Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH2:13])=S)[CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][NH2:19]>CO.C(O)C>[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:19][CH2:18][C:17]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])=[NH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: NC(=S)Nc1cccc(Br)n1
Reactant: COc1cccc(OC)c1CN
Solvent: CO
Solvent: CCO
Solvent: CI
Product: COc1cccc(OC)c1CNC(=N)Nc1cccc(Br)n1
Yield: 73.5 %

Procedure:
0.37 mL (5.89 mmol) methyl iodide diluted in 2 mL methanol was added dropwise to 1.032 g (4.46 mmol) N-(6-bromopyridin-2-yl)thiourea suspended in 30 mL methanol, and the mixture was heated for 2 hr under reflux. The reaction mixture was in solution. The methylated intermediate product, consisting of methyl N-(6-bromopyridin-2-yl)imidothiocarbamate hydroiodide (ESI-MS [M+H+]=247.85 calculated for C7H8BrN3S=246), was freed of solvent under vacuum. The intermediate product was then suspended in 30 mL ethanol, and 1.122 g (6.442 mmol) 2,6-dimethoxybenzylamine was added, whereupon the solid completely dissolved. The mixture was then heated for 2.25 hr under reflux. The colorless solid which precipitated was suctioned off and washed with ethanol. 1.197 g N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine was obtained as crude product. Repeated crystallization from acetonitrile/water resulted in the isolation of 1.311 g (3.589 mmol, 81%) N-(6-bromopyridin-2-yl)-N-(2,6-dimethoxybenzyl)guanidine, which was also used for the subsequent reaction and derivatizations.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C(=O)[N:19](Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[NH2:12][C:3]1[C:2]([CH2:1][NH2:19])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CN)c1N
Yield: 21.7 %

Procedure:
To a mixture of methyl 3-methyl-2-nitrobenzoate (45.0 g, 0.23 mol) and NBS (45.0 g, 0.25 mol) in CCl4 (1500 mL) was added AIBN (1.2 g, 7.3 mmol) portion-wise under reflux. The mixture was refluxed (48 hours), and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (6% to 10% Ethyl acetate gradient in petroleum ether) to obtain methyl 2-amino-3-(aminomethyl)benzoate (9.0 g, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:20][CH2:19][CH2:18][N:17](CC4C=CC(OC)=CC=4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:30])[C:12]3=2)[C:7]1=[O:33]
Reactant: COc1ccc(CN2CCCn3c(c4c(c(O)c3=O)C(=O)N(Cc3ccc(F)c(Cl)c3)CC4)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1NCCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 110 °C

Procedure:
A mixture of 10-(3-chloro-4-fluorobenzyl)-8-hydroxy-2-(4-methoxybenzyl)-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione (18 mg, 30 μmol) and p-toluenesulfonic acid (26 mg, 0.14 mmol) in toluene (0.5 mL) was heated at 110° C. for 8 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)N1CCOCC1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1NCCCNC(=O)N1CCOCC1)CCCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.2 %

Procedure:
A solution of N-(3-{[4-amino-2-(ethoxymethyl)-1 H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)morpholine-4-carboxamide (0.120 g, 0.281 mmol) in 12 mL of TFA was treated with platinum (IV) oxide (0.064 g, 0.28 mmol). The mixture was placed under an atmosphere of hydrogen (3.8×105 Pa) and shaken at ambient temperature. After 17 h, the reaction mixture was diluted with 15 mL of 4:1 CHCl3:MeOH and then filtered through a pad of CELITE filter agent and rinsed through with portions of 4:1 CHCl3:MeOH (1% TFA). The clear colorless filtrate was concentrated under reduced pressure to yield a white solid. The material was suspended in 15 mL of H2O and treated with 10% NaOH solution until the pH of the liquid was 13. A white solid was collected by vacuum filtration. The solid was purified by chromatography (SiO2, 25–30% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a white foam. The foam was triturated with Et2O and filtered to yield N-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)morpholine-4-carboxamide (0.050 g) as a white solid. mp 152–154° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.52 (t, J=5.4 Hz, 1H), 6.31 (t, J=5.9 Hz, 1H), 5.83 (s, 2H), 4.61 (s, 2H), 3.58–3.50 (m, 6H), 3.24–3.21 (m, 4H), 3.12 (q, J=6.7 Hz, 2H), 3.06–3.00 (m, 4H), 2.67–2.64 (m, 2H), 1.78–1.72 (m, 4H), 1.66–1.61 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 157.6, 149.4, 148.9, 146.5, 137.1, 105.0, 65.8, 65.2, 62.9, 51.3, 43.7, 37.8, 32.0, 28.1, 22.8, 22.5, 22.0, 14.9; MS (APCI) m/z 432 (M+H)+; Anal. Calcd for C21H33N7O3•5H2O: C, 57.25; H, 7.78; N, 22.26; Found: C, 57.30; H, 7.82; N, 22.29.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH:34]1([C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Yield: 68 %

