Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:20]=[CH2:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[O:7][C:8]1[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=1.C1COCC1>CO>[CH2:20]([C:3]1[C:2]([F:1])=[CH:17][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:21]
Reactant: C=Cc1cc(OC)c(Oc2cccnc2[N+](=O)[O-])cc1F
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(OC)c(Oc2cccnc2N)cc1F

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine (3.7 mmol, 1.1 g) and THF by methanol, the title compound was prepared as a white solid (800 mg; 80.5%) and used without further purification.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[S:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[N:14]2)=[C:8]([O:25]C)[CH:7]=1>ClCCl>[Br:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[S:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[N:14]2)=[C:8]([OH:25])[CH:7]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1nc(-c2ccc(Br)s2)[nH]c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(Br)s2)nn1-c1cc(Cl)c(Br)cc1O
Temperature: -78 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
2-(4-Bromo-5-chloro-2-methoxyphenyl)-2,4-dihydro-5-(5-bromothien-2-yl)-3H-1,2,4-triazol-3-one (Intermediate 3) (1.395 g) was suspended in anhydrous dichloromethane (20-25 mL/mmol of Intermediate 3) under argon and cooled to −78° C. A 1 M solution of BBr3 (9 mL) in anhydrous dichloromethane was added via a dropping funnel over a 45 minute period. After the addition was complete, the reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched by the addition of 5-10 mL water. Volatile solvent was removed under vacuum and the crude product was filtered and washed with water. The solid was refluxed in a mixture of acetone and ethanol for 15 minutes. After cooling to room temperature, the purified product was filtered and washed with acetone and ethanol. The solid was dried under high vacuum to yield 1.1 g (81%) of the desired product, Compound II.
Reaction SMILES: Br[CH2:2][CH:3]([F:7])[CH2:4][CH2:5]Br.[C:8]1(=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9]1.[K]>CN(C)C=O.C(OCC)(=O)C>[F:7][CH:3]([CH2:4][CH2:5][N:9]1[C:10](=[O:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]1=[O:18])[CH2:2][N:9]1[C:10](=[O:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(CBr)CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCC(F)CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 1,4-dibromo-2-fluoro-butane (4.0 g, 17.09 mmol) in N,N-dimethylformamide (60 mL) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 51.27 mmol). The reaction mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with water (60 mL), brine (60 mL), dried over sodium sulfate, and concentrated in vacuo to afford 4.5 g of 2,2′-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][CH:25]=2)=[CH:6][CH:5]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
A solution of 2-[4-(2-aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (140 mg) in dichloro-methane (3.0 mL) was treated benzoic acid (40 mg) and DCC (60 mg) sequentially and allowed to stir at ambient temperature for 17 h. The reaction mixture was then concentrated and fractionated by column chromatography with 5% Et3N in EtOAc to afford the product (141 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O>[Pd].CCO>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[F:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(F)c(N)c1
Reaction time: 24 h
Yield: 98.5 %

