Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:12].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:12])[CH:16]=[CH2:15]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Methyl 4-hydroxy-3-iodobenzoate (1.85 g, 6.65 mmol) is dissolved in anhydrous DMF (15 mL) in a dry flask under nitrogen, treated with NaH (60% dispersion in oil, 265 mg, 6.65 mmol) and stirred for 1 h at RT. Allyl bromide (633 μL, 7.32 mmol) is added and the mixture is stirred for 16 h. The mixture is concentrated and the residue is partitioned between EtOAc (25 mL) and H2O (25 mL). The organic layer is washed with a 50% saturated mixture of 1:1 NaC/NaHCO3 (2×10 mL), dried (MgSO4) and concentrated to a yellow oil which solidified to a white solid upon standing (2.12 g). The crude material is chromatographed over 100 g slurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.27 g (60%) of methyl 4-(allyloxy)-3-iodobenzoate as a colorless oil which solidified on standing. MS for C11H11IO3 (EI) m/z: 318 (M)+.
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[S:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: c1cn[nH]c1
Reactant: S=c1c(Br)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2cc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 79 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (90.5 mg; yield=84.6%) as white needle crystals. Melting point: 189° C. 1H-NMR(CDCl3, δ ppm): 7.16 (s, H3), 8.50 (d, H5), 7.52-7.60 (m, H6), 7.66 (t, H7), 7.52 (m, H8), 7.82 (d, H3'), 6.60 (dd, H4'), 8.08 (d, H5').
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](O)(=[O:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:37]([C:38]2[CH:46]=[CH:45][C:44]3[O:43][CH2:42][O:41][C:40]=3[CH:39]=2)=[O:47])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1ccc2c(c1)OCO2)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and piperonylic acid (19.9 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[C:33](O)[CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:36])=[C:31]([CH:30]=1)[O:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Reactant: Cc1ccc(F)cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1-1, 511.7 mg, 1.39 mmol), 5-fluoro-2-methylphenol (182 μL, 1.67 mmol), tri-n-butylphosphine (521 μL, 2.09 mmol), and 1,1′-(azodicarbonyl)dipiperidine (526 mg, 2.08 mmol) were dissolved in anhydrous benzene (8 mL), and then the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (15 mL) was added to the reaction mixture, and the unsoluble materials were filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (411.4 mg) as a colorless amorphous product. (Yield 62%)
Reaction SMILES: I[CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([OH:8])[CH2:4]1.[CH2:9]([NH2:11])[CH3:10]>>[CH2:9]([NH:11][CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([OH:8])[CH2:4]1)[CH3:10]
Reactant: O[C@@H]1CO[C@@H](CI)C1
Reactant: CCN
Product: CCNC[C@H]1C[C@H](O)CO1

Procedure:
A solution of 4.0 g of product from Example 121, Isomer B, and 20 ml of 70%aqueous ethylamine is stirred at room temperature, in a pressure bottle, for 60 hours. The reaction is concentrated in vacuo and the residue purified by chromatography (silica gel: 30% methyl alcohol/chloroform) to give 3.2 g of the desired product.
Reaction SMILES: [O:1]([C:8]1[N:9]=[C:10]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.[NH2:39][C@H:40]([CH:48]([CH3:50])[CH3:49])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:42]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:49][CH:48]([CH3:50])[C@@H:40]([NH:39][C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=2)[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=1)=[O:18])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:42]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Oc3ccccc3)cnc21
Reactant: CC(C)[C@@H](N)C(=O)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.26 mmol), 4-dimethylaminopyridine (0.048 g, 0.39 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide (0.075 g, 0.39 mmol) in CH2Cl2 (2 mL) was added (R)-2-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one (0.066 g, 0.39 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with ethyl acetate (3×). The organic layer was washed with water and saturated aqueous NaCl solution and dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 column chromatography (0-100% EtOAc/hexanes) to afford 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>O>[Br:7][C:8]1[C:18]([O:19][CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC2CCC2)c1Br
Temperature: 125 °C

