Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH3:12])=[CH:5][CH:4]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:29][C@H:30]([CH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[C@H:31]([CH3:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(C(C)(C)C)(C)C>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.C1(C)C=CC=CC=1>[CH3:12][NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:36]2[CH:35]=[CH:34][C:33]([O:32][C@@H:31]([CH3:42])[C@H:30]([OH:29])[CH2:43][CH2:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[CH:38][CH:37]=2)=[CH:4][CH:5]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CNCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNCCc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 120 °C
Yield: 43.1 %

Procedure:
Prepared according to the method described in Example 12b) from [2-(4-bromophenyl)ethyl]-N-methylamine hydrochloride (0.214 g, Example 30a)), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.2 g, Example 11)), and tetrakis(triphenylphosphine)palladium (0) (0.02 g) with heating at 120° C. for 4 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-25% ethanol in dichloromethane to give the title compound as a pale yellow solid (0.081 g).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]=2[NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>[N+](C1C=CC=CC=1)([O-])=O>[C:18]1([C:17]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:7]3[NH:11][N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]=3[N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: FC(F)(F)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Temperature: 185 °C
Reaction time: 6 h

Procedure:
A mixture of 1.02 g of N-(5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-benzamide in 10 mL of nitrobenzene was treated with 0.41 mL of phosphorous oxychloride and stirred at 185° C. for 6 h. The solvent was distilled off under high vacuum and the residue was partitioned between ethyl acetate and water. The organic portion was washed with saturated sodium bicarbonate, water and brine and dried over magnesium sulphate. Concentration and purification by MPLC, eluting with 1/3 ethyl acetate/heptane, gave the title compound as a white solid, melting point 264–265° C.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)(C)(C)C.Cl.[CH2:24](N(CC)CC)C.C(Cl)(=O)C>ClCCl>[CH:20]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:5])[CH3:24])[CH:12]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCn1cc(C=O)c2ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)NCCCn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred dichloromethane (0.09 M) solution of tert-butyl[3-(3-formyl-1H-indol-1-yl)propyl]carbamate from the previous step was added HCl (4 N solution in dioxane, 45 eq.). The resulting solution was stirred at RT for 1 h before the volatiles were removed in vacuo. Dichloromethane was then added to the red residue and the volatiles were again removed in vacuo to afford a red gum. To the crude amine thus obtained was then added dichloromethane (0.09 M) and triethylamine (2.2 eq.). When the reaction solution became homogeneous, acetyl chloride (1.05 eq.) was added and the resulting mixture was allowed to stir at RT for another 2 h. The reaction was finally quenched with 1 N aq. NaOH and extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and concentration of the filtrate in vacuo afforded the crude title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C@H:14]([OH:26])[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:58]([OH:61])(=[S:60])[CH3:59]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:60][C:58](=[O:61])[CH3:59])[CH2:10][C@H:9]1[C@H:14]([OH:26])[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH3:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CN(CC[C@@H](O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1C[C@@H]([C@H](O)CCN(C)C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 680.3 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-2-[(R)-3-(N-tert-butoxycarbonyl-N-methylamino)-1-hydroxypropyl]-4-hydroxypyrrolidine (1.0 g, 2.67 mmol, intermediate prepared in REFERENCE EXAMPLE 27-2) in tetrahydrofuran (10 ml) were successively added triphenylphosphine (842 mg, 3.21 mmol) and diethyl azodicarboxylate (0.505 ml, 3.21 mmol) under a nitrogen atmosphere under cooling with ice. The mixture was stirred at the same temperature for 10 minutes, and then thioacetic acid (0.25 ml, 0.35 mmol) was dropwise added thereto. The reaction solution was stirred at the same temperature for 2.5 h and then concentrated in vacuo. A mixture (10 ml) of hexane-ethyl acetate (5:1) was added to the residue. The precipitate was filtered off, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, hexane-ethyl acetate=5:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-acetylthio-2-[(R)-3-(N-tert-butoxycarbonyl-N-methylamino)-1-hydroxypropyl]pyrrolidine (1.03 g, yield: 89.2%). The data of this compound agreed with those of the compound prepared in REFERENCE EXAMPLE 27-2. ##STR411##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(OC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)cc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of compound 55 (25.0 g, 89.4 mmol) in THF (100 mL), H2O (100 mL) and MeOH (100 mL) was added aq. 5 N NaOH dropwise at 0° C. The mixture was stirred at room temperature for 1 hour. Conc. HCl was added to the mixture to acidify and the mixture was extracted with EtOAc (500 mL×2). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the crude acid 56 (22.6 g, 96%) as an orange solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([N:8]1[N:9]=[C:10]2[C:2]([C:31]3[S:30][CH:29]=[CH:33][CH:32]=3)=[CH:3][CH:4]=[C:5]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:6]2=[N:7]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCCCCCCCn1nc2c(Br)ccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nc2c(-c3cccs3)ccc(-c3cccs3)c2n1

