Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH2:3][C:4]#[N:5].N.[H][H]>C(O)C.[Ni]>[NH2:5][CH2:4][CH2:3][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:1]
Reactant: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)CCN

Procedure:
A solution of 17.0 g of ethyl 1-methyl-2-cyanoethyl(diethoxymethyl)phosphinate in 150 ml of ethanol is added to 155.0 g of an 8% solution of ammonia in ethanol. To this are added 10 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-1-methylpropyl(diethoxymethyl)phosphinate, b.p. 140° C./0.01 mbar, 31P=+47.0 and +46.7 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(−)-1-amino-2-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.94 (m, 1H), 3.30 (m, 2H), 2.20 (s, 3H), 1.18 (s, 3H). ESHRMS m/z 464.1167 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=1)[C:10]=34)[CH3:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][N:27]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:28][CH:29]=1)[C:10]=34)[CH3:4]
Reactant: CCC1C(C2=CCNCC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C(C2=CCN(S(C)(=O)=O)CC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Example 9 (35 mg, 0.08 mmol) in dichloromethane (5 mL) was added triethylamine (0.07 mL, 0.482 mmol) and methanesulfonyl chloride (14 mg, 0.121 mmol). The mixture was stirred at room temperature for 2 hours, and purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, CD3OD): δ 0.81-0.86 (m, 3H), 1.22-1.30 (m, 1H), 1.37-1.45 (m, 1H), 2.62-2.69 (m, 1H), 2.73-2.81 (m, 1H), 2.88 (s, 3H), 2.98 (s, 3H), 3.36-3.41 (m, 1H), 3.42-3.48 (m, 1H), 3.96 (dd, J=5.80, 3.05 Hz, 2H), 4.28 (dd, J=9.00, 5.65 Hz, 1H), 6.11 (s, 1H), 7.21-7.29 (m, 2H), 7.35 (d, J=5.49 Hz, 1H), 7.77 (dd, J=10.68, 2.75 Hz, 1H), 8.22 (d, J=5.19 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 441 (M+H)+.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:4][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCC(F)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.9 %

Procedure:
To a solution of 6.7 g of 2-fluorooctanol in 25 ml of pyridine, a solution of 10.4 g of p-toluenesulfonyl chloride in 40 ml of pyridine was added dropwise in 20 minutes below 0° C. on an ice water bath, followed by stirring for 7 hours at room temperature. After the reaction, the reaction mixture was poured into 200 ml of ice water and acidified with 6N-hydrochloric acid aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to precipitate a crystal. The crystal was purified by silica gel column chromatography to obtain 12.7 g of 2-fluorooctyl-p-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20])=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane (50 ml) was added to a stirred solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine (0.02 g, 0.164 mmol) and triethylamine (3.34 g, 33.0 mmol) in dichloromethane (50 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for a further 2 hours. The solvent was evaporated under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane and methanol (250 ml), and then the solution washed with 1N hydrochloric acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude material was chromatographed on silica gel (200 g), eluting with a 97:3 mixture of dichloromethane and methanol, to give a pink solid; crystallisation from ethyl acetate-hexane gave the pyrazole-5-carboxamide as a pale pink solid (2.2 g, 40%), m.p. 153-155° C. Found: C,61.66; H,6.77; N,16.95. C17H22N4O3 requires C,61.80; H,6.71; N,16.96%.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=C[CH:25]=3)[CH2:19][C:20]([NH:22][CH3:23])=O)[CH:16]=2)[NH:11][N:10]=1.[NH:30]1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:25]=[N:30][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][NH:22][CH3:23])[CH:16]=2)[NH:11][N:10]=1
Reactant: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1
Agent: O=C([O-])C(F)(F)F
Product: CNCCC(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
[3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-propyl]-methyl-amine CCXXVI was prepared as a trifluoracetate from 3-(3-chloro-1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=301.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4 step 2a and 2b) (13.96 g, 32.96 mmol), trimethylsilylacetylene (5.5 mL, 39.72 mmol) and Et3N (9.2 mL, 67.9 mmol) in dry DMF (33 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (116 mg, 0.5 mol %), PPh3 (43 mg, 0.5 mol %) and CuI (19 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The react mixture was then cooled to 23° C., diluted with EtOAc, washed water (twice) and brine, dried over Na2SO4. Removal of the solvent left an orange solid (13.30 g, 102%). MS (ISP) 394.1 [(M+H)+] and 396.1 [(M+2+H)+]; mp 198° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.F[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH2:11].[C:21](Cl)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O>[C:21]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Sodium bicarbonate (17 g, 202 mmol) and 150 mL water were added to a solution of 3-fluoro-4-morpholinyl aniline (26 g, 133 mmol) of acetone (200 mL). The reaction mixture was cooled to −10˜0° C. Carbobenzoxy chloride (26 g. 152 mmol) was added dropwise within 1 hour. The mixture raised to room temperature (25° C.) naturally, and stirred at this temperature for 2 hours. Then the material liquid was poured into 500 mL ice water, filtered, and dried to provide 39 g of off-white solid in 90% yield.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[O:31]1[CH2:30][CH:29]1[CH2:27][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1
Reactant: ClCC1CO1
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 54 %

