Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)n2)CC1
Yield: 77.9 %

Procedure:
A solution of 220 mg (0.793 mmol) 5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 134 mg (0.753 mmol) N-bromosuccinimide at room temperature for 20 min. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 10-35% EtOAc-hexanes afforded 209 mg (74%) of the title compound as a colorless glassy solid. 1H-NMR (CDCl3; 400 MHz): δ 6.97 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.0 Hz), 4.28-4.15 (br s, 2H), 4.06-3.90 (m, 2H), 2.85-2.75 (m, 2H), 2.77-2.68 (m, 1H), 1.92-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][C@@H:33]([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl.O1CCOCC1>>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][C@@H:33]([CH3:41])[C:34]([OH:36])=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (S)-tert-butyl 2-(3-(4′-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanamido)propanoate 2,2,2-trifluoroacetate (4.4 mg, 7.60 mol) was added 4M hydrogen chloride in dioxane (0.665 mL, 2.66 mmol). The reaction was stirred at room temperature for 4 h. The mixture was concentrated to give the title compound. LCMS m/z=409.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=511 [M+H]+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:18]([F:21])([F:20])[F:19].[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:42][CH2:43][C@H:44]([C:47]([O:28][C:25]3[CH:26]=[CH:27][C:22]([C:17]([F:29])([F:16])[C:18]([F:20])([F:19])[F:21])=[CH:23][CH:24]=3)=[O:48])[CH2:45][CH2:46]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)C(F)(F)F)cc3)CC2)CC1

Procedure:
0.1 mol of dicyclohexylcarbodiimide (DCC) in 30 ml of CH2Cl2 is added with stirring at about 10° to a mixture of 0.1 mol of 4-(pentafluoroethyl)-phenol (preparation analogously to Bull. Chem. Soc. Japan, 57 (1984) 3361), 0.1 mol of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarboxylic acid and 0.01 mol of dimethylaminopyridine and 150 ml of CH2Cl2, and the mixture is then stirred for 15 hours at room temperature. It is filtered over silica gel, the solvent is evaporated and further purification gives 4-(pentafluoroethyl)-phenyl trans-4-(trans-4-pentylcyclohexyl)-cyclohexanoate.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl.C(Cl)(Cl)Cl>[O:11]([CH2:10][CH2:9][NH:8][C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=[CH:5][N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Clc1nccnc1NCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: c1ccc(OCCNc2nccnc2N2CCNCC2)cc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of the product from Step 1 above (1.59 g, 6.37 mmol), piperazine (1.56 g, 18.2 mmol), and K2CO3 (0.88 g, 6.4 mmol) in acetonitrile (10 mL) was stirred at 140° C. for 12 h in a sealed tube. After cooling, the reaction mixture was diluted with CH2Cl2, filtered, and concentrated. The semisolid residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give a beige oil. This oil was redissolved in CHCl3, and filtered through a short (3 cm) plug of alumina covered with K2CO3. The pad was washed with several portions of CHCl3 and the resulting filtrate was concentrated to afford 1.48 g (78%) of the title product as a pale yellow oil. HRMS m/z calcd for C16H21N5O (M)+ 299.1746, found 299.1753. Anal. (C16H21N5O.1/3H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.[B:25](OC)([O:28]C)[O:26]C.Cl>C(OCC)(=O)C.C1COCC1.C1CCCCC1.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([B:25]([OH:28])[OH:26])=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCOc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
4′-Butoxy-2,3-difluoro-1,1′-biphenyl (18) (20.0 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 83.9 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Then, trimethyl borate (9.5 g) in a THF (50 ml) solution was added dropwise thereto in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. Then, the reaction mixture was poured into a vessel containing 1N-hydrochloric acid (100 ml) and ice-water (500 ml), and mixed. Ethyl acetate (300 ml) was added thereto and the mixture was allowed to be separated into organic and aqueous phases, and extraction into an organic phase was carried out. The obtained organic layer was fractionated, washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 21.3 g of 4′-butoxy-2,3-difluoro-1,1′-biphenyl-4-boronic acid (19). The yield based on the compound (18) was 91.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.C1COCC1.CCO>C(O)C>[F:11][C:10]([F:12])([F:13])[C:8]1[CH:7]=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([NH2:1])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1-c1ccccc1

Procedure:
The product from Example 218a was reacted as described in Example 212c substituting 3:1 THF/EtOH (4 mL) for ethanol to give the title amine in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:21][CH2:20][C@@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Yield: 95.6 %

Procedure:
tert-Butyl [(1R,3S)-3-(4-[3-(trifluoromethyl)phenyl]-piperazin-1-ylcarbonyl)-cyclopentyl]-carbamate (82 mg, 0.18 mmol) was treated with trifluoroacetic Acid (3 mL, 0.04 mol) in methylene chloride (3 mL) at room temperature for 1 h. The mixture was concentrated to provide the desired product (98 mg, 93%). MS calculated for C20H28F3N3O: (M+H) 384.3; found 384.2.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][NH2:18])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[CH3:19][C:20]([CH3:22])=O.C([BH3-])#N.[Na+].N#N>>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][NH:18][CH:20]([CH3:22])[CH3:19])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)=O
Reactant: NCCNc1ccc2ncc(Br)n2n1
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)NCCNc1ccc2ncc(Br)n2n1

