Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O:10][C:11](=[O:26])[CH:12]([O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22]Br)[CH:15]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:22][CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH2:13][CH:12]([O:24][CH3:25])[C:11]([OH:26])=[O:10])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Reactant: Oc1cccc(F)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2cccc(F)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-fluoro-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C18H19FO5 [M−H]−: 333.1.
Reaction SMILES: [K].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15](=[O:38])[CH:16]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[CH2:26][CH2:27][CH3:28])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C[Sn]([N:43]=[N+:44]=[N-:45])(C)C>C1(C)C=CC=CC=1>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15](=[O:38])[CH:16]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:45][N:44]=[N:43][N:25]=3)=[CH:20][C:19]=2[CH2:26][CH2:27][CH3:28])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCc1cc(C#N)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [K]
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nnn[nH]2)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Yield: 37.6 %

Procedure:
A stirred solution of 600 mg (1.15 mmol) of the product of Example 151, Step F and 284 mg (1.38 mmol) of trimethyltin azide in 2 mL of toluene was heated with an oil bath at reflux overnight. The reaction was evaporated in vacuo, purified by silica gel flash chromatography eluting with methylene chloride/methanol/acetic acid 100:3:1, and the purified fractions concentrated in vacuo to afford 244 mg (38%) of the title compound as an amorphous solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH2:46]([O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:47].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:52]([CH:53]([CH3:55])[CH3:54])[NH:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 344 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 191 μl (1.74 mmol) of NMM in 5.6 ml of DMF are added to 132 mg (0.7 mmol) of N-ethoxycarbonyl-(L)-valine (EP 0 604 368, Example 9a) and 173 mg (0.58 mmol) of TPTU in 2.9 ml of DMF, and the mixture is stirred at room temperature overnight and worked up analogously to Example 3, yielding the title compound: TLC: Rf =0.45 (methylene chloride/THF 4:1); HPLC20-100 : tRet =14.7; FAB MS (M+H)+ =711.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (60, 589 mg, 1.53 mmol) and cyclopentylamine (2.3 mmol, 227 μl). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 476 mg (1.36 mmol, 89%), mp 164–166° C.; Rf 0.51 (eluens 10% MeOH in CH2Cl2). The product was re-crystallized from CH3CN); 1H NMR (DMSO-d6) δ 8.28 (s, 1H, H-8), 8.18 (s, 1H, H-2), 7.70 (d, 1H, J=7.55 Hz, NH), 5.89 (d, 1H, J=4.80 Hz, H-1′), 5.50 (d, 1H, J=5.15 Hz, OH-2′), 5.26 (d, 1H, J=5.15 Hz, OH-3′), 4.56 (q, 1H, J=4.12 Hz, H-2′), 4.13 (q, 1H, J=4.46 Hz, H-3′), 3.99 (q, 1H, J=4.12 Hz, H-4′), 3.57–3.42 (m, 2H, H-5′), 3.28 (s, 3H, OCH 3), 2.01–1.83 (m, 2H, cyclopentyl), 1.73–1.52 (m, 4H, cyclopentyl); MS m/z 350 (M+H)+; Anal. (C16H23N5O4.0.7 CH3CN) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25][C@@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[CH3:27][C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:19]([CH3:21])([CH3:20])[CH3:18])[C:28]([NH:17][C:14]1[CH:13]=[N:12][C:11]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)=[N:16][CH:15]=1)=[O:29]
