Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl 4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanoic acid ethyl ester (which was obtained in Example 165) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.3 Hz, 3 H), 0.92 (d, J=6.3 Hz, 3 H), 1.18 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.45–1.95 (m, 5 H), 2.55–2.92 (m, 5 H), 2.92 (s, 3 H), 3.70–3.85 (m, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.40–4.55 (m, 2 H), 6.82 (d, J=8.3 Hz, 1 H), 6.94 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2 H), 8.33 (d, J=7.7 Hz, 1 H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S (MH+): 591.2847. Found: 591.2840.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1.Br[CH:19]([OH:21])[CH3:20].C(=O)([O-])O.[Na+].C(C(C)=O)C>O>[OH:21][CH2:19][CH2:20][N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1
Reactant: CC(O)Br
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)C3)cc12
Yield: 43.1 %

Procedure:
To the obtained (−)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (3.0 g) were added bromoethanol (8.21 g), sodium hydrogen carbonate (5.6 g), methyl ethyl ketone (84 ml) and water (8.4 ml), and the mixture was stirred under reflux for 2 hr. The reaction mixture was concentrated, extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (methanol/ethyl acetate; 2/5) and crystallized from ethyl acetate to give (−)-3-[1-(2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (1.5425 g).
Reaction SMILES: [NH3:1].CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)[CH:18]=3)[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)=O.O>C(O)(C)C>[N+:26]([C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH:13]=[CH:12][N:11]3[C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH2:1])[N:10]=3)=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1)([O-:28])=[O:27]
Reactant: N
Reactant: CS(=O)c1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Solvent: CC(C)O
Solvent: O
Product: Nc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Ammonia solution (2.0 M in isopropanol) was added to 1-(2-(methylsulfinyl)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (102 mg) dissolved in isopropanol. After stirring at 100° C. for 3 hours and cooling to room temperature, the reaction mixture was added to water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. 4-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-2-amine (76.8 mg) was yielded.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24]([Cl:3])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CCCCCCCCCCOCc1ccccc1)C(=O)O
Solvent: c1ccccc1
Product: CC(C)(CCCCCCCCCCOCc1ccccc1)C(=O)Cl

Procedure:
1.2 ml of thionyl chloride was added to a solution of 3.34 g of the obtained carboxylic acid in 5 ml of anhydrous benzene, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give 3.53 g of 12-benzyloxy-2,2-dimethyldodecanoyl chloride as a colorless oily material.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7](CC#N)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]>C1COCC1.O.[Pd](Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:2][C:1]([NH2:4])=[O:3])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]
Reactant: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2cc(Cl)c(CC(N)=O)cc12
Reaction time: 18 h

Procedure:
Palladium(II)-chloride (4.3 mg, 0.024 mmol, 0.1 equiv) and acetamide (60 mg, 1.0 mmol, 4.2 equiv) were added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile in THF (0.75 ml) and water (0.25 ml). After 18 hours at room temperature, the reaction mixture was adsorbed on silica gel, concentrated to dryness, and purified via two flash columns. Since purification on silica gel failed to remove unreacted acetamide, the resulting mixture was used directly in the next step. MS (ES+): 277 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]3[CH:20]=[CH:19][CH:18]=[C:22]3[CH2:23]2)=[O:17])=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 2 h

