40° C., 5-phenylpentylbromide solution (1.15 g, 5 mmol) in ether (5 mL) was slowly added to magnesium turnings with vigorous agitation under Argon. The exothermic reaction was initialized after addition of one quarter of the bromide solution. Once the addition was completed, the suspension was heated at reflux for 30 minutes and most of magnesium was dissolved. The resulted 1M Grignard reagent was cooled to −70° C. and added the methyl ester (compound 90, 100 mg, 0.25 mmol) in THF solution (2 mL). The mixture was warmed to 25° C. and stirred at that temperature for 20 hours. Saturated amonium chloride (1 mL) was introduced to quench the reaction. The suspension was extracted with ether (1×50 mL). The organic phase was collected, dried and concentrated. The residue was purified by flash column chromatography (25% EtOAc in hexanes) followed by preparative TLC (1% THF in CH2Cl2) to give 1.2 mg (1% yield) of the title compound.