Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:16]=[CH2:17])[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[N:7][CH:8]=1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1.C(N(CC)CC)C>C(O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]1[CH2:23][CH2:24][N:20]([CH2:17][CH2:16][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3=[O:15])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=2)[CH2:21]1
Reactant: C=Cc1cc(C(F)(F)F)cnc1N1CCCCC1=O
Reactant: c1ccc(C2CCNC2)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CCCCN1c1ncc(C(F)(F)F)cc1CCN1CCC(c2ccccn2)C1
Temperature: 90 °C
Reaction time: 7 h
Yield: 19 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)-3-vinylpyridin-2-yl]piperidin-2-one a18-2 (310 mg, 1.147 mmol, 1 eq) and 2-pyrrolidin-3-yl pyridine (221 mg, 1.491 mmol, 1.3 eq) in ethanol (10 ml) is added triethylamine (348 mg, 479 μl, 3.441 mmol, 3 eq). The reaction mixture is stirred at 90° C. for 7 hours, then heated overnight at 85° C. The reaction mixture is evaporated to dryness and retaken in dichloromethane. This organic phase is washed with aqueous NH4Cl (1 time), saturated aqueous NaHCO3 (2 times), then dried over MgSO4, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography over silicagel (12 g; gradient: from dichloromethane/MeOH 100/0 to 94/6), dried under vacuum to afford 91.4 mg of 1-[3-{2-[3-(pyridin-2-yl)pyrrolidin-1-yl]ethyl}-5-(trifluoromethyl)pyridin-2-yl]piperidin-2-one 110.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8](/[CH:9]=[N:10]/[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:4].CO.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)c1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the intermediate from step B (8.4 g, 30.18 mmol) in THF (150 mL) was added methanol (15 mL), Na(CN)BH3 (5.7 g, 90.54 mmol) and AcOH (30 mL). The resulting solution was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo. To the residue was added 1 M Na2CO3 solution (800 mL) and extracted with ether (3×). The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo to give the desired product as a white solid. 1H NMR (CDCl3, 500 MHz): 8.04 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 4.08 (s, 2H), 3.94 (s, 3H), 1.49 (s,9H). LC-MS=2.43; (M+H−56)=224.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.27 (d, J=1.4, 1H), 8.17-8.13 (m, 1H), 7.98 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.47-7.43 (m, 1H), 7.34-7.26 (m, 2H), 3.39 (s, 2H), 3.14 (s, 4H).
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][OH:7])[NH2:2].[C:9]([O:13]CC)(=[O:12])[CH:10]=[CH2:11]>>[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][OH:7])[NH2:2]
Reactant: C=CC(=O)OCC
Agent: NC(=O)OCCCO
Product: C=CC(=O)O
Reaction time: 160 h

Procedure:
250 g (comprising 0.9 mol of hydroxypropyl carbamate) were taken from the output from example 2 with a purity of 52.9%, and admixed with 2010 g (20.08 mol) of ethyl acrylate. At a temperature of 40° C., this mixture was conducted through a second jacketed glass column (length 40 cm, diameter 1.35 cm) charged with 12 ml of lipase (Novozym® 435) with the aid of a pump at a rate of 15 ml/h. The total reaction time was approx. 160 h, and the output in the reservoir vessel, the conversion and the purity were determined by means of GC analysis after various time intervals. The results are compiled in table 2.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:3])[CH3:2]>CC(O)=O.[Pd]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(=O)O)c2ccccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)Oc1cc2c(c(C(=O)O)c1)CCCC2
Reaction time: 13 h
Yield: 100.9 %