Reactant: CC(C)c1cccc(Oc2ncc(N)cn2)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1cccc(Oc2ncc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinamine (Intermediate 85, 229 mg) in acetonitrile (20 mL) were added N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (378 mg, 2 mmol), HBTU (474 mg, 1.25 mmol) and DIPEA (387 mg, 3 mmol) and the mixture was heated at reflux and stirred overnight. The resulting mixture was concentrated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=1/5−1/2) to afford the title compound (300 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21]([C:18]4[CH:19]=[CH:20][O:16][CH:17]=4)=[O:22])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccoc1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3-furoyl chloride (39 mg; 0.3 mmol; 1.2 eq.) as a white powder (45.3 mg, 61%). HPLC, Rt: 2.65 min. (purity 97.5%). LC/MS, M+(ESI): 295.4, M−(ESI): 293.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC1(c2cccnc2)CCCC1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3cccnc3)CCCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=329.0, tR (minutes, Method A)=1.14
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH3:9])=[N:4][C:3]1=[O:20].[OH-:29].[K+].Cl>CC(O)(C)C>[CH3:1][C:2]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:29])=[CH:27][CH:28]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:17])([F:18])[F:19])[CH3:9])=[N:4][C:3]1=[O:20]
Reactant: [OH-]
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(N)=O)cc2)S1)c1ccccc1C(F)(F)F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 4-(5-methyl-4-oxo-2-((S)-1 -(2-(trifluoromethyl)phenyl) ethylamino)-4,5-dihydrothiazol-5-yl)benzonitrile (0.080 g, 0.20 mmol), prepared according to Example 1, and potassium hydroxide (0.14 g, 2.6 mmol) and t-BuOH (2 mL) was gradually heated to 85° C. After 1 h, 2N HCl was added to the reaction mixture until the pH reached 7-8. The reaction mixture was extracted with CH2Cl2 three times (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo. The crude product was purified by preparative TLC: 10% MeOH—CH2Cl2. The product (3a) was obtained as a white solid. MS (ESI, pos. ion) m/z: 422 (M+1), 420 (M-1). 1H NMR (CDCl3, 400 MHz): δ1.73-1.77 (m, 3H), 1.98, 2.08 (s, 3H), 5.04 (q, J=8 Hz, 1H), 6.17-6.39 (m, 2H), 7.36-7.42 (m, 2H), 7.52-7.75 (m 4H), 7.80-7.86 (m, 2H).
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][SH:9].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15]>C(O)C>[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCBr
Reactant: Cc1[nH]cnc1CS
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCCC#N

Procedure:
Sodium (5.0 g) was dissolved in ethanol (300 ml) and 5-methyl-4-(mercaptomethyl)imidazole (17 g) added, followed by a solution of 4-bromobutyronitrile (16 g) in ethanol (50 ml). The mixture was stirred under reflux for 45 minutes, cooled, filtered and the filtrate evaporated to dryness. The residue was taken up in water and extracted with ethyl acetate. The extract was dried (MgSO4) and solvent removed. Recrystallisation of the product from ethanol-ether gave 4-(5-methyl-4-imidazolylmethylthio)butyronitrile as its hydrochloride salt (12 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:30])[CH:14]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([Cl:28])[CH:22]=1)[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][CH:14]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:30])=[O:29])=[CH:22][C:23]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)c1ccc(N)c(Cl)c1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of 4 (15.9 g, 36.3 mmol) in CH2Cl2 (30 mL) was added TFA (trifluoroacetic acetic acid)(30 mL) and the solution stirred at room temperature for 3 hours under N2. The reaction was transfered to a beaker (1 L) and diluted with CH2Cl2 (60 mL). To the solution at 0° C. was added solid NaHCO3 (39 g, 46 mmol) and stirred for 15 minutes before partitioning between EtOAc (300 mL) and H2O (300 mL). After extraction the aqueous layer was acidified to pH 4–5 and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to dryness to give 5 as a white solid (14.0 g, quantitative yield): 1H-NMR (500 MHz, CDCl3) δ1.08 (s, 9H), 1.97–2.22 (m, 3H), 2.29–2.41 (m, 1H), 3.71–3.78 (m, 1H), 3.90–3.98 (m, 1H), 4.55–4.62 (m, 1H), 4.86 (d, 1H), 6.64 (d, 1H), 6.74 (d, 1H), 7.53 (d, 1H), 7.74 (s, 1H). Analytical HPLC (cyano column): 8.24 min. LC-MS (ES+) m/e=382.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[C:5]([CH:11]=[CH:12][N:13](C)C)=[C:4]([N+:16]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]2[CH:11]=[CH:12][NH:13][C:6]=2[CH:7]=1
