Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:15]1([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=CC(=O)O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(NC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
To a stirred solution of glyoxylic acid monohydrate (92 mg, 1 mmol) in dichloromethane (7 mL) was added aminodiphenylmethane (183 mg, 1 mmol), followed by phenylboronic acid (122 mg, 1 mmol). After the flask was purged with argon and sealed, the reaction mixture was stirred vigorously at room temperature for 48 h. The resulting precipitate was isolated by filtration, washed with dichloromethane (10 mL) and purified by ion-exchange chromatography (Dowex 50W-X8) to give pure (±)-N-(diphenylmethyl)-α-phenylglycine (266 mg, 84% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH2:13]([O:15][C:16](=[O:38])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=2)=[C:21]([O:33]CCOC)[CH:20]=1)[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16](=[O:38])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([CH3:12])([CH3:11])[CH3:1])[CH2:6][CH2:7]3)=[CH:27][CH:26]=2)=[C:21]([O:33][CH2:18][CH2:17][CH2:16][O:15][CH3:13])[CH:20]=1)[CH3:14]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCOC)c1
Reactant: CC(C)(C)C(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C(=O)C(C)(C)C)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.6 %

Procedure:
To a solution of 2,2-dimethyl-1-piperazin-1-yl-propan-1-one (37.45 mg, 0.22 mmol) in THF (2 mL) concentrated acetic acid (63 μL, 1.1 mmol), Ethyl-3-[4′-Formyl-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-propionate (74 mg, 0.2 mmol) dissolved in THF (1 mL) and cyanoborhydride resin (123 mg, 0.3 mmol) was added. The reaction was shaken in a closed-vessel under argon at r.t. overnight. The mixture was filtered and dried under reduced pressure. The residue was redissolved in ethyl acetate (20 mL) and washed with an aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and dried under reduced pressure to give 80.6 mg of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([CH2:14][CH:13]([OH:15])[CH2:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(Cl)Cl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:17][CH2:16][C:11]4([CH2:14][CH:13]([OH:15])[CH2:12]4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OC1CC2(CCN(c3ccc(Br)cn3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 70.3 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.7.). Starting with 0.138 g (0.46 mmol) of 7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]nonan-2-ol, obtained in step 10.1., 0.078 g (0.56 mmol) of 4-fluorophenylboronic acid, 0.454 g (1.39 mmol) of caesium carbonate suspended in 3 mL of a 9/1 mixture of tetrahydrofuran and water. 0.038 g (0.05 mmol) of PdCl2dppf.CH2Cl2 is then added. 0.101 g of pure product is thus obtained in the form of a grey powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](N(CC)CC)[CH3:12].[CH2:18](OC(ON=C(C#N)C(N)=O)=O)[CH3:19]>O1CCCC1>[C:1]([O:10][CH2:18][CH3:19])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][CH3:12])=[O:7]
Reactant: CCOC(=O)ON=C(C#N)C(N)=O
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of adipic acid (1.46 g) and triethylamine (2.8 ml) in tetrahydrofuran (30 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (3.7 g) is added, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is treated as in Example A to give diethyl adipate (1.5 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CO.ClCCl>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1cccn2cc(-c3ccc(O)cc3)nc12
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccn2cc(-c3ccc(OCC4CO4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step B (27 g) in methanol (500 mL) was treated with potassium hydroxide (14 g) and stirred at ambient temperature for 2 hours. To this solution was then added epichlorohydrin (9.4 mL) and the mixture stirred for an additional 48 hours. The reaction mixture was diluted with dichloromethane, filtered and the filtrate washed with water, dried, sodium sulfate filtered and evaporated to afford the title compound (18.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2OS(C)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>ClCCl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[S:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][CH:32]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CS(=O)(=O)OC1CCCc2ccc([N+](=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(Sc1ccc(C(F)(F)F)cc1)CCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanesulfonic acid 7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl ester (1.3 g, 4.8 mmol), was dissolved in a solution of triethylamine (3.35 mL, 24 mmol) and dichloromethane (10 mL). 4-Trifluoromethylbenzenethiol (1.7 g, 9.6 mmol) was then added and the reaction mixture was stirred at room temperature for 6 hours. Next, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic solution was dried (Na2SO4), concentrated, and purified by column chromatography (EtOAc/hexanes) to give 7-nitro-1-(4-trifluoromethylphenylsulfanyl)-1,2,3,4-tetrahydronaphthalene. Yield 1.45 g (86%). LCMS (ESI): calc. C17H14F3NO2S=353; obs. low ionization.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O>O1CCCC1>[CH2:3]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCOCc1ccccc1
Yield: 56.3 %

Procedure:
60% Sodium hydride (1.2 g) was suspended in tetrahydrofuran (30 ml), and benzyl alcohol (3.0 g) was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 min, and again ice-cooled. 1,4-Dibromobutane (6.0 g) was added and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.8 g of 4-benzyloxybutyl bromide.