Procedure:
2.990 g (21.60 mmol) of potassium carbonate and 3.050 g (9.40 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced into 50 ml of N,N-dimethylformamide. 1.401 g (9.40 mmol) of bromomethylcyclobutane were added at room temperature and the mixture was heated for 6 hours at 120-130° C. The mixture was subsequently poured into water and extracted with diethyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated completely on a rotary evaporator. Drying in an oil-pump vacuum gave ethyl 2,4-dibromo-3-cyclobutylmethoxybenzoate as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Reactant: CCCc1ccc(B2OCC(C)(C)CO2)cn1
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: O
Solvent: CCO
Product: CCCc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (0.8 g, 2.4 mmol) was refluxed for 8 hours with dimethyl-2-(2-n-propylpyridin-5-yl)-1,3,2-dioxaborinane (0.72 g, 3.1 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol) and sodium carbonate (0.5 g) in tolune/ethanol/water 8:2:1 (11 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-n-propylpyridin-5-yl)phenyl]oxazoline was obtained, 0.20 g, pale solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]#[N:21])=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2c(Cc3nnn[nH]3)cnn2-c2ccccc2)cc1

Procedure:
A mixture of 29.4 g of (5-p-chlorophenyl-1-phenyl-pyrazol-4-yl)-acetonitrile, 8.06 g of sodium azide, 6.64 g of NH4Cl and 140 ml of dry DMF is heated at 120° for 17 hours, with stirring, and is then evaporated. After the customary working up, 5-p-chlorophenyl-1-phenyl-4-(tetrazol-5-ylmethyl)-pyrazole is obtained; m.p. 230°-232°.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CC(C)n1cc(Br)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
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: C1COCCO1
Product: CC(C)n1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 100 °C
Yield: 43.3 %

Procedure:
To 5-bromo-7-(1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.392 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (188 mg, 0.470 mmol) was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vial. The mixture was then bubbled with N2 for 10 minutes then Pd(Ph3P)4 (45.3 mg, 0.039 mmol) was added and bubbled for an additional 5 minutes. It was then capped and heated at 100° C. overnight. The reaction was then checked with LCMS and 10% of the bromide starting material remained. 50 mg of the boronic ester was added, and the reaction was capped and heated at 100° C. for an additional 5 hr. The reaction was diluted with water (5 ml) then extracted with EtOAc (3×10 ml). The organics wer combined, washed with brine and dried over MgSO4, filtered and concentrated. The residual oil was then diluted with DMSO (3 mL) then purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 28% ACN/H2O, 0.1% TFA to 53% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred into a 40 mL vial with MeCN then added water and freeze-dried to isolate 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mgt, 43.3% yield) as a white solid. LC-MS (ES) m/z=448.4 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 7.14-7.30 (m, 4H), 6.08 (br. s., 2H), 4.97 (quin, J=6.76 Hz, 1H), 4.29 (t, J=8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 1.46 (d, J=6.82 Hz, 6H).
Reaction SMILES: IC.[OH:3][CH2:4][CH2:5][C:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:12]=2[CH2:13][CH2:14][CH:15]=1>C(O)C.[C].[Pd]>[OH:3][CH2:4][CH2:5][CH:6]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:8][C:7]1=2
Reactant: CCOC(=O)c1ccc2c(c1)CCC=C2CCO
Agent: [Pd]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)CCCC2CCO

Procedure:
14.3 g of the above product was allowed to react using procedures analogous to those described in steps (5) and (6) of Referential Example 1 but using iodomethane instead of bromoethane to give an oily product containing a small amount of ethyl 5-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenecarboxylate as a by-product. The product was dissolved in 10 ml of ethanol and 0.5 g of 10% palladium carbon was added thereto. The mixture was catalytically reduced. After absorption of hydrogen gas was completed, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.4 g of ethyl 5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c2ccccc2c(=O)n1C(c1ccccc1)c1ccccc1
Yield: 37.6 %