Procedure:
A mixture of 3-(isopropoxy)-1-naphthalenecarboxylic acid (0.38 g, 1.65 mmol) and 10% Pd/C (0.10 g) in HOAc (20 mL) was hydrogenated on Parr apparatus at 60° C. and 50 psi for 13 h. After filtration through diatomaceous earth the solvent was removed in vacuo, water was added and the precipitate was extracted into EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to yield the title acid as a light yellow oil (0.39 g, 100%). 1H NMR (CDCl3) δ 7.39 (d, 1H), 6.83 (d, 1H), 4.55 (m, 1H), 3.02 (s, 2H), 2.80 (s, 2H), 1.77 (m, 4H), 1.34 (s, 3H), 1.32 (s, 3H); MS m/z 233 (M−H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:24])([F:26])[F:25])[CH:12]=2)[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 93.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid methyl ester (870 mg, 2.27 mmol) in ethanol (12 mL) was treated with a 1N aqueous sodium hydroxide solution (8 mL). The solution was heated at 45-50° C. for 3 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×60 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (781 mg, 93%) as a white solid: EI-HRMS m/e calcd for C17H19F3N4O2 (M+) 368.1460, found 368.1460.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of the product of above-mentioned (13-a) (5.5 g, 20 mmol) in methylene chloride (1.4.0 ml) was added triethylamine (5.4 ml, 29 mmol) and methanesulfonyl chloride (2.4 ml, 21 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 5.5 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1C
Yield: 73.2 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-methyl-4-(methyloxy)phenyl]boronic acid (740 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), pyridine (0.36 mL, 4.46 mmol) and powdered molecular sieves (400 mg) in DCM (75 mL) were stirred at room temperature in the presence of air. After 41 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.17 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 0 to 30% in hexane to afford 562 mg of title compound (D34) containing an impurity.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[C:24](F)[S:23][CH:22]=4)=[CH:15][C:14]3=[O:27])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].C(C1N(C)C2C=C(N3C=CC(OCC4C=CSC=4F)=CC3=O)C=CC=2N=1)C>>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[CH:15][C:14]3=[O:27])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(OCc4csc(F)c4)cc3=O)cc2n1C
Agent: CCc1nc2ccc(-n3ccc(OCc4ccsc4F)cc3=O)cc2n1C
Product: CCc1nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cc2n1C

Procedure:
A mixture of the title compound, 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one obtained in step B in example 231 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (26.8 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[ClH:32].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[C:40][CH2:41][Cl:42])[CH:34]=1.[I-].[K+].O>CN(C)C=O>[ClH:42].[ClH:32].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:41][C:40]#[C:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: ClCC#Cc1cccnc1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(CC#Cc3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.38 g) potassium carbonate (0.42 g), 3-(3-pyridyl)-2-propynyl chloride hydrochloride (1.9 ml) and small amount of potassium iodide in N,N-dimethylformamide (10 ml) was stirred for 2 hours at 40° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine dihydrochloride (0.26 g).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(Cc2nccc3ccccc23)c(N)c1OC
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)CCl)c1OC

Procedure:
1-(2-[2-chloro-acetyl]amino-3,4-dimethoxybenzyl)isoquinoline was prepared from 5.9g (0.02 mol) of 1-(2-amino-3,4-dimethoxybenzyl) isoquinoline dissolved in 400 ml. of ethyl acetate, and stirred for 2 hours with 15 ml. of chloro-acetyl chloride. The precipitate which formed was filtered and dried to yield 7.1g (87%) of the hydrochloride salt, mp 193°-194°, which was suspended in 200 ml. of water and stirred for 10 min. with 10% Na2CO3 solution. The free base was extracted with chloroform, and the organic layer was washed with water, dried (sodium sulfate) and concentrated to yield a residue which was crystallized from methanol to give the pure base; mp 166°-167°; maxKBR 1650 cm-1 (aminde C=0); δtmsCDCl3 3.75 (s, 3, OCH3), 3.90 (s, 3, OCH3), 4.20 (s, 2, CH2Cl), 4.55 (s, 2, CH2), 6.63-7.00 (m, 2, aromatic), 7.23-7.85 (m, 4, aromatic), 8.20-8.45 (m, 2 aromatic) and 9.80 (broad s, 1, NH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[N+:16]=[N-:17]
Reactant: COc1cccc(N(C)CCCBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C)CCCN=[N+]=[N-])c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Compound 15 (0.5 g, 1.94 mmol) was dissolved in anhydrous DMF (20 mL) and sodium azide (1.26 g, 19.43 mmol) was added, followed by stirring of the reaction mixture at 70° C. for 16 hours. The remaining procedure was followed as described for compound 16 to obtain compound 17. Yield: 0.340 g (80%). 1H NMR (500 MHz, CDCl3): δ 1.86 (tt, 2H, J=6.5, 13.5 Hz, Hc), 2.93 (s, 3H, NCH3, Ha), 3.36 (t, 2H, J=6.5 Hz, Hd), 3.40 (t, 2H, J=7.5 Hz, Hb), 3.79 (s, 3H, OMe), 6.20-6.25 (m, 1H, Hi), 6.26-6.30 (m, 1H, Hg), 6.33-6.38 (m, 1H, He), 7.10-7.18 (m, 1H, Hf); 13C NMR (125 MHz, CDCl3): δ 26.32 (Cc), 38.56 (Ca), 49.14 (Cd), 49.77 (Cb), 55.10 (OCH3), 98.90 (Ci), 101.16 (Ce), 105.39 (Cg), 129.91 (Cf), 150.47 (Cj), 160.81 (Ch). EI-MS: [M+H]+ C11H17N4O calcd 221.14, obsd 221.12.
Reaction SMILES: [NH:1]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:63][C@H:64]([C:68]([NH:70][C@H:71]([C:82]([NH:84][C@H:85]([CH2:89][OH:90])[C@@H:86]([CH3:88])[OH:87])=[O:83])[CH2:72][S:73][CH2:74][C:75]1[CH:81]=[CH:80][C:78]([CH3:79])=[CH:77][CH:76]=1)=[O:69])[C@@H:65]([CH3:67])[OH:66].FC(C(O)=O)(F)F.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCN(CC)CC>[NH:1]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:63][C@H:64]([C:68]([NH:70][C@H:71]([C:82]([NH:84][C@H:85]([CH2:89][OH:90])[C@@H:86]([CH3:88])[OH:87])=[O:83])[CH2:72][S:73][CH2:74][C:75]1[CH:76]=[CH:77][C:78]([CH3:79])=[CH:80][CH:81]=1)=[O:69])[C@@H:65]([CH3:67])[OH:66])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.5 ml NEt3, 11.2 g BOC-Phe-(D)Trp-Lys(Z)-OH and 4 g HOBT are added to 9 g H-Thr-Cys(MBzl)-Thr-ol trifluoroacetate in 100 ml DMF. 3.7 g DCCI in 10 ml DMF are added to the solution at -20° C. and the whole is stirred for ca. 18 hours at 0° C. and 2 hrs. at room temperature. Precipitated dicyclohexyl-urea is filtered off and the filtrate concentrated under vacuum and diluted with methanol. H2O is added until the product precipitates. The precipitate is filtered, washed with MeOH/H2O (4:1) and dried to yield the title compound:
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCOCC1>[CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:34](=[O:35])[O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:25][CH:26]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:3]
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
(4-{4-[1-Methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)amine (3.6 g, 8.77 mmol) was dissolved in dioxane (20 mL). Sodium bicarbonate (1.1 g, 13.15 mmol) was added, followed by phenyl chloroformate (1.1 mL, 8.77 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (2 g).
Reaction SMILES: C([Mg]Br)C.[O:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[CH2:30]=[O:31].Cl>C(OCC)C.C1(C)C=CC=CC=1>[O:5]([C:12]1[CH:13]=[C:14]([CH:30]=[O:31])[C:15]([OH:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 80 °C
Yield: 41.7 %