Procedure:
4-fluoro-3-nitrobenzoic acid (2.5 g, 14 mmol, 1.0 eq) was dissolved in MeOH (68 mL) and heated to reflux. 2.0M oxalyl chloride in CH2Cl2 (14 mL) was added to the refluxing solution slowly and stirred for 2 h at reflux. The reaction was concentrated in vacuo, crystallized at 0° C., and filtered to give 1.7 g (63%) of crude methyl 4-fluoro-3-nitrobenzoate as a white solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 4-fluoro-3-nitrobenzoate (1.7 g, 8.4 mmol, 1.0 eq) and 5% palladium on carbon (89 mg, 0.84 mmol, 0.10 eq) were dissolved in EtOH (40 mL) and stirred under H2 atmosphere (1 atm) for 24 h. The mixture was filtered through celite and concentrated in vacuo affording 1.4 g (97%) of crude methyl 3-amino-4-fluorobenzoate as a brown solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 3-amino-4-fluorobenzoate (1.4 g, 8.2 mmol, 1.2 eq), 5-bromopyrimidine (1.1 g, 6.8 mmol, 1.0 eq), cesium carbonate (3.1 g, 9.6 mmol, 1.4 eq), Bis(dibenzylideneacetone)palladium (0.50 g, 0.55 mmol, 0.080 eq), and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.47 g, 0.82 mmol, 0.12 eq) were dissolved in Dioxane (17 mL) and stirred under argon at 100° C. overnight. The mixture cooled to rt and was filtered through celite and washed with 5% MeOH in CH2Cl2. The filtrate was collected, concentrated in vacuo, and purified by flash chromatography on silica gel afforded 1.5 g (90%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (s, 1H), 8.50 (s, 2H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.63 (ddd, J=8.5, 4.7, 2.1 Hz, 1H), 7.42 (dd, J=11.2, 8.6 Hz, 1H), 3.83 (s, 3H); ES-MS [M+1]+:248.1.
Reaction SMILES: [CH2:1]([C:4]1C=CN=C(C#N)C=1)[CH2:2]C.[C:12]([C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[CH:20]=[C:19]([CH2:2][CH2:1][CH3:4])[CH:18]=[CH:17][N:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(Cl)ccn1
Reactant: CCCc1ccnc(C#N)c1
Product: CCCc1ccnc(C(C)=O)c1

Procedure:
The title compound was prepared from 4-propyl-2-pyridinecarbonitrile according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[C:9]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([Si:21]([Cl:20])([CH3:23])[CH3:22])[CH:7]=[C:6]([CH3:8])[CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution composed of tetrahydrofuran (31.5 ml), hexane (139 ml) and 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (45 g) synthesized in the above-described procedure (2) was added a 1.6 mol/liter hexane solution (115 ml) of n-butyllithium dropwise at −40° C. over 20 minutes. The resultant mixture was kept at −40° C. for 1 hour, and tetrahydrofuran (31.5 ml) was then added dropwise. To a solution composed of dichlorodimethylsilane (131 g) and hexane (306 ml) was added the above-described mixture dropwise at −40° C. The resultant mixture was allowed to warm to room temperature over 2 hours, and further stirred at room temperature for 12 hours. The solvent and excess dichlorodimethylsilane were removed under reduced pressure from the reaction mixture, hexane-soluble components were extracted from the residue with hexane, and the solvent was distilled off from the resultant hexane solution to obtain 41.9 g of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane as a pale yellow oil. Yield was 84%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[N:19]=[CH:18][CH:17]=[C:16](Br)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:16]1[C:13]([C:14]#[N:15])=[C:12]([Br:11])[N:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(Br)ccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccc2)ccnc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a suspension of NaH (1.756 g, 45.818 mmol, mineral oil 60%) in DMF (200 ml) cooled at 0° C., was added benzyl alcohol (4.542 g, 42 mmol). The resulting mixture was stirred for 5 min. Then, intermediate compound D1 (10 g, 38.18 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h, then quenched with NH4Cl (aqueous sat. solution) and diluted with H2O. The resulting mixture was extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 1% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D2 (9.2 g, 83%).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]#[C:6][CH2:7][CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[CH:22]=2)[CH:14]=1)[C:9](O)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[CH3:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]#[C:6][CH2:7][CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[CH:22]=2)[CH:14]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)C#CC#CCC(Cc1cccc(/C=C/c2cccc(-c3ccsc3)c2)c1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)C#CC#CCC(CO)Cc1cccc(/C=C/c2cccc(-c3ccsc3)c2)c1
Yield: 65.8 %