Procedure:
A suspension of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (1.0 g, 4.38 mmol) in thionyl chloride (6 mL) was heated at reflux for 30 min. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow solid. The latter was then dissolved in dichloromethane (10 mL) and the solution was slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.97 g, 5.27 mmol) and N,N-diisopropylethyl amine (1.6 mL, 9.19 mmol) in dichloromethane (30 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 25% of ethyl acetate in hexane provided the title compound as a white foam which was crystallized by sonication from ethyl acetate/hexane (1.4 g, 81.0%) to give a white solid m.p. 145–147° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][S:20][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[OH:29][C:7]1[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]2[S:20][N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: COc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3c(-c4ccccc4)nsc23)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-(4-methoxy-phenyl)-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 436.2 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1>>[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: COCCOc1ccc(N)cc1
Product: COCCOc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 529.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(2-methoxy-ethoxy)-phenylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29]([NH:24][C:11]1[S:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:30]
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: COc1ccc(-c2nc(NC(=O)c3cc(F)cc(F)c3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 66.7 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and 3,5-difluorobenzoyl chloride prepared in the step 1 of Example 16 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 66.7%, mp: 189-190└. 1H-NMR (CDCl3, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.34 (2H, s, CH2), 6.72 (2H, d, J=8.68 Hz, ArH), 6.85 (1H, t, 3JFH=8.40 Hz, ArH), 7.18 (2H, d, 3JFH=5.32 Hz, ArH), 7.25 (2H, d, J=8.68 Hz, ArH), 7.40 (2H, d, J=8.40 Hz, ArH), 8.21 (2H, d, J=8.40 Hz, ArH), 12.05 (1H, br, CONH); EI-MS m/e (%): 481.1 (M+, 100), 141.0 (63); HREI-MS Calcd. for C24H17F2N3O4S: 481.0908. found: 481.0902. Anal. Calcd. for C24H17F2N3O4S: C, 59.87; H, 3.56; N, 8.73. found: C, 59.98; H, 3.80; N, 8.67.
Reaction SMILES: C(O[C:6](=O)[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([CH3:12])CO)(C)(C)C.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:37]1(OC(N(C)C)=[N+](C)C)[C:41]2N=CC=[CH:45][C:40]=2N=N1.C(=O)(O)[O-:55].[Na+]>C(Cl)(Cl)Cl.O>[CH2:13]([N:8]1[CH2:7][CH2:6][C:12]2([NH:37][CH2:41][CH:40]2[CH3:45])[C:9]1=[O:55])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(CO)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CNC12CCN(Cc1ccccc1)C2=O
Reaction time: 4 h

Procedure:
To a solution of an optically-active compound of 2-(2-benzylaminoethyl)-3-methylazetidine-2-dicarboxylic acid 2 hydrochloride (29.1 g) and N,N-diisopropylethylamine (65 ml) in chloroform (290 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (41.3 g) at room temperature, and the mixture was stirred for 4 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution (200 ml) and water (100 ml), and the mixture was extracted with chloroform (200 ml). The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the titled compound (21.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:11])([CH3:10])[OH:9].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[CH3:10][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]1)([OH:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(O)c1ccccc1N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(C)(C)O)CC1