Procedure:
To a solution of 50% aqueous DMSO (280 ml) containing sodium hydroxide (5.60 g, 140 mmol) was added 7-hydroxy-2,3-diphenylchromone (44.01 g, 140 mmol) and the resultant mixture was stirred until most of the solid went into the solution. Epichlorohydrin was then introduced into the suspension. The solution was stirred at room temperature (RT) for 2.5 days and solid formed during the reaction was collected from time to time (about twice a day). The white solid (total=47.58 g) was recrystallized from isopropyl alcohol several times to afford 28.15 g of relatively pure white prisms, m.p. 143°-145°; yield 54%. The mother liquor was concentrated to produce more crystals.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:12][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Brc1ccc(N2CCCC2)cc1
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of N-phenylpyrrolidine (73.8 g, 0.501 moL) in tetrahydrofuran (500 mL) was added N-bromosuccinimide (124.8 g, 1.4 equivalents) at 20° C. to 30° C., and the mixture was stirred at the same temperature for 4 hr. 1 mol/L Aqueous sodium hydroxide solution (300 mL) was added to the mixture at 27° C., and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (97.4 g, brown crystals). yield 86%. melting point 88.1° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][CH2:25][CH2:26][CH:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:31][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:25][CH3:24])=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCC(N)CCC
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCC(CCC)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-heptylamine (50.9 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-heptyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (36.4 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:11])[N:19]([CH3:20])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylearbodiimide hydrochloride (2.48 g) was added to a stirred suspension of N-tert-butoxycarbonyl-L-hydroxyproline (2.0 g), 4-(dimethylamino)pyridine (5.28 g) and dimethylamine hydrochloride (1.4 g) in methylene chloride (100 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated sodium bicarbonate and saturated brine before drying over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine as a colourless gum (1.01 g); 1H NMR Spectrum: (DMSO d6) 1.29-1.40 (m, 9H), 1.74-1.83 (m, 1H), 2.04-2.15 (m, 1H), 2.80-2.87 (m, 3H), 3.03 (s, 3H), 3.26 (m, 1H), 3.40 (m, 1H), 4.28 (m, 1H), 4.64 (m, 1H), 4.95 (d, 1H).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][CH2:10]1>O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(Oc2cccc(Cl)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(Oc2cccc(Cl)c2)CCC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (1.7 g, 40.3 mmol) was added to a suspension of Example 15A (4.7 g, 13.4 mmol) in tetrahydrofuran (320 mL) and water (160 mL) at room temperature. The reaction mixture was stirred at 55° C. overnight. The reaction was concentrated under reduced pressure to remove tetrahydrofuran, acidified to pH˜3 by adding aqueous 1 M HCl while cooling. The precipitate was collected by filtration and dried in a dessicator containing KOH overnight. Recrystallization from heptane afforded the titled compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][N:24]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCC(O)(Cc3ccccc3)CC2)c2ccccc12
Yield: 30 %