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33](O)=[O:34])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C1COCC1.CN(C=O)C>[C:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([NH:45][OH:46])=[O:34])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (200 mg, 0.398 mmol), HOBT (107.4 mg, 0.796 mmol), EDC (152 mg, 0.796 mmol), TEA (0.111 ml, 0.796 mmol) and NH2OTHP (56 mg, 0.477 mmol) in THF (5 ml) and DMF (5 ml) was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH 98:2) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 2 h. The precipitate was filtered giving 115 mg of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy acrylamide as its hydrochloride salt.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:10]=1[N+:31]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1.CO.O.[Fe]>[NH2:31][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[C:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (21) (6.7 g, 12.4 mmol) in THF/MeOH/H2O (100 mL/50 mL/30 mL) was added Fe powder (3.47 g, 62 mmol) and NH4Cl (6.63 g, 124 mmol). The reaction mixture was heated at 50° C. for 5 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (30 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (22) (6 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:13]=[C:12]([C:22](O)=[O:23])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:13]=[C:12]([C:22]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:23])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: COc1cc(Br)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccnc(Cl)c2)c1

Procedure:
80 mg (0.20 mmol) of the compound of Example 51A is reacted analogously to the synthesis of the compound of Example 1 with 26 mg (0.22 mmol) of 4-imidazolinone-hydrochloride. 70 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH:11]3[CH2:15][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:13](=[O:25])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:28][S:29]([C:32]1[C:40]2[C:35](=[CH:36][N:37]=[CH:38][CH:39]=2)[NH:34][N:33]=1)(=[O:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH:11]3[CH2:15][N:14]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:13](=[O:25])[CH2:12]3)[C:7]([CH2:9][N:34]3[C:35]4=[CH:36][N:37]=[CH:38][CH:39]=[C:40]4[C:32]([S:29]([CH3:28])(=[O:30])=[O:31])=[N:33]3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2CC(n3c(CCl)nc4cc(Cl)ccc43)CC2=O)cc1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2CC(n3c(Cn4nc(S(C)(=O)=O)c5ccncc54)nc4cc(Cl)ccc43)CC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]-1-(4-methoxybenzyl)pyrrolidin-2-one (294 mg, 1.492 mmol) in 50 mL of DMF was added 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (722 mg, 1.791 mmol) and Cs2CO3 (584 mg, 2.985 mmol). The resulting mixture was stirred at RT for 4 hours, then diluted with 40 mL of H2O and EtOAc. The separated aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were washed with 30 mL of brine, and then dried over Na2SO4, then filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM: MeOH=20:1) to give 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one as a solid.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO[C:39]1[C:40]([O:47][CH3:48])=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O.C1C[O:52][CH2:51]C1>>[CH3:48][O:47][C:40]1[CH:39]=[C:46]([O:52][CH3:51])[CH:45]=[CH:44][C:41]=1/[CH:42]=[CH:7]/[CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: C1CCOC1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc(/C=C/CCC(=O)O)c(OC)c1
Temperature: -15 °C

Procedure:
An oven-dried 2 L 3-neck flask was secured over a dry ice/isopropanol bath and magnetic stirring plate, fitted with an oven-dried 500 ml dropping funnel, a magnetic stir bar, an argon inlet, and a thermometer. The flask was flushed with argon, charged with 71.3 grams (166 mmol) of 3-carboxypropyltriphenylphosphonium bromide followed by 400 ml of THF, and closed. An argon balloon was used to cap the addition funnel and the reaction mixture was stirred for a half hour while cooling. A mixture of 63.9 grams (381.8 mmol) of lithium bis (trimethylsilyl) amide in 400 ml of THF was added to the reaction mixture via an addition funnel, with stirring, after the temperature had gone below −50° C. and at such a rate as to keep the temperature at or below −40° C. When the addition was complete, the dry ice bath was carefully removed and replaced with a ice/salt (NaCl) bath to maintain a reaction temperature about −10 to −20° C. The reaction mixture was stirred for about 2 hours to give a clear orange mixture. The temperature was reduced to −40° C. with a dry ice bath and a solution of 27.6 grams (166 mmol) of dimethoxybenzaldehyde in about 320 ml of THF was added to the reaction mixture over a half hour via an addition funnel. The temperature was held at −18 to −20° C. with the ice/salt bath for two hours, then the flask was allowed to warm to room temperature. The reaction mixture was allowed to warm overnight, then transferred to a 3 L evaporation flask, and the solvents were evaporated. The by-product, triphenylphosphene oxide, and any remaining starting material was removed by extraction with a 1:1 mixture of ethyl acetate/water (1.4 L) and washing with saturated sodium bicarbonate (300 ml). The combined aqueous layers were washed with 600 ml of ether to remove residual triphenylphosphene oxide, and acidified with 10% citric acid solution until the pH of the mixture was around 2-3. This mixture, which contained some solids, was extracted with ethyl acetate (2×300 ml). The combined extracts were dried and evaporated in vacuo. The yield was 36.2 grams of solid product (>98%). 