Procedure:
980 mg of (E)-2-(6,6-dimethyl-2,4-heptadiynyl)-3-[3-[2-[3-(3-thienyl)phenyl]ethenyl]phenyl]propionic acid is dissolved in 20 ml of ethyl ether, 132 mg of lithium aluminum hydride is added in several portions thereto under ice cooling and stirring, and the mixture is stirred at that temperature for 10 minutes. Saturated saline is added to the reaction solution to decompose the excessive reducing agent, and 20 ml of 10% aqueous citric acid solution and 30 ml of ethyl ether are added to form two liquid phases. The organic layer is taken, washed successively with 5% aqueous sodium bicarbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The desiccating agent is filtered, the solvent is distilled off under reduced pressure, and the residue is crudely purified by silica gel short column chromatography [hexane/ethyl acetate=1/1] and then purified by medium pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si 60 F (produced by Merck Co.); eluent: hexane/ethyl acetate=5/1→3/1 ] to obtain 625 mg (yield: 68%) of the captioned compound as a colorless oily matter.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.S=[C:7]1[CH2:11][S:10][C:9](=[O:12])[NH:8]1>C(O)C>[CH:1]1([CH2:4][NH:5][C:7]2[CH2:11][S:10][C:9](=[O:12])[N:8]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCC2CC2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 1-cyclopropylmethanamine (2.34 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.92 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and washed with ethanol to give the title compound (1.60 g).
Reaction SMILES: P(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.CCCCCC.[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[N:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2.N1C(N)=C2C(N=CN2)=NC=1.[O:51]1[C:53]2[CH2:54][CH2:55][CH2:56][C:52]1=2>O1CCCC1.CC(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O.CS(C)=O>[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[N:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:55]1[CH2:56][CH:52]([OH:51])[CH:53]=[CH:54]1
Reactant: CN1CCCC1=Nc1ncnc2nc[nH]c12
Reactant: C1CC2=C(C1)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN1CCCC1=Nc1ncnc2c1ncn2C1C=CC(O)C1
Yield: 27.1 %

Procedure:
224 mg (1 mmol) of palladium(II) acetate, 2.5 ml (10 mmol) of triisopropyl phosphite and 1.5 ml of 1.6 molar n-butyllithium solution in n-hexane (2 mmol) are brought together in 40 ml of dry tetrahydrofuran at 0° C. under inert nitrogen gas and the mixture is stirred. After addition of 30 ml of dry dimethylsulfoxide, 4.32 g (20 mmol) of N6 -(N-methyl-pyrrolidin-ylidene)adenine (prepared by reaction of adenine with the diethyl acetal of N-methyl-pyrrolid-2-one in 2-propanol; beige powder, melting point: 248°-251° C.) are added; a solution of 1.64 g (20 mmol) of epoxycyclopentene in 20 ml of dry tetrahydrofuran is then added dropwise in the course of one hour. The solution is stirred at room temperature for 12 hours and then concentrated and the residue is chromatographed over silica gel (methylene chloride/methanol 9/1). 1.62 g (27% of theory) of N6 -(N-methyl-2-pyrrolidin-ylidene)-9-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]adenine of melting point 135°-138° C. are obtained in a regiospecific manner. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 8.42 (s, 1H), 8.16 (s, 1H), 6.20 (m, 1H), 6.00 (m, 1H), 5.50 (m, 1H), 5.46 (d, 1H), 4.73 (m, 1H), 3.50 (t, 2H), 3.04 (s, 3H), 2.90 (m, 1H), 2.85 (t, 2H), 1.97 (p, 2H), 1.74 (m, 1H). N6 -(N-Methyl-2-pyrrolidin-ylidene)-9-(cyclopent-1-en-3-on-1-yl)adenine of melting point 200°-205° C. is isolated as a by-product (20 mg, 0.3% of theory). 1H NMR (270 MHz, CDCl3), δ[ppm]: 8.64 (s, 1H), 8.13 (s, 1H), 7.19 (m, 1H), 3.53 (t, 2H), 3.34 (m, 2H), 3.20 (s, 3H), 3.07 (t, 2H), 2.65 (m, 2H), 2.10 (p, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CN(C(=O)Oc1ccc([N+](=O)[O-])cn1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Yield: 102.6 %

Procedure:
A solution of methyl-phenyl-carbamic acid 5-nitro-pyridin-2-yl ester (10.41 g, 38.1 mmol) in tetrahydrofuran (100 mL) was hydrogenated in a Parr apparatus with wet 5% palladium on carbon and 20 psi hydrogen pressure. After 2 hours the solution was filtered over a short pad of Celite, washed thoroughly with ethyl acetate and evaporated in vacuo, yielding title compound (9.51 g, 103% yield) as a thick oil, which solidified upon standing.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Reactant: COc1cc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c15) the title compound is obtained as off white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].F[C:10]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1cc(C(F)(F)F)ccc1C#N
Temperature: 60 °C

