Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]2=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].P(Br)(Br)[Br:25]>C1COCC1>[Br:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)C2=O
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Temperature: 25 °C
Yield: 74 %

Procedure:
Add 2-(4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.0 eq.); hyflo (20 wt %), and toluene (7.5 vols) to a three neck flask with a reflux condenser and nitrogen vent purge. While stirring at room temperature, add PBr3 (1.75 eq.) in one portion. Heat the reaction to reflux (˜110° C.) overnight allowing it to vent through a caustic scrubber. After refluxing for 15 hours, cool the yellow solution to 45° C. and slowly add THF (20 vols). Stir this mixture for 30 minutes at 45° and filter it, while warm, over a pad of Hyflo. Wash the pad with 45° C. THF (2×2 vols). Concentrate the filtrate at reduced pressure to remove all of the THF. Carefully add water (7.5 vols) to the remaining mixture keeping the temperature below 40° C. Cool the slurry to room temperature and stir it for 2 to 3 hours. Filter the slurry over a polypropylene pad and wash it with water (2×2 vols). Dry the resulting filter cake in a vacuum oven overnight at 50° C. to provide the title compound (74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:33]([OH:35])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC(O)(C)C.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]>[OH:35][C:33]1[CH:34]=[C:29]([NH:28][C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[C:4]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[N:3]=2)[CH:30]=[CH:31][C:32]=1[N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reactant: Nc1ccc(N2CCOCC2)c(O)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)nc3c2cnn3C2CCCCO2)c1
Temperature: 100 °C
Yield: 28.5 %

Procedure:
N-(3-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (50 mg, 0.130 mmol), 5-amino-2-morpholinophenol (25.3 mg, 0.130 mmol) and potassium carbonate (45.0 mg, 0.326 mmol) were dissolved in t-BuOH (80 mL). 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (3.01 mg, 5.21 μmol) and Pd2dba3 (2.386 mg, 2.61 μmol) were then added to the solution. The reaction mixture was refluxed at 100° C. for 12 h, and the reaction was monitored by TLC. Following completion of the reaction, the reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting crude material was purified by flash chromatography (2% methanol/DCM) to yield the title compound (20 mg, 0.037 mmol, 28.3% yield) as yellow solid. Crude material was used without further purification and used directly in the next reaction.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2cnc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (78 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (19 mg) as a pale-yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: Clc1cccc(-c2nc3c(c(Nc4ccccc4)n2)CCC3)c1
Yield: 95.4 %

Procedure:
Following general procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.185 g, 0.70 mmol) was reacted with aniline (0.130 g, 1.4 mmol) to afford the title compound (0.215 g, 95%) as an orange solid. MW=321.80. 1H NMR (DMSO-d6, 500 MHz) δ 8.25 (s, 1H), 8.30-8.22 (m, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.41-7.35 (m, 2H), 7.10-7.05 (m, 1H), 2.93-2.86 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 322 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].I[CH3:36]>>[NH2:1][C:2]1[C:7]([N:8]([CH3:36])[C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1
Reactant: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 6 with 75 mg (0.17 mmol) of isopropyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 3, 10.31 mg (0.26 mmol) of sodium hydride and 24.4 mg (0.17 mmol) of iodomethane. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([OH:27])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:39][C:40]([CH3:59])([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:41][C:42](Cl)=[O:43]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([O:27][C:42](=[O:43])[CH2:41][C:40]([CH3:59])([CH3:39])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCC(C)(C)CC(=O)Cl
Reactant: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCCCCCCC(C)(C)CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)c1ccc(C)c(OC)c1Cl

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate is reacted with 3,3-dimethylheptadecanoyl chloride there is obtained 3-(3,3-dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol), 2-(pyridin-2-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol) and DIEA (8.5 g, 65.77 mmol) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:50) to afford the title compound as a red solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:8][CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C

Procedure:
1.69 kg (9.51 moles) of NBS and 156 g (0.95 moles) of AIBN were well mixed and placed in a vinyl wrapper (at this time, the previous reaction was regarded to be proceeded to 100%). The benzene solution of Example 2 was heated. The NBS-AIBN mixture was portionwise added to the heated solution at 73° C. for 40 minutes. The solution was refluxed for 1.5 hours after the addition was done. After confirming completion of the reaction by HPLC, the solution was cooled to room temperature. The reaction solution was washed with [1 L of H2O+4 L of 5% NaHCO3], and then [2 L of H2O+1 L of 5% NaCl].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]([OH:25])[C:23]([F:30])([F:29])[F:22])=[CH:9][N:10]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cnc(C2OCCO2)s1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (2.00 g) in tetrahydrofuran (50 mL) was slowly added a 1.6M n-butyllithium hexane solution (8.7 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and ethyl trifluoroacetate (5.4 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (30 mL), and sodium borohydride (0.27 g) was added by small portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (2.56 g, yield 79%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 256 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 55.1 %