1H NMR (DMSO-d6) δ: 12.09 (s, 1H), 7.29 (d, J=8.2 Hz, 1H), 6.49 (m, 3H), 6.06 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.34 (br s, 4H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:27][C:28]1[N:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Br:27][C:28]1[N:33]=[CH:32][C:31]([O:1][C@H:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])=[CH:30][CH:29]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C1OCC[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1OCC[C@@H]1Oc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a suspension of (R)-3-hydroxydihydrofuran-2(3H)-one (500 mg, 4.9 mmol) in toluene (15 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) and 6-bromopyridin-3-ol (1.02 g, 5.88 mmol). The solution was cooled to 0° C. and degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-1,2-dicarboxylate was dissolved in toluene (5 mL) and added over a 5 minute period. The reaction was allowed to stir for 12 hours with warming to ambient temperature. The reaction was concentrated in vacuo and the resulting material purified by silica gel chromatography eluting 1:1 hexanes/EtOAc to yield (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 79%) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].[OH2:36].[NH2:37][NH2:38]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)=[O:36])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:38][N:37]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To cis-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclopentyl-6-(trifluoromethyl)-3-piperidinecarboxamide (37 mg, 0.075 mmol) in ethanol (2 mL) was added hydrazine monohydrate (0.11 mL, 2.26 mmol) into a 5 mL sealable vial, and the reaction was capped and heated overnight at 100° C. The reaction was concentrated, then redissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (35 ml/min, 25% CH3CN/H2O, 0.1% TFA to 50% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined, and the volume was reduced by reduce pressure until most of the CH3CN was removed. To the resulting aqueous mixture was added saturated aqueous NaHCO3 (10 mL) solution. The mixture was then extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting material was transferred to a vial and water was added to freeze dried overnight and afford the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=503 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.30-1.45 (m, 3H), 1.47-1.58 (m, 2H), 1.64 (dd, J=8.3, 4.3 Hz, 2H), 1.73-1.87 (m, 5H), 2.08 (bs, 1H), 2.33 (d, J=1.8 Hz, 1H), 2.84 (bs, 3H), 3.94-4.07 (m, 1H), 5.39 (s, 2H), 6.78 (bs, 2H), 7.62-7.74 (m, 2H), 7.94 (d, J=7.1 Hz, 1H), 8.02 (bs, 1H), 11.52 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:10]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:3].Cl.[C-:36]#[N:37].[Na+].CC(=O)C.[CH2:43]1[CH2:47]OC[CH2:44]1>O>[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]4[CH2:20][CH2:21][N:22]([C:43]([CH3:44])([CH3:47])[C:36]#[N:37])[CH2:23][CH2:24]4)[N:15]3[CH3:18])=[C:11]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:10]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:3]
Reactant: C1CCOC1
Reactant: [C-]#N
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCNCC3)n(C)c2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(C)(C)C#N)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-yl-9H-purine hydrochloride (396 mg, 0.89 mmol) in THF (3 mL) and H2O (4 mL) was added 1M HCl to give pH 4 followed by NaCN (261 mg, 5.32 mmol) and propan-2-one (590 μL, 7.98 mmol). The resulting mixture was allowed to stir at r.t. for 16 h then partitioned between H2O and DCM. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was triturated with Et2O and the solid collected by filtration and dried in vacuo affording 2-{4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-1-yl}-2-methylpropionitrile (316 mg, 69%). LCMS (method H): RT 2.64 min, [M+H]+ 514.4
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([NH:12][N:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=2)[CH2:16][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Na+]>C(O)(=O)C>[C:5]([O:9][C:10]([NH:12][NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]2[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=2)[CH2:16][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[C:5]([O:9][C:10]([NH:12][NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=2)[CH2:16][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)c1noc(C2CCC(=NNC(=O)OC(C)(C)C)CC2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Product: CC(C)c1noc([C@H]2CC[C@H](NNC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium cyanoborohydride (389 mg, 6.2 mmol) was added in 8 portions to a solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (from Step 1; 1.9 g, 5.9 mmol) in 50% aqueous acetic acid, and the mixture was stirred at room temperature for 2.5 h. The mixture was cooled slightly using cold water, and then 2 M aqueous sodium hydroxide solution was added to bring the pH to approximately 7. The mixture was extracted four times with dichloromethane, and the combined extracts were washed with water and brine, then dried (sodium sulfate), filtered, evaporated, and held under high vacuum to give a gum. This was purified on a Supelco 100 g column, eluting with 0-3% methanol/dichloromethane, to give N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (309 mg), N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (680 mg, 36%), and some mixed fractions. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, 6H, J=7.0 Hz), 1.36 (s, 9H), 1.45-1.53 (m, 4H), 1.60-1.68 (m, 2H), 1.94-2.04 (m, 2H), 2.90-3.05 (m, 3H), 4.20-4.25 (m, 1H), 8.16 (br s, 1H).