Reactant: CN(C)C=Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cc2[nH]ccc12
Reaction time: 8 h

Procedure:
2-(4-fluoro-2,6-dinitrophenyl)-N,N-dimethylethenamine (18 g, 0.071 mol) was dissolved in ethanol (1000 mL), and charged with 10% palladium on carbon (2.0 g). The mixture was hydrogenated at room temperature overnight. The mixture was filtrated through celite and washed with ethanol. The filtrate was combined and evaporated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=2:1) to afford the title compound. LC/MS m/z=151.2 [M+H]+.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 86 (1.33 g, 4.2 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 4 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 87 (1.05 g, 76%) as a red gum: 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.34-3.40 (m, 4H, 2×CH2), 3.27 (t, J=7.1 Hz, 2H, CH2N), 3.12-3.21 (m, 4H, H-6, H-8), 3.05-3.12 (m, 2H, CH2), 2.42-2.51 (m, 2H, CH2), 2.22-2.32 (m, 2H, H-7), 1.64-1.73 (m, 4H, 2×CH2), 1.40-1.51 (m, 2H, CH2); 13C NMR δ 161.8, 155.2, 150.8, 139.1, 134.0, 115.8, 113.9, 58.9, 53.7, 53.4, 33.4, 32.9, 28.0, 25.6, 24.0 (2), 19.7, 13.6; HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1974, found 329.1974.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:18])=[CH:15]/[CH:16]=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C/C(=C\C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 84.3 %

Procedure:
3.42 g (E)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-en-1-ol were dissolved in 23 ml of CH2Cl2 and treated with 16.1 g of MnO2. The reaction mixture was vigorously stirred at ambient temperature over night and then filtered through Celite. Evaporation of the solvent followed by flash chromatography (silica gel, hexane/AcOEt=92:8) afforded 2.86 g of (E)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal as pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[C:16]([C:25](OC)=[O:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=2[O:21][CH3:22])=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[C:6]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[CH2:25][OH:26])=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COC(=O)c1cc(OC)cc(OC)c1-c1c(OC)cc(OC)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(-c2c(CO)cc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester (2.5 g) was dissolved in THF (96 mL), and 1M LiAlH4 in THF (9.6 mL) was added. After stirring at room temperature for overnight, the mixture was quenched with water and 2N HCl (24 mL) was added. The mixture was evaporated under vacuum and partitioned with DCM (300 mL) and water (200 mL). The organic layer was dried over Na2SO4 and crystallized with DCM to provide (6′-hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol (1.7 g, 77%) as a pale blue white triclinic crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[C:15]([F:18])([F:17])[F:16].O.O.Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[C:15]([F:17])([F:16])[F:18]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 6-chloro-3-nitro-4-(trifluoromethyl)quinoline (5.53 g, 20 mmol) (prepared according to the procedures described by Tarby, C. M., in WO 2003062238) in EtOAc (100 mL) was added SnCl2.2H2O (18 g, 80 mmol). The resulting mixture was stirred at RT for 18 h, then at 80° C. for 6 h. After cooling to RT, saturated aqueous K2CO3 (5 mL) was added. The reaction mixture was stirred at RT for 30 min, and then solid K2CO3 (16.6 g, 120 mmol) was added stirring was continued at RT for 4 more hours. EtOAc (200 mL) was added, the resulting mixture was filtered, and the filtrate concentrated in vacuo to give the title compound (4.8 g, 97% yield) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C(N)C.[Cl:24]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][N:10]=1)[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Agent: CCN
