Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([F:38])([F:37])[F:36])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH2:39])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>C(#N)C.CN(C=O)C>[Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:25]=4[C:35]([F:37])([F:36])[F:38])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH:39][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2OC[C@@H]1N
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,4R)-4-(tert-Butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-amine (50 mg, 0.09 mmol) was dissolved in acetonitrile (716 μl). To this solution was added K2CO3 (12.4 mg, 0.09 mmol) and tert-butyl 2-bromoacetate (15.9 μl, 0.11 mmol). The resulting solution was stirred at room temperature overnight. This was diluted with DMF and filtered to remove solid material and was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give tert-butyl 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetate (LCMS [M+H]+=673.3), which was dissolved in CH2Cl2 (4 mL) and TFA (1.5 mL). This solution was stirred for 2 h before it was concentrated. The resulting residue was dissolved in 4 N HCl in dioxane (1.0 mL) and 6 N HCl aqueous solution (0.5 mL) and stirred overnight. Next, the reaction was stirred at 50° C. for 4 h. After cooling, the solution was mixed with MeCN and purified by preparative HPLC (Column: PHENOMENEX® Luna C18, 5-μm particles (30×100 mm; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15%-100% B over 10 minutes; Flow: 30 mL/min, uv detection 254 nM) to give 2-((3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetic acid, TFA salt Ex 67 (44.5 mg): LCMS [M+H]+=503.0; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (1H, dd, J=8.03, 1.65 Hz), 7.60-7.76 (8H, m), 5.17 (1H, d, J=4.18 Hz), 4.44-4.58 (2H, m), 4.06 (2H, d, J=2.64 Hz), 3.90-3.97 (1H, m); HPLC Peak RT=7 5 min (Analytical Method A).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared from 4-hydroxybenzonitrile and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate using a method similar to that described for D13.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[N:15]=[N+:16]=[N-:17].C(N(C(C)C)CC)(C)C.[Cl:27][C:28]1[N:29]=[C:30]([C:35](Cl)=[O:36])[NH:31][C:32]=1[CH2:33][CH3:34]>ClCCl>[N:15]([C@H:3]1[C@@H:2]([NH:1][C:35]([C:30]2[NH:31][C:32]([CH2:33][CH3:34])=[C:28]([Cl:27])[N:29]=2)=[O:36])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](N=[N+]=[N-])C1
Reactant: CCc1[nH]c(C(=O)Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])nc1Cl
Reaction time: 2.5 h
Yield: 78.4 %

Procedure:
tert-Butyl cis(±)-4-amino-3-azidopiperidine-1-carboxylate obtained in Example (81a) (about 0.29 mmol) was dissolved in dichloromethane (4 mL). Diisopropylethylamine (0.2 mL, 1.15 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carbonyl chloride obtained in Example (81b) (about 0.29 mmol) were added, followed by stirring for 2.5 hours. Dichloromethane was added to the reaction solution, and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 70/30, 55/45) to obtain 90.4 mg of the title compound (78%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH:8]1[CH2:11][CH:10]([C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:21])[CH2:9]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: COc1ccc(C(=O)C2CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 714 mg (2.45 mmol) 3-(4-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester in 10 mL DCM was added 10 mL TFA and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Cl:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Cl
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Cl)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.46 g) in N,N-dimethylacetamide (6 mL) was rapidly added thionyl chloride (0.35 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Chloro-4-aminobenzophenone (0.45 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into ice water and filtered through diatomaceous earth. The diatomaceous earth was washed with methylene chloride, the organic solution dried and the solvent removed. Chromatography (eluent methylene chloride, then 5% ethyl acetate in methylene chloride) gave the title compound (0.31 g) as a white solid; mp 142-144° C. Analysis for C17H13ClF3NO3 : Calculated: C, 54.92; H, 3.53; N, 3.77; Found: C, 54.89; H, 3.63; N, 3.68.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[C:9]1([CH2:11][CH2:10]1)[NH:12][C:25]2=[O:26]
Reactant: CN(C)C=O
Reactant: NC1(c2ccc(F)cc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CC2)c2ccc(F)cc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 1-(2-bromo-4-fluorophenyl)cyclopropanamine (3.0 g, 17.4 mmol), Pd(dppf)Cl2 (0.4 g), DIPEA (5.05 g, 39.1 mmol) in DMF (40 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. After it was cooled down to room temperature, the reaction mixture was diluted with EtOAt (300 mL) and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (600 mg, yield 26%) as a brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=C.O.I([O-])(=O)(=O)=[O:23].[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=[O:23]
Reactant: C=Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water then osmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was added and stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) and the reaction was stirred for 2 h. The reaction was then extracted with dichloromethane (3×10 mL), dried over Na2SO4 and concentrated. Purification via MPLC (DCM/MeOH+1% NH4OH) afforded title compound as a tan solid (350 mg, 72% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[N:22]1([CH2:21][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH2:4][OH:3])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 355 mg of 4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 1 mL of tetrahydrofuran was added 0.88 mL of a 1M solution of lithium aluminium hydride in tetrahydrofuran. The resulting mixture was stirred at room temperature for 1 h. Water was slowly added and the mixture was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) to give 276 mg of [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(Cl)Cl.OS(O)(=O)=O.[Br:22]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:22][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (215.0 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402.0 g, 2.26 mol) in equal portions over seven hours. The reaction mixture was stirred for four days at room temperature, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water and subsequently treated with saturated NaHCO3 (1.5 L) for two hours. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)=[C:13]([F:23])[CH:12]=2)[CH2:6]1.C[C:25]1[O:26][C:27]([CH:30]=S(=O)=O)=[N:28][N:29]=1.O>CS(C)=O>[CH3:30][C:27]1[O:26][C:25]([O:3][CH2:4][C@@H:5]2[O:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:18][CH2:19][O:20][CH2:21][CH:22]=4)=[C:13]([F:23])[CH:12]=3)[CH2:6]2)=[N:29][N:28]=1
Reactant: Cc1nnc(C=S(=O)=O)o1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc(OC[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
Sodium hydride (28 mg of a 60% suspension in mineral oil, 0.69 mmol) was added to a solution of 5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (0.2 g, 0.69 mmol) in DMSO (5 ml) and the mixture was stirred for 1 hour. 2-Methyl-5-sulfonylmethyl-1,3,4-oxadiazole (RB Woodward et al, (Journal of the American Chemical Society 105, 904 [1983]) (0.11 g, 0.69 mmol) was added and the solution heated at 110° C. for 9 hours. Water (40 ml) was added and the mixture extracted three times with EtOAc. The combined extracts were dried by filtration through phase separation paper (Whatman 1PS) and evaporated. The residue was purified by flash column chromatography, eluting first with EtOAc and then with EtOAc/MeOH (20:1) to give the title product (23 mg, 9%) as a solid (mp 146-147° C.). MS: 376 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-])=O)[CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[NH2:21][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:24]
Reactant: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(C(=O)NCCN2CCOCC2)cc(C(F)(F)F)c1

