Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccc(CCO)cc1
Product: COc1ccc(CCOc2cncc(Cl)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 4-methoxyphenethyl alcohol (1.99 g, 13.1 mmol), K-t-BuO (1.34 g, 12.0 mmol) and 2,6-dichloropyrazine (1.56 g, 10.5 mmol). The yield of the title compound was 2.14 g (77%) and was obtained as a white solid. Anal. (C13H13ClN2O2) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[OH:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:17][C:18]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ncc(CO)c(CN(CCCCCC(=O)O)C(=O)OC(C)(C)C)c1O
Product: Cc1ncc(CO)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 72.9 %

Procedure:
The coupling of 6-[tert-butoxycarbonyl-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-hexanoic acid (41) (3.0 g, 7.8 mmol) and benzyl chloride (7.0 g, 55 mmol), as described in Example 3, gave 6-[(3-benzyloxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-tert-butoxycarbonyl-amino]-hexanoic acid benzyl ester (42) (3.2 g, 73% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16](N)[CH2:17][NH2:18].[S]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]1[NH:18][CH2:17][CH2:16][N:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCN
Reactant: N#CC(c1ccccc1)c1ccccn1
Agent: [S]
Product: c1ccc(C(C2=NCCN2)c2ccccn2)cc1
Temperature: 125 °C

Procedure:
Under a nitrogen atmosphere, carefully reflux (bath temperature of 125° C) a mixture containing 19.4 g. of 2-pyridylbenzyl cyanide, 6.6 g. of ethylene diamine and 0.2 g. of sulphur for 5 hrs. Cool the reaction mixture and under a nitrogen atmosphere dissolve the residue in 300 ml. of benzene, and water wash, dry (over anhydrous potassium carbonate) and filter the benzene solution. Concentrate the filtrate to a small volume whereupon the product crystallizes. Filter the crystals to yield 2-[α-(2-pyridyl) benzyl]-imidazoline, m.p. 134°-136° C. The maleate salt, m.p. 132°-135° C, is prepared from maleic acid and is crystallized from isopropanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[C:29]([C:33]1[O:37][N:36]=[C:35]([OH:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:29]([C:33]1[O:37][N:36]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=2[S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[C:35](=[O:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1Cl
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1-n1oc(C(C)(C)C)cc1=O
Reaction time: 4 h
Yield: 50.7 %

Procedure:
After mixing 32 g of 4-methanesulfonyl-2-tetradecylsulfonylchlorobenzene, 20 g of 5-t-butyl-3-hydroxyisoxazole, 20 g of potassium carbonate, and 140 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic phase obtained was purified by silca gel column chromatography to provide 20.0 g of the aforesaid compound with a yield of 50.8%. The melting point thereof was 97° C. to 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1B(O)O>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]5[S:35][CH:39]=[CH:38][CH:37]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: OB(O)c1cccs1
Product: c1cc(-c2cccs2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 42 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (200 mg, 0.39 mmol) and thiophene-2-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (84 mg, 42%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.00 (d, 1H), 7.95 (s,1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.34–7.27 (m, 3H), 7.09 (m, 1H), 6.39 (d, 1H), 6.17 (m, 2H), 5.16 (m, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 2.16 (m, 4H), 1.82–1.56 (m, 12H); MS m/z 521 (M+1). U16951-72
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(CC)CC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[O:11])[S:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.03 g, 0.08 mmol) in 10 mL DCM was added methyl bromoacetate (0.01 g, 0.08 mmol) followed by Et3N (0.008 g, 0.08 mmol). After stirring at room temperature overnight, reaction was concentrated and purified by flash chromatography on silica gel with 5% MeOH/EtOAc to obtain the product in 50% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[CH2:11][CH:10]=1.C(N(CC)CC)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O>[C:30]([O:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([CH:12]2[CH2:13][CH2:14][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:10][CH2:11]2)[CH2:20][CH2:19]1)(=[O:29])[CH:31]=[CH2:32]
Reactant: C1CCOC1
Reactant: O[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)O[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 4.6 g of trans-4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanol, 1.76 g of triethylamine, and 60 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.57 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The resultant reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=2/3) and recrystallized from hexane to obtain 2.74 g of trans-4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexyl acrylate (Y: 50.4%). The compound thus obtained had a purity of 99.8% by HPLC and 1 spot by TLC. Furthermore, the phase transition temperature of the compound was as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:26]=2)[C:21]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:20]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:36][C:34](=[O:35])[C:33]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCCC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Cl)ccc12
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(Cl)cc21
Yield: 39.1 %