Procedure:
The title compound (12 mg, 30% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-benzyl-4-hydroxypiperidine (89 mg, 0.468 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:21]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(CCCO)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(CCCO)c1ccc(Oc2ccccc2)cc1
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Part C: A solution of 13 g (58 mmol) of 3-[(4-fluorophenyl)sulfonyl]propan-1-ol from part B and 16 g (175 mM) of phenol in 100 mL of anhydrous DMF was purged with nitrogen for one-half hour then treated with 24 g (175 mM) of potassium carbonate. The reaction mixture was then placed in a 100° C. oil bath. After 24 hours, the reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with 1N HCl solution, saturated sodium bicarbonate solution and brine, dried (MgSO4), and concentrated to afford 29 g of crude product. This was chromatographed on silica gel using 30-45% ethyl acetate/hexane to yield 12 g of pure 3-[(4-phenoxyphenyl)sulfonyl]propan-1-ol, m/z=299 (M+Li).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)#[N:2].[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42]2[NH:46][CH:45]=[N:44][N:43]=2)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:17](=[O:19])[C:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[N:14][CH:13]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]3[N:44]=[CH:45][N:46]=[C:42]23)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2nnc[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A mixture of ethyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.8 g), N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4H-1,2,4-triazol-3-amine (1.4 g) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 8 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 21%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8](I)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:17]([C:24]1[CH:25]=[CH:26][C:27]2B(O)[O:30][CH2:29][C:28]=2[CH:33]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[C:8]([C:27]3[CH:26]=[CH:25][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:33][C:28]=3[CH2:29][OH:30])[C:9]=12
Reactant: OB1OCc2cc(Oc3ccccc3)ccc21
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1CO)nn2C1CCCC1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
A mixture of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.36 g, 0.0011 mol), 5-phenoxy-1,3-dihydro-2,1-benzoxaborol-1-ol (0.30 g, 0.0013 mol), tetrakis (triphenylphophine)palladium (0.077 g, 0.000067 mol) and sodium carbonate monohydrate (0.34 g, 0.0028 mol) in ethylene glycol dimethyl ether (7 mL) and water (5 mL) was heated at 80° C. under an atmosphere of nitrogen for seventeen hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and aqueous saturated solution of sodium carbonate (20 mL). The aqueous layer was further extracted with ethyl acetate (3×20 mL). The organic solvent was removed under reduced pressure. Ethyl acetate (15 mL) was added to the residue and white precipitate was formed. The solid was filtered and washed with acetone (2×15 mL) and dichloromethane (1×15 mL) to yield [2-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-phenoxyphenyl]methanol (0.267 g, 0.00067 mol):
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[Cl:38])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-4[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2 eq), CDI (2 eq), and DBU (2 eq) according to the procedure of Example 51 to give a 48% yield of the desired material as a cream-colored solid after flash chromatography, mp >160° C. (gradual), homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 681 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(Cl)c(Cl)nc1Cl

Procedure:
A solution of 2,5,6-trichloronicotinonitrile (30 g, 144.92 mmol, 1.00 equiv) in sulfuric acid (98%, 162 mL, 1.00 equiv) was stirred for 1 h at 60° C. in an oil bath. The reaction mixture was cooled and then quenched by the addition of water/ice. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 26 g of 2,5,6-trichloronicotinamide as a white solid. LC-MS (ES, m/z): 225 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.38 (1H, s), 8.12 (1H, s), 7.95 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:12]([NH2:14])=O>O>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:11])[NH:14][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cc(Br)cnc12
Temperature: 25 °C

Procedure:
A solution of 3-amino-5-bromopicolinic acid (1.0 g, 4.6 mmol) in formamide (1.1 g, 25 mmol) was stirred at 150° C. for 4 h. After it was cooled to room temperature, the reaction mixture was poured into water (50 mL). A suspension was formed and filtered. The cake was washed with water and dried to give the desired product. MS (ESI): 226, 228 (MH+).