Procedure:
Glacial acetic acid [64-19-7] (1.6 mL, 28.0 mmol) was added to a stirred suspension of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)ethane-1,2-diamine (7.0 g, 27.2 mmol), acetone [67-64-1] (2.4 mL, 32.6 mmol), sodium cyanoborohydride [25895-80-7] (1.8 g, 27.2 mmol) and powdered, activated 4 Angstrom molecular sieve (4 g). The flask was N2 blanketed, closed with a septum, and the mixture allowed to stir at ambient temperature for 3d, then filtered. The filtrate was evaporated, and the residue partitioned between 10% (w/v) aqueous NaHCO3 and ethyl acetate. The extract was dried (CaSO4), and evaporated to afford a clear orange oil. This oil was triturated in heptane to precipitate N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N2-isopropylethane-1,2-diamine as 2.3 g of yellow powder, mp. 87-88° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.32 Hz, 5H) 1.60 (br. s., 1H) 2.71-2.81 (m, 3H) 3.34 (q, J=6.32 Hz, 2H) 6.73 (d, J=9.85 Hz, 1H) 7.07 (t, J=5.31 Hz, 1H) 7.47 (s, 1H) 7.68 (d, J=9.60 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 22.92, 41.48, 45.29, 47.81, 98.98, 112.99, 125.26, 130.24, 136.53, 154.24. LRMS (ESI) m/z 297.9/299.9 [(M+H)]+, calc'd for C11H16BrN5. 289.19.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro-1-(2-dimethylaminoethyl)-2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-(dimethylamino)ethyl chloride hydrochloride by following General Procedure 3.
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:12]([C:14]1[CH:19]=[C:18]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:29])[C:15]=1O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:12]([C:14]1[CH:19]=[C:18]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:29])[C:15]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([CH3:11])[CH3:1])[CH3:13]
Reactant: CC(C)=CCOCCCCO
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCCCCOCC=C(C)C
Yield: 78.9 %