Agent: CN
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-methyl-amino)-nicotinic acid (12.5 g, 47.0 mmol) [prepared analogously to A-05 using methylamine in stead of ethylamine] is taken up in 300 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (10.0 mL, 74.8 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([F:15])([F:14])[F:13])(=O)=O)=CC=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([C:40]3[NH:41][CH:42]=[CH:43][CH:44]=3)[S:30][C:31]=2[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:23][CH:22]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[C:29]([C:40]3[N:41]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:42]=[CH:43][CH:44]=3)[S:30][C:31]=2[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(-c3cccn3CC(F)(F)F)sc2-c2ccc(OC)cc2)cc1
Yield: 36 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole obtained in the same manner as described in Reference Example 6 (1.81 g, 5 mmole), 2,2,2-trifluoroethyl p-toluenesulfonate (1.27 g, 5 mmole), and tetra-n-butylammonium bromide (0.16 g, 0.5 mmole) are refluxed in two phases of benzene (20 ml) and 50% aqueous sodium hydroxide (20 ml) for 16 hours. To the mixture are added water and benzene under ice-cooling, and the mixture is shaken. The benzene layer is taken, and the aqueous layer is further extracted with benzene. The benzene layers are combined, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to give an oily residue. The oily residue is subjected to silica gel column chromatography (solvent: benzene) and then is recrystallized from n-hexane to give 4,5-bis(4-methoxyphenyl)-2-[1-(2,2,2-trifluoroethyl)pyrrol-2-yl]thiazole (0.80 g, yield: 36%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.[C:11](Cl)([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[N:2]1
Reactant: Nc1noc2ccccc12
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: O=C(Nc1noc2ccccc12)OCC(Cl)(Cl)Cl

Procedure:
Using General Method A, benzo[d]isoxazol-3-amine (500 mg, 3.37 mmol) and Troc-Cl (1.185 g, 5.59 mmol) were combined, purified by column chromatography (ethyl acetate/hexanes), triturated with hexanes (30 mL), filtered and dried to afford 2,2,2-trichloroethyl benzo[d]isoxazol-3-ylcarbamate. 1H NMR (300 MHz, DMSO-d6): δ 5.15 (s, 2 H), 7.50 (t, 1 H), 7.77-7.83 (m, 2 H), 8.16 (d, 1 H), 11.51 (s, 1 H); MS (ESI) m/z: 310.9 (M+H+).
Reaction SMILES: [Si]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)([CH3:26])[C:23]([C:38]([O:40][CH3:41])=[O:39])=[CH:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2([CH3:26])[C:23]([C:38]([O:40][CH3:41])=[O:39])=[CH:22][CH2:21][CH:20]([CH2:19][OH:18])[CH2:25]2)=[CH:28][C:29]=1[C:34]([F:35])([F:36])[F:37]
Reactant: COC(=O)C1=CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 17.5 h
Yield: 94.1 %

Procedure:
A solution of methyl (4RS,6RS)-4-((tert-butyl-diphenylsilyloxy)methyl)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-6-methylcyclohex-1-enecarboxylate (495 mg, 0.823 mmol) in THF (5 mL) was treated at rt with acetic acid (0.118 mL, 2.058 mmol), followed by tetrabutylammonium fluoride (1.0 M in THF, 1.235 mL, 1.235 mmol). The resulting solution was stirred for 17.5 h. After this time, the solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 20-50% ethyl acetate-hexane, to provide methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate as a colorless gum (281 mg, 94%). Mass spectrum m/z 363.0 (M+H+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.39 (d, J=8.6 Hz, 1 H), 7.32 (dd, J=8.6, 2.2 Hz, 17 H), 7.28 (dd, J=5.4, 2.5 Hz, 1 H), 3.64 (s, 3 H), 3.42 (m, 2 H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.76 (m, 1 H), 1.65 (s, 3 H), 1.53 (m, 2 H), 1.42 (br. s, 1 H).