Procedure:
3-(6-Chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (70 mg, 37%) was prepared from methyl (6-chloro-1-methyl-1H-indol-3-yl)glyoxylate (98 mg, 0.39 mmol) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-acetamide (100 mg, 0.39 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N:18]=[C:19]=[S:20])(C)C.CO>C1COCC1>[OH:13][N:12]([C@H:10]1[CH2:11][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)[C:19]([NH2:18])=[S:20]
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reactant: C[Si](C)(C)N=C=S
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (1.81 g, 10 mmol) in THF (30 ml) was added trimethylsilylisothiocyanate (1.58 g, 12 mmol) at room temperature. After stirring for 3 hours at 70° C., MeOH (20 ml) was added. Volatiles were removed in vacuo, and the residue recrystallized from ethyl acetate/n-hexane/EtOH to afford 1.34 g (55.8% yield) of the title compound, m.p. 156-158° C.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]1([O-])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[CH2:1]([C:8]1=[N:9][NH:10][C:11](=[O:13])/[C:12]/1=[C:15]1\[NH:14][C:23]2[C:18]([CH:17]=[CH:16]\1)=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc2ccccc21
Reactant: O=C1CC(Cc2ccccc2)=NN1
Solvent: CC(=O)OC(C)=O
Product: O=C1NN=C(Cc2ccccc2)/C1=C1\C=Cc2ccccc2N1

Procedure:
A mixture of 3-benzyl-1H-pyrazol-5(4H)-one (0.234 g, 1.34 mmol) and quinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H) 7.23-7.29 (m, 6H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C19H15N3O 301.12. found 302.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:5]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2cnccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C=Nc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of phosgene (20% in toluene, 5.8 ml, 11 mmol) was added to 50 ml methylene chloride and cooled to 0° C. 4-Dimethylaminopyridine (2.86 g, 23.4 mmol) in 30 ml methylene chloride was added dropwise. A thick white suspension formed. A solution of 5-aminoisoquinoline (1.44 g, 10 mmol) in 30 ml methylene chloride was then added dropwise to this suspension. The reaction was allowed to warm to ambient temperature and stirred overnight. At the end of this time, a solution formed, and the solvent was removed under reduced pressure. The residue was triturated with 50 ml diethyl ether to give an approximately 0.1 M solution of 5-isocyanato-isoquinoline.
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]=[O:16].O>CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]([OH:16])[CH3:2]
Reactant: [Li]C
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1CC(C)O
Temperature: -10 °C
Yield: 83.8 %