Procedure:
4,7-Dibromo-2-dodecylbenzotriazole (100 mg, 0.224 mmol), and tributyl(thiophen-2-yl)stannane were dissolved in anhydrous THF (100 ml) and dichlorobis (triphenylphosphine)-palladium(II) (50 mg, 0.045 mmol) was added at room temperature. The mixture was refluxed for 12 hours under argon atmosphere. Solvent was evaporated under vacuum and the crude product was purified by column chromatography on silica gel to obtain 75 mg (74%) TBT. 1H NMR (400 MHz, CDCl3, δ): 8.01 (d, J=5.6 Hz, 2H), 7.52 (s, 2H), 7.28 (d, J=6.0 Hz, 2H), 7.09 (t, JA=8.8 Hz, JB=4.8, 2H), 4.60 (t, J=7.0 Hz, 2H), 2.10 (m, 2H), 1.38-1.15 (m, 18H), 0.80 (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, δ): 142.4, 140.2, 128.4, 127.3, 125.8, 123.9, 123.0, 57.1, 32.2, 30.3, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 26.9, 22.9, 14.4. MS (m/z): 451 [M+]
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[P:5]([CH:10]([CH3:18])[CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[OH-].[NH4+:23]>C(O)C>[NH2:23][C:12](=[O:13])[CH:11]([F:17])[CH:10]([P:5]([CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9])[CH3:18]
Reactant: CCOC(=O)C(F)C(C)P(=O)(OCC)C(OCC)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)C(F)C(N)=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluorobutanoate (1.8 g, 5.5 mmol) in ethanol (3 mL) was added concentrated ammonium hydroxide (14.8 M, 0.5 mL, 7.4 mmol). The solution was stirred for 24 h at 40° C. and then evaporated to give 1.6 g (97%) of a diastereomeric mixture of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxymethyl)phosphinate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 5.7–6.7 (m, 2H), 4.9–5.5.6 (m, 1H), 4.7–4.8 (m, 1H), 4.1–4.4 (m, 2H), 3.8–4.0 (m, 4H), 2.8–3.0 (m, 1H), 1.2–1.4 (m, 12H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14].CON(C)[C:18](=[O:28])[CH2:19][O:20][C@@H:21]([CH:26]=[CH2:27])[C:22]([F:25])([F:24])[F:23].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CCCCCC.CCOCC>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:18](=[O:28])[CH2:19][O:20][C@@H:21]([CH:26]=[CH2:27])[C:22]([F:24])([F:23])[F:25]
Reactant: Fc1cccc(Br)c1F
Reactant: C=C[C@H](OCC(=O)N(C)OC)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C[C@H](OCC(=O)c1cccc(F)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexane (2.50 M, 13.5 mL) was added dropwise over 20 mins to a solution containing 1-bromo-2,3-difluorobenzene (6.50 g) in Et2O (50 mL) under a N2 atmosphere at −78° C. The reaction solution was allowed to stir for 60 mins. (S)—N-Methoxy-N-methyl-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)acetamide) (5.20 g) in Et2O (10 mL) was then added dropwise to the reaction solution, and after stirring at −78° C. for 1 h, aqueous NH4Cl (50 mL) was added to the reaction solution, followed by warming to RT. NaHCO3 (sat. aq., 100 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue was purified by silica gel column chromatography (1% to 10% EtOAc in hexanes) to obtain the title compound (3.91 g). 1H NMR (400 MHz, CDCl3) δ ppm: 4.33-4.43 (m, 1H), 4.80-4.84 (m, 2 H), 5.55-5.67 (m, 2 H), 5.76-5.94 (m, 1 H), 7.18-7.28 (m, 1 H), 7.37-7.47 (m, 1 H), 7.70 (ddt, J=7.9, 6.0, 1.7 Hz, 1H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C.CO>[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOP(=O)(Cc1nc(N2CCOCC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (1.2 g), triethyl phosphite (2.1 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v), then ethyl acetate-methanol (10:1, v/v) to give diethyl {[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}phosphonate as a yellow oil (1.7 g, yield 95%). NMR (CDCl3) δ: 1.30 (6H, t, J=7.1 Hz), 2.27 (3H, d, J=4.1 Hz), 3.11 (2H, d, J=20.9 Hz), 3.31-3.43 (4H, m), 3.72-3.85 (4H, m), 3.99-4.20 (4H, m).
Reaction SMILES: [CH2:1]([C:3]1([NH2:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28][NH:12][C:3]2([CH2:1][CH3:2])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC1(N)Cc2ccccc2C1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: CC#N
Product: CCC1(NCC(=O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2C1