Procedure:
N-(3-Chloro-4-fluoro-phenyl)-7-(2-methoxyethoxy)-6-nitro-quinazolin-4-amine 8b (392 mg, 1 mmol) and iron powder (392 mg, 7 mmol) were dissolved in 20 mL of acetic acid. The reaction mixture was heated to reflux for 4 hours, concentrated under reduced pressure. The residue was added with 100 mL of saturated sodium bicarbonate, extracted with dichloromethane (100 mL×3). The combined organic extracts were washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound N4-(3-chloro-4-fluoro-phenyl)-7-(2-methoxyethoxy)quinazoline-4,6-diamine 8c (200 mg, yield 55.2%) as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:17]1)=[O:37]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 68 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.35 g, 0.92 mmol) and iPr2NEt (0.75 g, 5.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 84%).
Reaction SMILES: [CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCC[C@]1(O)Cc1ccccc1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@]1(O)Cc1ccccc1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of 5.0 g (24 mmol) (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine in 150 ml DMF were added 7.4 g (24 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 5.0 g (36 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 72 hours. After the addition of water the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 10.5 g (24 mmol, 100%) (3R,4R)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][CH2:9][C:10]([CH3:37])([CH3:36])[CH2:11][O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][O:8][CH2:7][C:6]([OH:38])=[O:5])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)COCC(=O)OC(C)(C)C)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)COCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Put 280 mg (0.54 mmol) (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2,2-dimethylpropoxy)acetic acid tert.-butyl ester in 8 ml dichloromethane. Add 2 ml trifluoroacetic acid and stir for 1 h at RT. Then concentrate by evaporation and mix the residue with petroleum ether. Filter the solid on a frit with suction, and dry at high vacuum. 220 mg (88.1% of theor.) of the target compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]1[O:11][C@H:10]1[CH2:12]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C@@H:10]2[CH2:9][O:11]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClC[C@H]1CO1
Product: Brc1ccc(OC[C@@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-bromophenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:37]([O:44][CH2:45][CH2:46]Br)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:46][CH2:45][O:44][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:8]1=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(CN2CCC(Cc3ccccc3)C2=O)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccccc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-2-oxopyrrolidine (1.0 g, 2.81 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (3.09 mL, 1 M in THF, 3.09 mmol). After 30 minutes, add a solution of 2-(t-butyldimethylsilyloxy)ethyl bromide (0.74 g, 3.09 mmol) in tetrahydrofuran (1 mL). After the addition of 2-(t-butyldimethylsilyloxy)ethyl bromide is complete, warm slowly to ambient temperature. After 2 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/3 ethyl acetate/hexane to give the title compound: Rf=0.58 (silica gel, 1/3 ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20](Br)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[NH2:28].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>O.C(#N)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:33]5[CH:34]=[CH:35][C:30]([C:27](=[O:29])[NH2:28])=[CH:31][CH:32]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)cc4)ccc31)C2
Temperature: 90 °C
Yield: 90.8 %

Procedure:
2-((R)-5-Bromo-indan-1-yl)-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1a, 500 mg, 1.19 mmol), 4-carbamoylphenylboronic acid (587 mg, 3.56 mmol), Pd(OAc)2 (14 mg, 0.06 mmol) and TPPTS ligand (3,3′,3″-phosphinidynetris[benzenesulfonic acid]trisodium salt, 135 mg, 0.24 mmol) were suspended in 10 mL water and 5 mL acetonitrile. Diisopropylamine (291 mg, 2.85 mmol) was added, and the mixture was heated to 90° C. for 2 hours. The mixture was cooled to room temperature and was diluted with ethyl acetate (150 mL). The organic solution was washed with water (50 mL), dried (MgSO4), filtered through Celite® and concentrated to give 499 mg (91%) of the title compound as a light pink powder. MS (ES+) 462.1 (M+H)+. 1H NMR (CD3OD) δ 1.42 (s, 9H), 1.64-1.74 (m, 4H), 1.83-1.96 (m, 1H), 2.17-2.30 (m, 1H), 2.80-2.93 (m, 1H), 3.10 (dt, 1H), 3.24-3.28 (m, 2H), 3.31-3.38 (m, 6H), 4.06 (dd, 1H), 6.79 (d, 1H), 7.39-7.49 (m, 2H), 7.53 (s, 1H), 7.67 (d, 2H), 7.73 (d, 1H), 7.89-7.94 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:17]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[C:2](=[O:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nccs2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1)c1nccs1
Reaction time: 0.03 h
Yield: 62.2 %

Procedure:
To a solution of tert-butyl 4-(2-oxo-2-(thiazol-2-ylamino)ethyl)piperazine-1-carboxylate (0.056 g, 0.17 mmol) in anhydrous DMF (1.0 mL) cooled into an ice-bath under argon was added sodium hydride (60% dispersion; 7.8 mg, 0.19 mmol). Stirring was continued at 0° C. for ˜2 min and then methyl iodide (0.048 g, 0.34 mmol) was added with the aid of DMF (0.4 mL), the reaction mixture was stirred for 1.5 h under argon, and then partitioned between ethyl acetate (30 mL) and brine (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL), and the combined organics were washed with brine (2×30 mL), dried (Na2SO4), and concentrated in vacuo. Purification by chromatography (10 g isolute column, 80% ethyl acetate in petroleum ether 60-80° C.) afforded the title compound as an oil (0.036 g, 62%); 1H-NMR (500 MHz, DMSO-d6) 1.40 (s, 9H, C(CH3)3), 3.33 (s, 4H, piperazine N(CH2)2), 3.58 (s, 2H, NCH2CO), 3.68 (s, 3H, CH3), 7.27 (d, J=3.5 Hz, 1H, thiazole H), 7.53 (d, J=3.5 Hz, 1H, thiazole H);