Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[F:32][C:33]([F:38])([F:37])C(O)=O.FC(F)(F)C([O-])=O.ClC(Cl)(Cl)S(OCC(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC(C)=O>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:33]([F:38])([F:37])[F:32])[CH2:21][CH2:20]3)[N:17]=[CH:18][C:10]2=[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: FC(F)(F)CN1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 100 °C

Procedure:
Tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.60 g, 1.3 mmol) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (5 mL). When LC/MS analysis revealed the deprotection of the Boc group, the mixture was concentrated to dryness under reduced pressure. Diethyl ether was evaporated three times from the crude material in order to afford a solid residue. The trifluoroacetate salt was dissolved in approximately 15 mL of warm acetone and added to a 10-20 mL Smith process vial charged with 2,2,2-trifluoroethyl trichloromethanesulfonate (0.56 g, 2.0 mmol). Potassium carbonate (0.90 g, 6.5 mmol) was added and the suspension was heated in the microwave for one hour at 100° C. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. 3-(6-Chloro-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane was thus obtained as a yellow foam (0.55 g, 100%). MS (ES+): 430.9, 432.9 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:15][CH2:14][C@:13]1([CH3:16])[C:12](=O)[N:11]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:15][CH2:14][C@@:13]1([CH3:16])[CH2:12][N:11]([C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CC[C@]2(C)C1=O
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@]2(C)CC[C@@]2(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A 1.09 M solution of a borane/tetrahydrofuran complex in tetrahydrofuran (3.6 mL, 3.98 mmol) was added dropwise to a solution of (1S,5S)-1-(tert-butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (548 mg, 1.59 mmol) in tetrahydrofuran (10 mL) at 0° C. over five minutes. After heating to room temperature and stirring for three hours, a 1.09 M solution of a borane/tetrahydrofuran complex in tetrahydrofuran (3.6 mL, 3.98 mmol) was added at the same temperature. The mixture was stirred at room temperature for 15 hours and then cooled to 0° C. A mixture of ethanol (9.0 mL)-water (1.0 mL) was carefully added dropwise. After addition of triethylamine (3.0 mL) dropwise, the mixture was heated to reflux for one hour. The reaction solution was concentrated, and the precipitated white solid was removed by filtration through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to give 184 mg (35%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Si](OCC1[C:32](F)=[C:33]([F:41])[C:34]([F:40])=[C:35]([C:37](=[O:39])C)[CH:36]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:40][C:34]1[C:35]([CH2:37][OH:39])=[CH:36][C:1]2[C:2]([CH3:3])=[N:4][O:5][C:32]=2[C:33]=1[F:41]
Reactant: CC(C)=NO
Reactant: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(F)c(CO)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propan-2-one oxime (1.73 g, 23.7 mmol) in THF (25 ml) was added potassium t-butoxide (1M solution in THF, 23.8 mL) at 0° C. under nitrogen atmosphere and the mixture was stirred with warming to room temperature for 1 hour. The mixture was cooled to −78° C. and a solution of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-2,3,4-trifluorophenyl)ethanone (Intermediate 332, 3.0 g, 6.8 mmol) in THF (15 mL) was added to the mixture and stirred for 20 minutes at −78° C. then at −20° C. for 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to give material that was used for the next step without any further purification. A stirred solution of the material dissolved in ethanol (130 ml) was treated with 5 ml of 5% aqueous HCl at 45° C. for 8 hours. The reaction quenched with 10% aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer washed with water, dried, and concentrated. The residue was purified over a silica gel flash column (elution with 15-20% EtOAc in hexanes) to give title compound as yellow solid. Yield: 600 mg, (46%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CCOC(C)=O>[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH:14]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH3:16]
Reactant: Nc1ccccc1N
Reactant: COC(=O)CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CCC(C)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a mixture of 1,2-phenylenediamine (3.0 g, 27.7 mmol) and levulinic acid methyl ester (2.7 mL, 21.8 mmol) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (4.6 g, 21.7 mmol) and acetic acid (1.5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (75 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 40% EtOAc in Hexane as the eluent to afford the desired 4-(2-amino-phenylamino)-pentanoic acid methyl ester (1.05 g, 22%).
Reaction SMILES: CN(C=O)C.[C:6](Cl)([C:8]([Cl:10])=O)=[O:7].[N:12]1[C:17]2[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3OC=2C(=O)[NH:14][CH:13]=1.O>ClCCCl>[Cl:10][C:8]1[C:6]2[O:7][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2c1oc1ccccc12
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2c1oc1ccccc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
DMF (0.23 mL, 3.1 mmol) is added dropwise to a solution of (COCl)2 (0.28 mL, 3.1 mmol) in 1,2-dichloroethane (15 mL) at 25° C. After gas evolution ceases, 3H-benzofurano[3,2-d]pyrimid-4-one (113 mg, 0.61 mmol) is added. The resulting mixture is heated at reflux for 1 h. After the reaction has cooled to 25° C., water is added and the resulting mixture is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure to give 4-chlorobenzofurano[3,2-d]pyrimidine (116 mg, 93%) as a yellow solid. 1H NMR (DMSO) δ9.08 (1H, s), 8.30 (1H, d. J=8.1 Hz), 8.02 (1H, d, J=8.5 Hz), 7.90, (1H, dt, Jd=1.3 Hz, Jt=7.1 Hz), 7.64 (1H, dt, Jd=1.0 Hz, Jt=7.8 Hz).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1>CCO.[Ni]>[O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1
Reactant: N#CCN1CCCOCC1
Agent: [Ni]
Solvent: CCO
Product: NCCN1CCCOCC1
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A mixture of nitrile 293 (3.2 g, 22.8 mmol) and Raney-Nickel (50% w/w in water, ca. 12 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3×10 mL) and the solvent evaporated to give crude diamine 294 (2.98 g, 91%) as a pale yellow oil, which was used without further purification: 1H NMR [(CD3)2SO] δ 3.64-3.67 (m, 2H, H-3), 3.57-3.59 (m, 2H, H-5), 2.49-2.62 (m, 8H, H-2, H-7, 2×CH2), 1.71-1.80 (m, 2H, H-6), NH2 not observed; HRMS (FAB+) calcd for C7H17N2O (MH+) m/z 145.13409, found 145.13439.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Na+:5].[C:6](=[O:9])([O-:8])[O-:7].[Na+].[Na+].[C:12](=[O:15])([OH:14])[O-:13]>>[C:1](=[O:2])([OH:4])[OH:3].[Na+:5].[C:6](=[O:7])([O-:9])[O-:8].[C:12](=[O:13])([OH:15])[OH:14].[Na+:5]
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)O