Procedure:
Ethyl magnesium bromide (67.5 mL of an approximately 3.0 M solution in diethyl ether, 202.5 mmol) was added to toluene (50 mL). A solution of 4-phenoxyphenol (25.00 g, 134.26 mmol) in diethyl ether (35 mL) was added resulting in the evolution of gas. The reaction was heated to 80° C. causing distillation of the diethyl ether. Toluene (300 mL), HMPA (23.4 mL, 24.059 g, 134.26 mmol), and paraformaldehyde (10.07 g, 335.65 mmol) were added and the reaction was heated to 85° C. for 4 hours. The reaction was cooled to room temperature and was acidified with 2N HCl. The resulting layers were separated and the organic phase collected. The organic phase was washed with brine. The combined aqueous phases were extracted with methylene chloride. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo yielding a yellow oil. The oil was purified by silica flash chromatography (hexanes-ethyl acetate, 95:5). Concentration in vacuo of the desired fractions provided the salicylaldehyde as a pale yellow powder (12.0 g, 42%) of suitable purity to use in subsequent steps.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:32]1([C:35](Cl)=[O:36])CC1.CO.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:36])[CH3:32]
Reactant: O=C(Cl)C1CC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ncc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1nc2cnc(N(C)c3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28124.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(trifluoromethyl)benzamide (268 mg, 604 μmol) in pyridine (5 mL) were added N,N-dimethylpyridine-4-amine (23.9 mg, 196 μmol) and cyclopropanecarbonyl chloride (200 μL, 2.20 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction solution were added methanol (10 mL) and 2N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 more hr. The reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate (100 mL) and tetrahydrofuran (10 mL). The diluted solution was washed with water (50 mL), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from ethyl acetate and tetrahydrofuran to give the title compound (compound of Example D2) (301 mg, 97%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[CH:33][NH:34]4)=[CH:30][CH:29]=3)[CH:25]=[C:24]([O:37][CH2:38][CH3:39])[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[CH:33][NH:34]4)=[CH:30][CH:29]=3)[CH:25]=[C:24]([O:37][CH2:38][CH3:39])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4cc[nH]c4c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3cc[nH]c3c2)c1
Yield: 79.1 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-6-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid ethyl ester (111 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (1.7 mL) to afford 4-[2-(2-carboxy-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-6-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid (79 mg, 78%) as a light brown solid: ES(+)-HRMS m/e calcd for C35H41NO7 (M+Na)+ 610.2775, found 610.2774.