Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:56][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH3:46])(=[O:54])=[O:55])=[O:8]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-yl-methyl]benzoic acid (14.28 g), 4-dimethylaminopyridine (4.39 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.34 g) and 2-methylbenzenesulfonamide (5.85 g) was dissolved in dry methylene chloride (270 mL) and the solution was stirred under an inert atmosphere for 48 h. The mixture was diluted with methylene chloride (300 mL) and washed three times with 1N hydrochloric acid. The combined hydrochloric washes were back washed with methylene chloride. The combined organic extracts were washed twice with water and evaporated. The residue was dissolved in a small volume of methanol and 1N sodium hydroxide and this solution was purified by flash chromatography over octadecylsilyl bonded silica gel ("Regis PREP-40-ODS"--irregularly shaped 32-74μ diameter particles, 72% silanol coverage, 21% carbon load) (450 g) eluting with 50:50 methanol:water, pH 7.1. The appropriate fractions (TLC, Rf =0.73, octadecylisilyl bonded silica gel, 200μ layer, 12% carbon load, 80:20 methanol:water, pH 6.1, 0.1% ammonium acetate buffer) were combined, the methanol evaporated, and the residual aqueous solution acidified to pH 1 with 1N hydrochloric acid. The resultant precipitate was filtered, washed (water), and dried under vacuum to give the title compound (16.7 g, 88%) as a white solid; mp 117°-120° C.; ee at least 99%.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:33]([SH:37])[CH2:34][CH2:35][CH3:36]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([S:37][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reactant: CCCCS
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CCCCS[C@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 26 h
Yield: 43.3 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.59 g, 6 mmol) and 1-butanethiol (0.773 mL, 7.20 mmol) in acetonitrile (30 mL) was added Scandium(III) trifluoromethanesulfonate (0.295 g, 0.600 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 26 hours. TLC analysis showed starting material was completely consumed. Quenched with saturated ammonium chloride, extracted with ethyl acetate. Washed the organic phase with brine, dried over MgSO4, filtered, concentrated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5˜40% ethyl acetate-hexane to afford the mixture of diastereomers 2.54 g (84%). This oily mixture was purified by BIOTAGE® again, eluted with gradient 0˜20% ethyl acetate-toluene. The first peak collected from the column afforded by-product (2S,4S)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(butylthio)pyrrolidine-1,2-dicarboxylate (1.54 g, 2.60 mmol, 43.3% yield) as a wax. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.77 (t, J=7.17, 3H), 1.21-1.24 (m, 2 H), 1.28-1.34 (m, 2 H), 2.20-2.29 (m, 2 H), 2.41-2.46 (m, 1 H), 2.86 (dd, J=12.82, 7.32 Hz, 1 H), 3.53, 3.75 (s, rotomer, 3 H), 3.89 (dd, J=17.09, 11.29 Hz, 1 H), 4.23-4.36 (m, 1 H), 4.69-4.77 (m, 1 H) 5.22-5.30 (m, 2 H) 7.28-7.44 (m, 10 H), 7.53-7.60 (m, 4 H). LC-MS (retention time: 3.28 min, method B), MS m/z 504 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: COc1ccc2c(=O)[nH]cc(Cl)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(Cl)c2c1
Yield: 65 %

Procedure:
A solution of 4-chloro-6-methoxyisoquinolin-1(2H)-one (1.5 g, 5.90 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (1.1 g, 65.0%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.53(s, 1H), 8.27-8.24 (d, J=12 Hz, 1H), 7.56-7.53 (d, J=12 Hz, 1H), 7.41 (s, 1H), 4.02 (s, 3H); MS: MS m/z 230.03 (M++2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([C:13]([CH3:22])([CH3:21])[O:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62].CN(C1C=CC=CN=1)C>CN(C)C=O>[F:69][C:66]1[CH:67]=[CH:68][C:59]([CH2:58][NH:57][C:23]([C:10]2[N:11]=[C:12]3[N:18]([C:19](=[O:20])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:22])=[O:24])=[C:60]([C:61](=[O:62])[NH:63][CH3:64])[CH:65]=1