Procedure:
In general, the composite particles are formed by mixing particles of sodium bicarbonate in an aqueous solution of sodium carbonate. The sodium bicarbonate reacts with the sodium carbonate in the aqueous binder solution to form the sesquicarbonate. More specifically, during the agglomeration of the sodium bicarbonate particles with the aqueous binder solution of the sodium carbonate, particles of the bicarbonate stick together upon being wetted by the binder solution. The surfaces of the sodium bicarbonate particles being wetted by the aqueous solution react with sodium carbonate in-situ to form sodium sesquicarbonate. The sesquicarbonate crystal forms especially upon cooling. Agglomeration of the sodium bicarbonate particles with the sodium carbonate solution, thus, yields composite particles comprised of two or more particles of sodium bicarbonate joined together by precipitated sesquicarbonate bridges and this formed composite comprises the bulk of the agglomeration product. As well, individual sodium bicarbonate particles can be coated with the sesquicarbonate if high levels of binder solution are utilized.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])=O>C(O)(=O)C>[CH3:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:5][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:17][N:16]=1
Reactant: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Yield: 43.8 %

Procedure:
Heat a mixture of ammonium acetate (16.5 g, 214 mmol) and 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (14.2 g, 42.3 mmol) in acetic acid (300 mL) at reflux under nitrogen for 15 hours. Remove the solvent under reduced pressure. Dilute the residue in ethyl acetate (500 mL) and adjust to pH 8 with saturated aqueous sodium bicarbonate solution. Extract the aqueous layer with additional. ethyl acetate (200 mL) and dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate, to afford 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.86 g, 44%): APCI mass spectrum m/z 317 [C18H24N2O3+H]+.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C[O:52][B:53](OC)[O:54]C>C1COCC1>[Si:5]([O:18][C@@H:19]1[C@@H:26]2[O:25][C:24]([CH3:27])([CH3:28])[O:23][C@@H:22]2[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:20]1[B:53]([OH:54])[OH:52])([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COB(OC)OC
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(B(O)O)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom 3-neck flask equipped with nitrogen inlet/outlet, stir bar, and thermocouple with temperature controller was charged 3.0877 g of compound 8 (3 mmol, 1.0 eq) and 30 mL tetrahydrofuran (10 V). Reaction was cooled to 0° C. To this solution was added 6.98 mL (9 mmol, 2.4 eq) of isopropylmagnesium chloride lithium chloride complex, 1.3 M in THF slowly over 15 minutes. The reaction was stirred at 0° C. for 1 hour. An HPLC assay indicated the formation of intermediate. 1.05 mL of trimethylborate (9 mmol, 2.5 eq) was added to the reaction. An HPLC assay after 1 hour at 0° C. indicated that the reaction was completed. Quenched reaction with saturated aqueous ammonium chloride solution (3V). The ice bath was removed and the reaction was warmed to room temperature. The reaction was charged with DI water (3V) and ethyl acetate (6V). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (6V). The organic phases were combined and washed with brine (3V) and dried over MgSO4. The resulting mixture was filtered. The filtrate was concentrated to dryness with a rotary evaporator. Obtained 2.87 grams (100% crude yield), 96 A % purity of [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (compound 9c-1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:24]3[N:25]=[C:26]([NH2:42])[C:27]4[N:28]=[CH:29][N:30]([C:40]=4[N:41]=3)[C@@H:31]3[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]3[OH:33])[CH2:9][CH2:8]2)=[O:11])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-10-021. 4-nitrobenzyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-109 (0.743 g, 2.458 mmol) was added to a solution of 2-iodoadenosine (0.658 g, 1.674 mmol) according to general procedure 2. Yield: 0.694 g, 42%. 1H NMR (CD3OD) δ 8.29 (s, 1H), 8.18-7.56 (2×d, 4H), 5.94 (d, 1H), 5.23 (s, 2H), 4.69 (m, 2H), 4.31-4.14 (2×m, 3H), 3.84-3.74 (2×d, 2H), 3.10-2.90 (bs, 4H), 2.44 (d, 5H), 1.91-1.40 (2×m, 5H). m/z MH+=568.10. HPLC rt=5.8 min.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:11]([C:12]1[NH:8][C:4]2[C:5]([CH:14]=1)=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[CH3:10])=[O:15])[CH3:18]
Reactant: Cc1c(F)cccc1NN
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc(F)c(C)c2[nH]1
Temperature: 0 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9 ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+)
Reaction SMILES: [CH2:1]([C:7]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]2[CH:18]=[C:17]3[C:20](=[O:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C1COCC1.C(O)C>[CH2:25]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[CH:20]([OH:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(O)C(C)C3
Reaction time: 12 h
Yield: 96 %