Procedure:
Preparation of example 59 from the title compound of Example 7 (70 mg, 0.25 mmol), (2R)-[(tert-butoxycarbonyl)amino](cyclohexyl)ethanoic acid (98 mg, 0.38 mmol), triethylamine (0.139 mL, 1.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (144 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 mL) was carried out analogously to Example 11 except that after 24 hours additional (2R)-[(tert-butoxycarbonyl)amino](cyclohexyl)ethanoic acid (32 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (48 mg, 0.13 mmol) were added to drive the reaction to completion. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (90 mg, 0.17 mmol) as a yellow powder in 70% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=2)=[CH:15][CH:16]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CN(CCc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 87.9 %

Procedure:
Combine [2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (5.0 g, 19.9 mmol), 6-chloronicotinamide (3.1 g, 19.9 mmol), and cesium carbonate (12.9 g, 39.8 mmol), in N,N-dimethylformamide (90 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (9.5 g). The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (6.5 g, 17.5 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.60 (s, 1H); 8.18-8.14 (m, 1H); 7.24-7.24 (m, 2H); 7.07 (d, 2H); 6.94 (d, 1H); 5.98 (br, 2H); 3.47-3.42 (m, 2H); 2.85-2.85 (m, 5H); 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:25])[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:26].O1CCOCC1>O1CCOCC1>[ClH:26].[ClH:26].[F:25][C:2]1([F:1])[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1CC(F)(F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC(F)(F)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of (R)-tert-butyl 4-(7,7-difluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.092 g, 0.260 mmol) in 2 mL dioxane was added 4M HCl/dioxane (2.27 ml, 9.09 mmol). The reaction mixture was stirred at room temperature 16 hours, after which it was concentrated to dryness and dried in vacuo to give (R)-7,7-difluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.079 g, 93.0% yield) as a pale yellow powder. MS (APCI+) m/z 255 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[F:13][C:14]([F:37])([F:36])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:26])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:17]([C:32]([F:35])([F:34])[F:33])[N:16]=1.C(Br)C=C>O1CCCC1>[F:37][C:14]([F:13])([F:36])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:3][CH:2]=[CH2:1])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:17]([C:32]([F:34])([F:33])[F:35])[N:16]=1
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCc1c(C(=O)OCC)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: -78 °C

Procedure:
A three-necked 250 ml flask is heated, desiccated, and purged with argon. Tetrahydrofuran (50 ml) is injected via syringe and the flask is cooled to -78° C. To this is added 8.33 ml (0.0133 mole) of 1.6M n-butyl lithium via syringe followed by 2 ml (0.0133 mole) of diisopropyl amine. To 10 ml of dried tetrahydrofuran, 5 g (0.0133 mole) of the product of Example 2 is added and the solution is injected into the reaction mixture. The mixture is stirred for an hour. Allyl bromide, 2.4 g (0.02 mole) is injected into the flask and the mixture is stirred for 90 minutes at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.N#N>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1([O:12][C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[S:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1ccc(OC2CC2)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC2CC2)c(SCc2ccc(OC)cc2)c1
Yield: 89.2 %

Procedure:
To a solution of methyl 3-bromo-4-(cyclopropoxy)benzoate (530.00 mg, 1.95 mmol, 1.00 eq) and (4-methoxyphenyl)methanethiol (451.12 mg, 2.93 mmol, 1.50 eq) in toluene (10.00 mL) were added Pd2(dba)3 (89.28 mg, 97.50 umol, 0.05 eq), Xantphos (112.83 mg, 195.00 umol, 0.10 eq) and DIPEA (504.04 mg, 3.90 mmol, 2.00 eq) under N2 protection. Then the mixture was stirred at 100° C. for 16 hr N2 protection. TLC detected the reaction was complete, the solvent was evaporated, the residue was washed with water, the aqueous layer was extracted with EA, the combined organic layer was dried over Na2SO4, concentrated, the residue was purified by silica gel chromatography (PE:EA=5:1) to afford product methyl 4-(cyclopropoxy)-3-[(4-methoxyphenyl)methylsulfanyl]benzoate (600.00 mg, 1.74 mmol, 89.34% yield) as white solid. LCMS: 345 [M+1].
Reaction SMILES: Br[C:2]([C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10])=[C:3]([CH3:5])[CH3:4].[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(O)CCC>[S:12]1[CH:16]=[CH:15][C:14]([C:2]([C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10])=[C:3]([CH3:5])[CH3:4])=[CH:13]1
Reactant: OB(O)c1ccsc1
Reactant: CCCCC(=O)C(Br)=C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCCCO
Product: CCCCC(=O)C(=C(C)C)c1ccsc1
Yield: 61.3 %