Procedure:
A mixture of N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide (300 mg, 0.865 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 ml) and MeOH (2 mL) was exposed to an atmosphere of H2 (balloon). Upon completion of the reduction, the reaction mixture was filtered through celite and concentrated in vacuo to afford 3-amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide, which was advanced without further purification. MS m/z: 318 (M+H+); Calculated for C14H18F3N3O2: 317.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[N+:5]([O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:15])[CH3:14]
Reactant: COc1cc[n+]([O-])c(C)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(COC(C)=O)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
4.8 g (28 mmol) of 3,4-dimethoxy-2-methylpyridine 1-oxide are metered into 25 ml of acetic anhydride at 85° C. in the course of one hour, the mixture is stirred at the same temperature for one hour and concentrated completely in vacuo. The brown oily residue is distilled in a bulb tube still under 1 Pa. 5.3 g (90% of theory) of 2-acetoxymethyl-3,4-dimethoxypyridine are obtained; b.p. 125°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[F:12][C:13]([F:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:14][OH:15].[OH-].[K+]>CN(C)C=O>[F:12][C:13]([F:23])([C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])[CH2:14][O:15][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
100.0 g (0.58 mol) of 3-nitrobenzyl chloride and 128.3 g (0.62 mol, 1.05 equivalents) of 2,2,3,3,4,4,4-heptafluorobutanol(purity: 96%) were dissolved in 300 ml of dimethylformamide. To the resultant mixture 49.0 g (0.88 mol, 1.5 equivalents) of KOH pellets were added while the mixture was being cooled in a water bath. The reaction temperature is elevated to 43° C. and thereafter gradually restored to room temperature, and the reaction was completed after 30 minutes.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[OH:24])[C:9]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[O:24][CH2:32]3)[C:9]2=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc(F)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (56%) as a colorless solid: mp 182-184° C.; 1H NMR (300 MHz, CDCl3) δ7.43-7.25 (m, 10H), 7.17-7.10 (m, 1H), 7.07-6.84 (m, 5H), 6.56-6.49 (m, 1H), 6.39-6.32 (m, 1H), 5.01 (t, J=9.0 Hz, 2H), 4.74 (t, J=9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.0, 159.3, 156.8, 156.1, 141.7, 137.5, 137.2, 131.9, 130.3, 130.2, 128.8, 128.7, 128.6, 128.4, 128.3, 128.1, 127.9, 123.8, 123.3, 116.5, 116.1, 112.4, 110.9, 110.8, 110.6, 110.2, 80.3, 58.8, 58.0; MS (ES+) m/z 444.0 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12](SCC)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2[N:28]=[N:29]C(S)=CC=2C1)=O)C.C(Br)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12]([NH:28][NH2:29])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Reactant: CCOC(=O)N1CCc2nnc(SCC)cc2C1
Solvent: CCBr
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-ethylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 41 (b), from 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and ethyl bromide. M.P. 54°-56° from ligroin.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)ccc1F
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1F
Yield: 81.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (380 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-5-hydroxyphenyl)propanoate (300 mg) and cesium carbonate (650 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (480 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].BrN1C(=O)CCC1=O.BrCC1C=C(C=CC=1CBr)C(OC)=O.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:1][C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH2:12]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(C)c(C)c1
Agent: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 54.4 %

Procedure:
18.1 g of methyl 3,4-dimethylbenzoate, 39.2 g of N-bromosuccinimide, 200 mg of benzoyl peroxide, and 200 ml of carbontetrachloride were processed in a similar manner as in Reference Example 6-(1) to give a mixture containing methyl 3,4-bis-(bromomethyl)benzoate as a major component. (3) The procedure of Reference Example 14-(3) was followed using the whole mixture prepared above, 11.8 g of benzylamine, and 22.9 g of triethylamine to give 16.0 g of 2-benzyl-5-methoxycarbonylisoindoline.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][C:15]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1>[CH2:14]1[C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH2:28][CH2:29][CH2:30][O:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCCOC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
Diethyl diazenedicarboxylate (390 μL, 2.46 mmol) was added to a solution of 1,1-dimethylethyl 4-(hydroxymethyl)-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 137, 560 mg, 2.05 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 24 hours. Further triphenylphosphine (646 mg, 2.46 mmol) and diethyl diazenedicarboxylate (390 μL, 2.46 mmol) were added and the mixture was stirred at room temperature for 24 hours. Methanol (5 mL) was added and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25), to give the title compound (78 mg, 15%). m/z (ES+) 256 (M+1).