Procedure:
2-Aminophenyldimethyl carbinol from Step 1 was reductively alkylated with 1-t-butyloxycarbonyl-4-piperidinone (2.6 g, 13.2 mmol) by the procedure given in Step 2 of Example 1 to give 4-(2-(1-methyl-1-hydroxyethyl)phenyl)amino-1-t-butyloxycarbonylpiperidine as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH3:2].[CH2:16]([O:18]CC)C.C([Li])CCC.CN(C=O)C>O>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:11]=1[CH:16]=[O:18])[CH3:2]
Reactant: CCOCOc1cccc(C(F)(F)F)c1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1cc(C(F)(F)F)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4.0 g of 1-ethoxymethoxy-3-trifluoromethylbenzene and 160 ml of diethyl ether was added dropwise 16 ml of n-butyllithium (1.6 N, n-hexane solution) under a nitrogen atmosphere at −70° C. This mixture was stirred at room temperature for 3 hours. Subsequently, 5.5 ml of DMF was added to this mixture at −70° C., and the temperature was returned to room temperature. The reaction mixture was added to water. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.90 g of 2-ethoxymethoxy-4-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]34[CH2:29][CH:17]5[CH2:18][C:19]([NH:21]C(=O)OC(C)(C)C)([CH2:20]3)[CH:15]([CH2:16]5)[CH2:14]4)=[CH:9][CH:8]=2)[C:3]1=[O:30].C(Cl)Cl>[Pd].CO>[NH2:21][C:19]12[CH2:18][CH:17]3[CH2:29][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:5][CH2:6][N:2]([CH3:1])[C:3]5=[O:30])=[CH:12][CH:11]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:20]2
Reactant: CN1CCN(c2ccc(C34CC5CC(C3)C(NC(=O)OC(C)(C)C)(C5)C4)cc2)C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(C34CC5CC(C3)C(N)(C5)C4)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of the compound obtained from step I (0.25 g, 0.56 mmol) in a 1:1-mixture of CH2Cl2 and MeOH (10 mL) was added Pd/C (10% w/w, 0.1 g) and stirred at room temperature under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3a-aminohexahydro-2,5-methanopentalen-2(1H)-yl)phenyl]-3-methylimidazolidin-2-one (0.15 g) as an off-white solid in 86% yield. M.R. 227-230° C.; m/z (M+1), 312; IR cm-1 3416, 3249, 2964, 1682, 1519, 1485, 1261, 810; 1H NMR (CDCl3+DMSO-d6) 300 MHz δ 8.38 (bs, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 3.76 (t, J=7.4 Hz, 2H), 3.43 (t, J=7.4 Hz, 2H), 2.77 (s, 3H), 2.48-2.40 (m, 2H), 2.22-2.14 (m, 1H), 2.10-2.0 (m, 2H), 2.0-1.86 (m, 4H), 1.80-1.60 (m, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:32]O)[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:31])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][C:17]2=[O:30])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.[CH3:34]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1>ClCCl>[OH:1][C:2]([CH3:34])([CH3:32])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:31])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][C:17]2=[O:30])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1
Agent: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of (S)-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 160, 300 mg, 0.94 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (161 mg, 1.03 mmol) and 1-hydroxybenzotriazole (135 mg, 0.99 mmol). The reaction mixture was stirred at 25° C. for 1 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 175 mg, 1.13 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (340 mg, 79%) as a light brown powder: HR-ES-MS m/z calculated for C24H32N4O5 [M+H]+ 456, observed 457; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.39-1.64 (m, 2H), 1.67-1.82 (m, 1H), 3.77 (s, 3H), 3.89 (s, 2H), 4.16 (d, J=18.4 Hz, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.68 (s, 1H), 4.84-4.93 (m 1H), 4.87 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.83-6.91 (m, 3H), 7.37 (t, J=8.2 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1)=[O:19]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1B(O)O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2C=O)cc1
Yield: 59 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) and 2-formylphenylboronic acid. Yield: 59%. 1H NMR (400 MHz, dMSO): δ 0.72-0.75 (d, 6H), 1.49 (s, 6H), 1.65-1.72 (m, 1H), 2.80-2.85 (t, 2H), 7.35-7.44 (m, 5H), 7.47-7.50 (d, 1H), 7.55-7.65 (t, 1H), 7.70-7.75 (t, 1H), 7.85-7.90 (d,1H), 9.9 (s, 1H); MS+H (324).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:8]([CH2:19][CH3:20])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)(C)(C)C.Br[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)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>[Cl:40][C:34]1[CH:33]=[C:32]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C@@H:8]([CH2:19][CH3:20])[C@H:7]([OH:6])[CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: CC[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@H](Oc1ccc(-c2ccc(C#N)c(Cl)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 73.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tertbutyldimethylsilanyloxy)-1-ethyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.18 g, Example 88b)), 4-bromo-2-chlorobenzonitrile (0.18 g), 2M aqueous sodium carbonate (0.48 ml) and tetrakis(triphenylphosphine)palladium (0) (0.012 g) in ethanol (3 ml) with heating at 90 ° C. for 4 hours. The residue was purified by column chromatography eluting with a gradient of 50-1 00% ethyl acetate in isohexane to give the title compound as a solid (0.125 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2]CCCCCC/C=C\CCCCCCCC.CC1C(C)=C([O:29][C:30]([CH2:32][CH2:33][C:34]([O:36]CCO)=[O:35])=[O:31])C(C)=C2CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)OC=12.[OH2:62]>>[C:30]([OH:29])(=[O:31])[CH2:32][C:33]([CH2:2][C:1]([OH:20])=[O:19])([C:34]([OH:36])=[O:35])[OH:62]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)OCCO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
3 g of methyl TMZ-8-carboxylate was weighed, pulverized into fine powder, and mixed with 20 g of water, 50 g of oleic acid, 30 g of VE TPGS and an appropriate amount of citric acid to form the microemulsion by grinding. An appropriate amount of rate-moderated membrane (copolymer of ethylene and vinyl acetate) and PSAs (polysiloxane pressure-sensitive gum) were added. The resulting mixture was stirred well, degassed by heat preservation using water bath, and spread on a polythene matrix. Dried and cut to 50 patches to obtain object product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]=[CH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]=[CH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=Cc1cccc(C=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=Cc1cccc(C=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1

Procedure:
Hydrolysis of ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenyl]-2-propenoate with sodium hydroxide analogously to the procedure of Example 10 provides the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])=[N+:2]=[N-:3].CN(C)C=O.[OH-].[Li+].Cl>O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCCN=[N+]=[N-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To ethyl 5-azidovalerate (1.6 g; 10 mmol; Example 2.1) in 5 ml-dimethylformamide, was added lithium hydroxide (1.0 g; 20 mmol; Fisher) in 5 ml water, and the reaction mixture was stirred 12 h at 25° C. The reaction mixture was adjusted to pH ˜4 by addition of 1 N HCl and was extracted with 100 ml diethyl ether. The resulting organic layer was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, and dried in vacuo. Yield: 1.4 g (9.8 mmol, 99% yield).