Procedure:
To a magnetically stirred solution of 3-bromo-2-methyl-oct-2-en-4-one (5 gram, 20.54 mmol) (Intermediate IIIc-1) in nitrogen-degassed n-butanol (50 ml) was successively added thiophene-3-boronic acid (3.94 gram, 30.80 mmol), palladium(II)acetate (46.11 mg, 0.21 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos) (168.6 mg, 0.41 mmol) and K3PO4 (8.72 g, 41.07 mmol) and the resulting mixture was reacted at 100° C. for 2 hours. The mixture was concentrated in vacuo and purified by sepacore chromatography (40×150 mm column), eluant: (Gradient: eluant 1: petroleum ether (40-60); Eluant 2: petroleum ether (40-60)/diethyl ether=95/5 (v/v)) to give 3-(3-thienyl)-2-methyl-oct-2-en-4-one (2.80 gram, 55%). 1H-NMR (400 MHz, CDCl3) δ 0.83 (t, J=7, 3H), 1.17-1.27 (m, 2H), 1.45-1.54 (m, 2H), 1.72 (s, 3H), 1.97 (s, 3H), 2.30 (t, J=7.4, 2H), 6.92 (br d, J=5, 1H), 7.04 (br d, J=3, 1H), 7.33 (dd, J=5 and 3, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(F)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 67.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.15 g of 4-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.19 g of 4-(4-fluorophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (62)), m.p.: 115.8° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Na]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc([N+](=O)[O-])cc2)cc(-c2ccccc2)n1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
The yellow suspension obtained by mixing ethyl 6-{[4-(4-nitrophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (5.3 g), stannous chloride (11.6 g) in ethanol (100 cc) is heated at 70° C. for 2 hours and 30 minutes under inert atmosphere. The clear brown solution thus obtained is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water (100 cc). The pH of this aqueous phase is brought to 6 by addition of sodium hydrogenocarbonate. The solution is then extracted with ethyl acetate (3×200 cc). The organic phases are combined, washed with distilled water (3×50 cc), dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 7-3). (yellowish oil).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1
Product: COC(=O)c1ccc(N=C2SC[C@H](CC(C)C)N2CC(C)C)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-1-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was saponified according to Method D6a, Step 1 to give (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The acid was coupled with ammonia as described in Method D6a, Step 2 to afford (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([C:37]#[N:38])[CH:36]=1)[O:5][C:6]1[C:7](=[O:33])[N:8]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19](C(OC(C)(C)C)=O)[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:36]=[C:35]([CH:34]=[C:4]([O:5][C:6]2[C:7](=[O:33])[N:8]([CH2:16][C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)[CH:9]=[CH:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:3]=1)[C:37]#[N:38]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(C#N)c3)c2=O)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask charged with tert-butyl 3-{[3-(3-chloro-5-cyanophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.940 g, 1.72 mmol) was added TFA (50 mL). After 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot acetonitrile (500 mL), hot filtered and allowed to cool to room temperature. After 1 day, the crystallized solids were filtered to yield the title compound as a white solid. 1H NMR (DMSO-d6) δ 13.65 (s, 1H), 8.52 (d, J=4.5 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.76-7.73 (m, 1H), 7.58-7.54 (m, 1H), 7.51-7.48 (m, 1H), 7.18 (dd, J=8.1 Hz, J=4.5 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 5.53 (s, 2H). HRMS (M+1)=446.0626.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27]/[CH:28]=[CH:29]/[C:30]([O:32]CC1C=CC=CC=1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O/C=C/C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.7 %

Procedure:
A suspension of (E)-benzyl 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)acrylate (490 mg, 0.908 mmol, 1.00 equiv) and 10% Pd/C (48 mg, 0.045 mmol, 0.05 equiv) in EtOAc (9.1 mL, 0.1 M) was stirred for 16 h under an atmosphere of H2 (1 atm, balloon pressure) at room temperature. The reaction mixture was filtered through a plug of Celite® and the plug was washed with EtOAc (50 mL). The filtrate was concentrated to provide a white solid that was shown to be a mixture of partially reduced products by 1H NMR. This material was resubjected to the reaction conditions and isolated as before to provide 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)propanoic acid (425 mg, 104%) as a white solid, contaminated with a small amount of EtOAc: IR (ATR) 3319, 2977, 2930, 2879, 1710, 1497, 1391, 1368, 1246, 1201, 1161, 1065, 851, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.22-7.12 (m, 3H), 5.14 (d, J=8.2 Hz, 1H), 4.93 (dq, J=9.0, 6.4 Hz, 1H), 4.59 (dd, J=15.2, 7.4 Hz, 1H), 3.99-3.84 (m, 2H), 3.79 (dt, J=8.9, 6.1 Hz, 1H), 3.48-3.31 (m, 2H), 3.24 (dd, J=11.2, 7.5 Hz, 1H), 3.16 (t, J=9.0 Hz, 1H), 3.12-3.06 (m, 1H), 2.60 (t, J=6.1 Hz, 2H), 2.32 (t, J=12.6 Hz, 1H), 1.90 (s, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.37, 172.28, 154.99, 139.74, 129.16, 128.42, 126.13, 85.30, 80.17, 75.27, 72.78, 72.16, 67.35, 52.88, 47.20, 35.09, 28.27, 18.71; HRMS-ESI (m/z) [M+Na]+ calc'd for C23H33NO8Na, 474.2098. found, 474.2118.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCBr)cc1
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 4-hydroxybenzonitrile (0.109 g, 0.913 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.930 mL, 9.16 mmol) followed by Cs2CO3 (0.439 g, 1.35 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.156 g, 71.4%). EI-MS Rt (2.10 min).