Reactant: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCOC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of intermediate 35, 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278 g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture was treated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121 g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, the solvent was removed in vacuo and the remaining residue dissolved in ethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2), eluting with ethyl acetate. Fractions containing the product were pooled, concentrated to dryness and triturated with ether to provide 0.366 g of the title compound as a white glassy solid. 1H NMR (500 MHz, d6-acetone) δ ppm: 8.71-8.82 (1H, m), 7.84-7.95 (1H, br), 7.47-7.62 (4H, m), 7.27-7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15-5.21 (2H, br s), 4.48-4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62-1.64 (6H, s).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([P+](CCCC)(CCCC)CCCC)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 847 mg (2 mmol) of tetrabutylphosphonium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 15 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 416.6 mg and 73%, respectively.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C@H:3]([NH:12][C:13](=[O:31])[C@@H:14]([CH2:19][N:20]([O:23]CC1C=CC=CC=1)[CH:21]=[O:22])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]>CO.C(OCC)(=O)C.[Pd]>[CH3:32][C:2]([CH3:1])([CH3:33])[C@H:3]([NH:12][C:13](=[O:31])[C@@H:14]([CH2:19][N:20]([CH:21]=[O:22])[OH:23])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2(R)-[(N-benzyloxy-N-formylamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide. (76 mg, 0.17 mmol) in methanol (2 mL) was added a slurry of 10% Pd/C (10 mg) in ethyl acetate (1 mL). Hydrogen gas was bubbled through the reaction for 15 minutes after which time the reaction was allowed to stir under one atmosphere of hydrogen for 2 hours. The reaction was flushed with argon and filtered through glass wool. The solvents were removed in vacuo to afford the title compound as a hygroscopic white crystalline solid (43 mg, 70%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cc(C)n[nH]4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 4-[1-phenyl-1-(3-methylpyrazol-5-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester(0.0190 g, 0.0538 mmol) in CH2Cl2 (1 mL) was added TFA (0.4 mL) and the mixture was stirred at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3 (2 mL). To this solution was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0187 g, 0.0621 mmol) and iPrNEt2 (0.050 mL, 0.287 mmol), followed by BOP—Cl (0.0221 g, 0.868 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The resulting residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O , brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0128 g, 44%) as a colorless solid:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:31](O)=[O:32])=[CH:24][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][C:31]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]3[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16]2)=[O:32])=[CH:24][CH:23]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccncc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccncc21
Yield: 85 %

Procedure:
(R)-3-(3-Methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-c]pyridine (35E) (0.279 mmol, crude oil) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.335 mmol, 0.086 g) and N-methylmorpholine (1.95 mmol, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.335 mmol, 0.127 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(3-(3-methoxypropyl)-3H-imidazo[4,5-c]pyridin-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (35F) as a clear oil (0.238 mmol, 0.146 g, 85% yield). ESI-ESI-MS: adz 614.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([C:15]#[CH:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I.C1COCC1.C(N(CC)CC)C>[CH:10]1([C:15]#[C:16][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: C#CC1CCCC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(Cl)nc(C#CC2CCCC2)n1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
2,6-Dichloropyrimidin-4-amine (0.2 g, 1.22 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.043 mmol) and copper iodide (14 mg, 0.07 mmol) were introduced in a flask. A mixture of THF-triethylamine 2:3 (5 mL) was added and the system was inertized 3 times with vacuum/argon cycles. Finally, cyclopentyl acetylene (0.16 mL, 1.34 mmol) was added and the resulting mixture was heated at 100° C. overnight. The reaction crude was cooled at room temperature and filtered over Celite®. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.15 g of the title compound, impurified with its regioisomer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(O)C.[BH4-].[Na+].Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc([C@H]2CC[C@H](O)CC2)c(O)c1