Procedure:
A mixture of 2-ethyl-indan-2-ylamine and N-(2-benzyloxy-5-bromoacetyl-phenyl)-methanesulfonamide is stirred in acetonitrile at room temperature for 20 hours. The product is isolated by filtration. ES+ MS m/e 479 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[K+].[F:13][C:14]([F:18])=[C:15]([F:17])[Cl:16]>CN(C)C=O>[F:13][C:14]([F:18])([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH:15]([F:17])[Cl:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cccc(OC(F)(F)C(F)Cl)c1
Temperature: 60 °C

Procedure:
139 grams (1 mole) of 3-nitro-phenol and 28 grams (0.5 mole) of potassium hydroxide were dissolved in 400 milliliters of dimethyl formamide, and 140 grams (1.2 mole) of trifluoro-chloroethylene were introduced in a gas pipe at 40° C; the mixture was then maintained at 60° C for 2 hours. The main amount of dimethyl formamide was distilled off in vacuo. The residue was poured into ice water, separated, dried over Na2SO4 and distilled in vacuo.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25]CC4C=CC=CC=4)=[C:21]([F:33])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:33])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(O)c(F)c3)cc3ccccc23)CC1
Reaction time: 72 h
Yield: 39.8 %

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3-fluorophenyl)isoquinoline (3.19 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was dissolved in methanol (200 ml), followed by the addition of 10% palladium/carbon catalyst (0.31 g), and the catalytic reduction was conducted at atmospheric pressure for 3 days. The catalyst was filtered off, while the solvent was evaporated. Water was added to the resulting residue, followed by the addition of an aqueous solution of saturated sodium bicarbonate, and then the mixture was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-(3-fluoro-4-hydroxyphenyl)isoquinoline (1.01 g) as a pale brown viscous oil.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-ol dihydrochloride (41 mg, 0.13 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino) -2-(4-chlorophenyl)propanoic acid (46 mg, 0.13 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (51 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (58 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.30-7.22 (m, 4H), 5.11 (m, 1H), 3.80-3.40 (m, 13H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.14 (m, 3H), 1.03 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H]+559.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:18]([NH:22][C:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:13])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)CCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.6 %

Procedure:
Dissolve 3-(4-cyanophenyl)-propionic acid (0.4 g, 2.48 mmol) and thionyl chloride (1.1 mL, 14.9 mmol) in toluene (2 mL) and reflux the mixture for 2 h. Concentrate in vacuo, dissolve the residue in DCM (1.5 mL) and add the solution to a cold solution (0° C.) of tert-butylamine (300 μL, 2.85 mmol) in DCM (1.5 mL) and triethylamine (97 μL, 0.69 mmol). Allow the mixture to stir at 0° C. for 15 min and at room temperature for 16 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (65:35) to obtain the desired intermediate (306 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][N:13]([CH3:14])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (3.00 g, 14.85 mmol), dimethyl amine hydrochloride (1.82 g, 22.30 mmol) and triethylamine (6.21 ml, 44.60 mmol) in 20 mL of DMF was added HATU (8.47 g, 22.30 mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 60-70% EtOAc in hexanes to give a yellow oil (1.56 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.77 Hz, 1 H) 7.88 (dd, J=8.34, 2.27 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 3.06 (d, J=14.15 Hz, 6 H); LCMS for C8H9BrN2O m/z 229.00 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+].Cl>COCCO>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[S:7]2)=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2sc1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccc(Cl)cc2sc1=O)C(=O)O
Temperature: 115 °C
Yield: 67.7 %

Procedure:
A mixture of 7-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 60 (f)) (125 mg, 0.46 mmol), L-alanine (494 mg, 5.55 mmol) and NaOMe (249 mg, 4.62 mmol) in 2-methoxyethanol (5 mL) was heated in a 115° C. sand bath for 24 h. 1 N HCl aq. solution was added to precipitate the product. The solid was collected and rinsed with water. It was dried in vacuo and then triturated with MeOH to provide the title compound (102 mg). MS ESI(−) m/e: 327.96, 325.97 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]([C:21](=[O:48])[N:22]([CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2Br)[N:40]=1)[CH3:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[CH3:50][N:51](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]([C:21](=[O:48])[N:22]([CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:50]#[N:51])[N:40]=1)[CH3:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3Br)c[nH]2)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3C#N)c[nH]2)cc1OC
Temperature: 100 °C

Procedure:
To a solution of [1-[{1-[4-(2-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (294 mg; 0.4 mmol) in DMF (2 mL) was added Zn(CN)2 (28 mg; 0.24 mmol). The resulting mixture was degassed with Argon for 5 min, then Pd(PPh3)4 (92 mg; 0.08 mmol) was added neat, and the system was immediately warmed to 100° C. After heating for 6 h, the reaction was cooled to rt and partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was subjected to reverse phase HPLC (water/acetonitrile/0.1% TFA). The fractions of interest were combined, basified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The EtOAc extracts were combined, dried over Na2SO4, filtered, and concentrated to afford 146 mg (54%) of desired {2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (HPLC: 96% @ 254 nm and 97% @ 214 nm). This sample was of sufficient quality to use in the next reaction without further purification.