Procedure:
In a 1000 mL round flask, 9,9-dihexyl-2-methyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (85 g, 211.1 mmol) was dissolved in THF 400 mL and ethanol 400 mL, and then stirred. Sodium borohydride (NaBH4) (10 g, 265.0 mmol) was added to the reaction product in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 82.0 g of 9,9-dihexyl-2-methyl-1,2,3,9-tetrahydrocyclopenta[b]fluoren-1-ol (yield: 96.0%) (two isomers), as highly viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:26]C(=O)OC(C)(C)C)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]2[C:23]([F:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]2[C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][N:41]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[C:38]2=[N:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:24][C:23]1[C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[NH:26])[CH2:12]2)=[N:19][C:20]([C:43]2[C:37]3[C:38](=[N:39][CH:40]=[C:35]([F:34])[CH:36]=3)[N:41]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)(=[O:54])=[O:55])[CH:42]=2)=[N:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=N)NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Temperature: 120 °C

Procedure:
Degassed a solution of (Z)-tert-butyl (tert-butoxycarbonylamino) ((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylamino)methylenecarbamate, 70b, (0.200 g, 0.411 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.205 g, 0.493 mmol) and Na2CO3 (0.616 mL of 2M solution, 1.232 mmol) in dimethoxyethane (15 mL) for 30 min. To the mixture was added palladium triphenylphosphane (0.023 g, 0.021 mmol) and the reaction mixture was heated in a pressure tube at 120° C. for 45 min. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo. Attempted purification of the resulting residue by silica gel chromatography (10% MeOH/CH2Cl2) yielded a mixture containing mostly desired product that was used without further purification: LCMS RT=2.30 (M+H) 641.02.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[C:14]3[C:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[C:17]([C:33]([O:35]CC)=[O:34])[NH:16][C:15]=23)[CH:7]=[CH:8][CH:9]=1)[CH3:2].CCO.O.[Li+].[OH-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[C:14]3[C:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=4)=[C:17]([C:33]([OH:35])=[O:34])[NH:16][C:15]=23)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(-c3cccc(OCC)c3)nccc2c1CCOc1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(-c2nccc3c(CCOc4ccc(OC(F)(F)F)cc4)c(C(=O)O)[nH]c23)c1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 7-(3-ethoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (80 mg, 0.15 mmol) in THF (2 mL) was added EtOH (0.4 mL)m and water (0.4 mL). Solid LiOH (75 mg, 3.1 mmol) was then added in a single portion. After 2 h at r.t. and 2 h at 50 C, the reaction was quenched with 5% potassium bisulfate until acidic (˜pH 3) which caused a white precipitate to form. This was filtered and washed with water to yield the title compound (65 mg). HRMS (ESI) calc (M+H)+=487.1475. found 487.1478.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>C(#N)C>[O:4]=[C:3]1[C@H:2]([O:1][C:15]([O:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][C:18]2=[O:23])=[O:24])[CH2:7][CH2:6][O:5]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=C1OCC[C@H]1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1CCOC1=O)ON1C(=O)CCC1=O

Procedure:
(R)-alpha-Hydroxybutyrolactone (8 μL, 0.11 mmol) was dissolved in acetonitrile (0.5 mL) and treated with triethylamine (45 μL, 1.5 equivalents), and disuccinimidyl carbonate (42 mg, 1.5 equivalent) at 25° C. for 16 hrs. The solvents were evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ylamine (0.158 g, 0.675 mmol, prepared as described in Example 3: Steps A-B from 5-amino-2-bromopyridine, Aldrich) was dissolved in anhydrous dichloromethane (10 mL), treated with acetic anhydride (Aldrich, 0.080 mL, 0.846 mmol), and stirred at ambient temperature under Ar for 18 h. The reaction was quenched with saturated aqueous NaHCO3, extracted thrice with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a pale solid.