Procedure:
To a mixture of 0.52 g of 4-(3-methyl-2-butenyloxy)butanol, 0.77 g of 2-ethyl-6-methyl-4-benzoyloxyphenol, 0.87 g of triphenylphosphine and 20 ml of tetrahydrofuran was slowly added dropwise 0.73 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.94 g of 3-ethyl-5-methyl-1-benzoyloxy-4-(4-(3-methyl-2-butenyloxy)butyloxy)benzene (yield, 79%), nD20.0 1.5361.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2,6-dimethyl-4-nitro-4′-(trifluoromethyl)biphenyl (600 mg, 2.03 mmol) in ethanol (20 mL) was added 10 wt % palladium on carbon (18 mg). The reaction was pressurized to 50 psi hydrogen and stirred at room temperature overnight. The reaction was filtered onto Celite and concentrated. Purification by column chromatography gave 2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-amine (480 mg, 89%) as a light yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.65 (d, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.48 (s, 2H), 3.80 (s, 2H), 1.94 (s, 6H). MS (M+1): 266.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 11: Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), formic acid (2.6 mL), aqueous formaldehyde (40%, 2.45 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) and by flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.125 g. [α]D=+19.8° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 150° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 14), 57 (bp), 58 (31), 113 (13), 127 (11), 141 (10).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12]C[C@@H:10]([O:14][Si](C(C)(C)C)(C)C)[C@H:9]1[C@H:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([Cl:33])[C:26]=1[CH3:34])[CH3:23])=[O:7])(C)(C)C.C(OC(N1CCC[C@@H](O[Si](C(C)(C)C)(C)C)[C@H]1[C@@H](NC1C=CC(C#N)=C(Cl)C=1C)C)=O)(C)(C)C>>[OH:14][C@H:10]1[C@@H:9]2[N:8]([C:6](=[O:7])[N:24]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:22]2[CH3:23])[CH2:13][CH2:12]1
Reactant: Cc1c(N[C@H](C)[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C)[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Compounds 81A-a and 81A-b were synthesized from 1-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-formyl-piperidine (18F) following a procedure similar to that used for 80F to give a mixture of 81A-a and 81A-b as the crude product. Purification and separation by flash chromatography (12 g ISCO silica gel column, 0-20% EtOAc/hexane gradient) provided 81A-a as colorless film (28 mg) and 81A-b (14 mg) as a colorless film. For 81A-a: HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.85 min (100%); MS (ES) m/z 508.0 [M+H]+; HRMS calcd for C26H43ClN3O3Si 508.2762, Found 508.2761. For 81A-b: HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.95 min (100%); MS (ES) m/z 508.0 [M+H]+; HRMS calcd for C26H43ClN3O3Si 508.2762, Found 508.2748.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:25](O)=[O:26])[C:12]2[C:17]([CH3:18])=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13]=2[N:14]=1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.[C:42]([N:49]1[CH2:54][CH2:53][NH:52][C:51]([CH3:56])([CH3:55])[CH2:50]1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>ClCCl.C(N(CC)C(C)C)(C)C>[C:45]([O:44][C:42]([N:49]1[CH2:54][CH2:53][N:52]([C:25]([C:11]2[C:12]3[C:17]([CH3:18])=[N:16][N:15]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:13]=3[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)=[O:26])[C:51]([CH3:56])([CH3:55])[CH2:50]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)O)c12
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)C)c12
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of 6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg) in dry dichloromethane (3 mL), N,N-diisopropylethylamine (70 μL), 2-bromo-1-ethylpyridinium tetrafluoroborate (221 mg) and 1-Boc-3,3-dimethylpiperazine (87 mg) were added. The solution was stirred for 30 min. Upon complete conversion, the solution is evaporated in vacuo and 3 mL of 30% sodium methoxide in methanol were added. The mixture was stirred for 30 min, the pH was adjusted to 5 by addition of 2M hydrochloric acid. Ethyl acetate was added and the organic layer was extracted with saturated sodium bicarbonate, 20% aqueous ammonium chloride solution and multiple times with water. The organic layer was dried over sodium sulfate and evaporated to dryness to give 132 mg (58%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[C:6](=[O:17])[NH:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:19]N(C)C=O.[H-].[Na+].CI>>[Br:1][C:2]1[S:18][C:5]2[C:6](=[O:17])[N:7]([CH3:19])[CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(Br)sc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1CC(c2ccc(Cl)cc2)c2cc(Br)sc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.0800 g, 0.233 mmol) in anhydrous N,N-dimethylformamide (3.00 mL, 38.7 mmol) and cooled to 0° C. NaH 60% in mineral oil (60:40, sodium hydride:Mineral Oil, 0.0500 g, 1.25 mmol) was added in portions and stirred for 10 minutes. Methyl iodide (0.0876 mL, 1.41 mmol) was added and the reaction mixture was slowly warmed to room temperature and allowed to stir for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (5.00 mL) and diluted with EtOAc (10.00 mL). The mixture was successively washed with water (10.0 mL×2) and brine (10.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was wet loaded onto silica gel and then purified using a ISCO (4 g cartridge, gradient hexanes to 75% EtOAc over 30 min) to afford the product (0.0812 g, 78%) as a yellow oil. LC/MS (AA) ES+ 356, 358, 360. 1H NMR (dmso-d6, 400 MHz): d 7.43-7.37 (2H, m), 7.25-7.19 (2H, m), 6.98 (1H, s), 3.81-3.73 (1H, m), 3.66-3.58 (1H, m), 2.85 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C([O-])=O.[NH4+].CO>[Pd].O>[NH:9]1[C:4]2=[N:5][C:6]([NH2:8])=[N:7][CH:2]=[C:3]2[CH:11]=[N:10]1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ncc2cn[nH]c2n1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A mixture containing 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-yl amine (0.6 g, 3.54 mmol, Chembridge), 10% palladium on carbon (0.15 g), ammonium formate (1.24 g, 19.6 mmol) and methanol (20 mL) was heated at reflux for about 4 h. The reaction mixture was cooled to ambient temperature and filtered through Celite®, which was subsequently washed with additional MeOH (2×20 mL). The combined filtrates were evaporated under reduced pressure to yield a white solid. The solid was suspended in water (50 mL), filtered, and dried to afford 1H-pyrazolo[3,4-d]pyrimidin-6-yl amine (0.15 g, 31%) as a white solid. LC/MS (Table 2, Method c) Rt=2.12 min; MS m/z: 136 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH2:12]([S:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCSc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCSc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 30 %

Procedure:
4-Cyanophenylboronic acid (7 g, 0.0476 m) was stirred and refluxed for 60 hours under nitrogen with 4-n-heptylthiobromobenzene (12.4 g, 0.0433 m), TTPP (0.9 g, 0.000783 m), 2 molar aqueous sodium carbonate (41 mls), toluene (86 mls) and industrial methylated spirit (20.5 mls). The mixture was then separated end extincted with toluene (2×10 mls) washed with water (100 mls) and dried over magnesium sulphate. The solvents were then evaporated off to give a brown solid products which was purified by column chromatography and recrystallisation from industrial methylated spirit. 4-Cyano-4'-heptylthiobiphenyl was produced (4.1 g, 100% HPCL, 30% yield melting point 64.4° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:35]([CH3:44])[CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([Cl:32])=[CH:34][C:35]=4[CH3:44])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)c(Cl)cc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-chloro-2,5-dimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=624.1)=93%.