Procedure:
A mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (G. Heller and P. Jacobsohn, Chem. Ber, 1921, 54B, 1107; 2.06 g), triethylamine (1.01 g) and bromodiphenylmethane (2.5 g) in chloroform (60 ml) was heated under reflux for 4 hours. The reaction mixture was then washed successively with water, M hydrochloric acid and then with water, dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride and purified by column chromatography using an increasing gradient of ether in methylene chloride as eluant to give (from the later fractions) 1,2-dihydro-1-carboethoxy-2-diphenylmethyl-3H-indazol-3-one as a solid (1.4 g), m.p. 115-118° C.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[Br:19][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=c1cc(-c2cccnc2)c2ccc(O)cc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Yield: 29.9 %

Procedure:
Commercially available 7-hydroxy-4-(3-pyridyl)coumarin (1.48 g, 6.19 mmol) and triphenylphosphine dibromide (5.22 g, 12.4 mmol) were heated in a sand bath at 320-350° for 1.5 h. The cooled solid was taken up with ethanol (200 ml) and silica gel (100 g) and evaporated to dryness. Column chromatography (toluene/acetone; 80:20) gave 0.56 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Mg]Br.CO[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=1>O1CCCC1>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=1
Reactant: FC(F)(F)CCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:15]([CH3:21])[C:16](OCC)=[O:17])[CH2:10]1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:15]([CH3:21])[CH2:16][OH:17])[CH2:10]1
Reactant: CCOC(=O)C(C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
0.4 g of lithium borohydride was added, whilst ice-cooling, to a solution of 2.95 g of ethyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propionate (prepared as described in Preparation 4) in 25 ml of tetrahydrofuran, and then a mixture of 0.37 ml of methanol and 5 ml of tetrahydrofuran was added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 2 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and an aqueous solution of sodium chloride was added to the resulting residue, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The ethyl acetate was then removed from the extract by evaporation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 0.93 g of the title compound, melting at 114° C. to 115° C.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:14][C:15]2=[O:18])=[CH:10][CH:9]=1>>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:14][C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCBr)cc12
Reactant: CN
Product: CNCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Methylamine (40% methanol solution) was added to the 7-(3-bromopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (245 mg, 0.576 mmol) obtained in step A, and the obtained mixture was then stirred at a room temperature for 3 hours. Thereafter, the reaction solvent was distilled away, and the obtained residue was purified by amino silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 142 mg of 7-(3-methylaminopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.C(N(CC)CC)C.Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(N2CCNCC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(CCN3CCOCC3)CC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O

Procedure:
A solution of EXAMPLE 42B (25 mg, 0.053 mmol) in tetrahydrofuran (1 mL), triethylamine (22.24 uL, 0.16 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (9.9 mg, 0.053 mmol) were heated to 75° C. over 18 hours. The reaction mixture was concentrated under reduced pressure and purified on RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (CDCl3) δ ppm 9.76 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.23-7.06 (m, 4H), 7.06-6.91 (m, 1H), 6.58-6.53 (d, J=2.5, 6H), 6.47 (dd, J=8.6, 2.5, 5H), 5.46 (s, 1H), 4.02 (d, J=1.9, 2H), 3.83-3.68 (m, 7H), 3.27-3.09 (m, 4H), 2.77-2.49 (m, 12H); MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C@:30]1(C)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=O.C(Cl)Cl>C(OCC)C>[CH3:28][C@@:30]1(/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: C(Cc1ccccn1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@]1(/C=C/c2ccccn2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 353 mg (1.0 mmol) of (2-picolyl)methylene-triphenylphosphorane and 381 mg (1.00 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo-[3.2.0]heptane-2-carboxylate in 10 ml of diethyl ether was stirred at room temperature under argon for 2 hours. The mixture was treated with 10 ml of methylene chloride, insoluble material was removed by suction filtration and the filtrate was concentrated. The residue remaining behind was chromatographed over silica gel (particle size 0.040-0.063 mm) with methylene chloride:ethyl acetate (95:5) as the eluent.