Reaction time: 16 h

Procedure:
4-(2,4-Dihydroxyphenyl)cyclohexanone (18 mg) was placed in a round-bottomed flask equipped with magnetic stirrer. Ethanol (5 ml) was added, followed by sodium borohydride (3.3 mg), and the reaction mixture was stirred for 16 hr. Aqueous HCl (20 ml, 1M), followed by ethyl acetate (20 ml), was added, and the organic phase removed and washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered, and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 60:40, v/v) to afford the title compound (14 mg, 78%) as a white solid. δH(CD3OD) 1.38-1.56 (4H, m), 1.85-1.88 (2H, m), 2.04-2.07 (2H, m), 2.80 (1H, tt), 3.58-3.65 (1H, m), 6.24-6.29 (2H, m), 6.90 (1H, d); m/z (ES−) 267 ((M+AcOH)−1)
Reaction SMILES: N[C:2]1[N:7]=[C:6](N)[C:5]([NH2:9])=[C:4]([NH2:10])[N:3]=1.[OH:11][CH:12](O)[C:13](=O)[CH3:14]>>[OH:11][CH2:12][C:13]1[N:9]=[C:5]2[C:4](=[N:10][CH:14]=1)[N:3]=[CH:2][N:7]=[CH:6]2
Reactant: CC(=O)C(O)O
Reactant: Nc1nc(N)c(N)c(N)n1
Product: OCc1cnc2ncncc2n1

Procedure:
Condensation of 2,4,5,6-tetraaminopyrimidine with dihydroxyacetone gave 6-hydroxymethylpteridine 1. Compound 1 was treated with bromine and triphenyl phosphine in dimethylacetamide to give the corresponding 6-bromomethylpteridine which was coupled in situ with 4-aminobenzoic acid to afford pteroylbenzoic acid 2. Purity of the crude product was about 85% as analyzed by HPLC. Due to the low solubility of this compound in most solvents, purification by recrystallization proved to be impractical. The corresponding sodium salt, however, was soluble in hot water and crystallized upon cooling. Although compound 2 decomposes in hot aqueous hydroxide, treatment of the crude product with dilute sodium bicarbonate gave the sodium salt without observable decomposition. Recrystallization of the salt from dilute aqueous bicarbonate raised product purity to 93% or above. The purified salt was then converted back to acid 2 by treatment with aqueous acetic acid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:35]#[N:36])[C:17]([C:20]2[CH:25]=[C:24](B3OCC(C)(C)CO3)[CH:23]=[CH:22][C:21]=2[F:34])=[CH:18][CH:19]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:24]3[CH:23]=[CH:22][C:21]([F:34])=[C:20]([C:17]4[C:16]([C:35]#[N:36])=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH:25]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(Cl)ccn23)ccc1F
Yield: 70.9 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (45 mg, 0.18 mmol) was coupled with 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (49 mg, 0.19 mmol), as described in Example 1, to afford 5′-(7-chloro-8-fluoroimidazo[1,2-α]pyridin-3-yl)-4,2′-difluorobiphenyl-2-carbonitrile as a white amorphous solid (49 mg, 71%): δH (360 MHz, CDCl3) 6.86 (1H, dd, J 7 and 7), 7.35-7.44 (2H, m), 7.58-7.64 (4H, m), 7.71 (1H, s), 8.20 (1H, d, J 7); m/z (ES+) 384 (100%, [MH]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(#N)C.CCOC(C)=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([F:13])[CH:15]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A mixture of 2-bromo-2-(4-fluorophenyl)acetic acid (500 mg, 2.15 mmol) and 3-fluoroaniline (477 mg, 4.29 mmol) in acetonitrile (8 ml) was heated under microwave irradiation at 100° C. for 50 minutes. Then 3-fluoroaniline (238 mg, 2.15 mmol) was added again, and the reaction mixture was heated at 120° C. for 45 minutes in a microwave oven (UPLC-MS monitoring: complete conversion). The organic solution was diluted with EtOAc and was washed with 2N HCl and then with brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated to give 2-(4-fluorophenyl)-2-(3-fluorophenylamino)acetic acid (510 mg, 90% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[OH:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)C(C)(C)CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
tert-Butyl 4-aminocyclohexylcarbamate (4:1 cis:trans mix of isomers, 1.00 g, 4.67 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (0.60 g, 5.13 mmol) and triethylamine (1.30 ml, 9.33 mmol) were dissolved in dimethylformamide (20 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (984 mg, 5.13 mmol) and 1-hydroxybenzotriazole (694 mg, 5.13 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol:0.880ammonia (95:5:0.5) as eluant to give tert-butyl 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate (840 mg) as a white foam as a ca. 4:1 mixture of diastereoisomers.