Procedure:
To a stirred −78° C. solution of TiCl4 (1.0 M in CH2Cl2, 1.43 mL, 1.43 mmol) in anhydrous Et2O (7 mL) was added MeLi (1.6 M in Et2O, 0.9 mL, 1.43 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to slowly warm to −30° C. at which point a solution of 2-(2-methoxy-4-nitrophenyl)acetaldehyde (275 mg, 1.43 mmol) (prepared as described in PCT WO 2000/73288 A1) in anhydrous Et2O (0.750 mL) was added dropwise and allowed slowly warm to −10° C. The reaction mixture was poured into cold water and extracted with Et2O (3×50 mL). The combined ether extracts were washed with water (1×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford 0.253 g (85%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J=6.0 Hz, 3 H), 1.62 (br. s., 1 H), 2.81 (dd, J=13.2, 7.7 Hz, 1 H), 2.89-2.94 (m, 1 H), 3.93 (s, 3 H), 4.06-4.15 (m, 1 H), 7.32 (d, J=8.2 Hz, 1 H), 7.72 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=8.2, 2.2 Hz, 1 H); HPLC (Method #1): 2.68 min retention time, (89%); LCMS (ES): m/z 194 [M−H2O+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=1)=[O:8]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Concentrated nitric acid (20 ml) was added cautiously with cooling to concentrated sulphuric acid (50 ml) maintaining a temperature of −5° C. Another solution of 2-methyl-1-phenyl-1-propanone (29.6 g, 0.2 mol) in concentrated sulphuric acid (70 ml) was made up with shaking, keeping the temperature at −5° C. The former nitric acid/sulphuric acid solution was added portionwise over 30 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1 l) and then extracted with diethyl ether (3×100 ml). The organic extracts were washed with water (300 ml) and then brine (300 ml), dried (Na2SO4) and then concentrated in vacuo. The crude product was obtained as an orange oil (40 g) which was purified by chromatography on silica gel (450 g) eluting with hexane :diethyl ether (9:1) to give the title compound as a pale yellow solid (16.3 g, 42%), m.p.33-35° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 53.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-3-pyrrolidinol (47 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, yield 53%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[C:19](=[N:32][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OCC(=O)N[C@]1(C)c1cc(Br)ccc1F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCC(=O)N[C@]1(C)c1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Temperature: 105 °C
Reaction time: 20 h
Yield: 112.5 %

Procedure:
In a sealed tube a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one (1.0 g, 3.2 mmol) in toluene (8 ml) was treated consecutively with sodium tert-butylate (912 mg, 9.5 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl-x-phos) (134 mg, 10 mol %) and tris(dibenzylideneacetone)-dipalladium chloroform complex [Pd2(dba)3.CHCl3] (98 mg, 5 mol %). Benzophenone imine (1.06 ml, 6.3 mmol) was added finally via syringe. The tube was sealed under argon and the mixture was stirred at 105° C. for 20 h. For the workup, the brown solution was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated at reduced pressure to give brown oil (1.5 g). The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one was obtained as a light yellow foam (1.13 g, 86% of theory). Mass (calculated) C26H25FN2O2 [416.493]; (found) [M+H]+=417.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=O)=[O:19])=[C:10]1[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]([N:32]([CH2:44][CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:34]=1)[CH3:31].C(OC(=O)C)(=O)C>>[CH2:40]([N:39]([CH2:42][CH3:43])[C:35]1[CH:34]=[C:33]([N:32]([CH2:30][CH3:31])[CH2:44][CH3:45])[CH:38]=[CH:37][C:36]=1[C:18]1([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10]=2[CH3:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:24])[O:19]1)[CH3:41]
Reactant: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part B of Example 5 above, 2.34 g (0.006 mole) of 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]benzoic acid prepared according to Example 5, part A, and 2.40 g of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of 2.40 g of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-n-octyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; R6 =(CH2)7CH3) as a tar-like semisolid. A toluene solution of this material developed a purple color when spotted on silica gel.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(Cl)(Cl)Cl.C(=O)=O.[Br:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O>ClCCl>[C:2]([O:16][C:14](=[O:15])[C@H:13]([Br:12])[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Into dichloromethane (80 mL) was condensed isobutene to double the volume (at -50° C. CHCl3 /dry ice). To this solution was added (2R)-2-bromo-4-methylpentanoic acid (28 g, 143.6 mmol) and maintaining the temperature between -40° and -50° C. concentrated sulphuric acid (1 mL) was added dropwise. The reaction was then allowed to warm to room temperature over 20 hours. The solution was then concentrated before adding additional methylene chloride (300 mL) which was subsequently washed with saturated NaHCO3 (2×100 mL) followed by water (2×100 mL). After drying over Na2SO4, the organic layer was filtered and concentrated to give a yellow oil. The material was distilled to give 23 g of (2R)-2-bromo-4-methylpentanoic acid t-butyl ester as a clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I-].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:34])[C:26](N2C=C[N+](C)=C2)=[O:27])=[CH:21][CH:20]=1>ClCCl>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:26](=[O:27])[N:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH3:34])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: [I-]
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and 3-[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane (67%). HPLC-MS m/z=422.9 (M+1), Rt: 5.5 min.