Procedure:
To N,N-dimethylaminoethanol (15 mL) cooled at 0° C. was added NaH 60% (1.15 g, 4 mol eq) and then 2-fluoro-4-trifluoromethyl-benzonitrile (1 mL, 7.18 mmol). The mixture was heated at 60° C. for 4 h then the solvent was removed at reduced pressure and water was added to the residue. The aqueous phase was extracted with EtOAc (3×30 mL), the organic phases were dried over sodium sulfate and evaporated to dryness to give 26b as pale yellow oil (2.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.21 (s, 3H), 1.31 (s, 3H), 2.21 (t, 2H, J=8), 2.48 (t, 2H, J=8), 6.54 (dd, 1H, J=2), 6.82 (m, 2H).
Reaction SMILES: Br[C:2]([F:11])([F:10])[C:3](Cl)([F:8])[CH2:4][C:5]([OH:7])=[O:6]>[Zn]>[F:8][C:3](=[C:2]([F:11])[F:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CC(F)(Cl)C(F)(F)Br
Agent: [Zn]
Product: O=C(O)CC(F)=C(F)F

Procedure:
Dehalogenation of 4-bromo-3-chloro-3,4,4-trifluorobutanoic acid (VIII) with zinc using conditions analogous to those disclosed in the literature to obtain the desired 3,4,4-trifluoro-3-butenoic acid (IV); or
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:25])[CH:5]=[C:6]3[C@:22]([CH3:23])([C@@H:2]12)[C@@H:21]1[C@H:9]([C@H:10]2[C@:18]([CH3:24])([CH2:19][CH2:20]1)[C@@H:13]([C@H:14]([CH3:17])[CH2:15][OH:16])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:38][O:39][C:40]([CH3:42])=[CH2:41]>C1(C)C=CC=CC=1.C(N(CC)CC)C.N1C=CC=CC=1>[O:1]1[C@H:3]2[C:4](=[O:25])[CH:5]=[C:6]3[C@:22]([CH3:23])([C@@H:2]12)[C@@H:21]1[C@H:9]([C@H:10]2[C@:18]([CH3:24])([CH2:19][CH2:20]1)[C@@H:13]([C@H:14]([CH3:17])[CH2:15][O:16][C:40]([O:39][CH3:38])([CH3:42])[CH3:41])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3
Reactant: C=C(C)OC
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(C)(C)OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 3.42 g (10 mmol) of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 100 ml of toluene is concentrated to 50 ml in a water-jet vacuum. The resulting suspension is treated at 0° C. with 2 ml of a suspension prepared from 50 ml of toluene, 0.172 g of p-toluenesulphonic acid and 0.2 ml of pyridine. Thereafter 3 ml of isopropenyl methyl ether are added and the resulting mixture is stirred at 0° C. for 3 hours. After the addition of 1 ml of triethylamine, the mixture is concentrated at 30° C./11 Torr. The crystalline residue is dissolved in a small amount of methylene chloride containing 0.1% triethylamine and treated with ether to give 2.91 g (70%) of (20S)-1α,2α-epoxy-21-(1-methoxy-1-methylethoxy)-20 -methyl-pregna-4,6-dien-3-one of melting point 150°-151° C.; [ α]D25 =+185.8° C. (c=1.0 in chloroform containing 0.1% triethylamine).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.[Cu]Br.C(OCC)(=O)C>[F:21][C:22]([F:31])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:9][CH:8]=4)=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3-c3ccc(OC(F)(F)F)cc3)c2)cc1
Yield: 44.4 %

Procedure:
A mixture of 0.6 g (2.6 mmol) 5-(4-trifluoromethoxy-phenyl)-1H-indole, 0.53 mL (2.8 mmol) 4-(trifluoromethoxy)iodobenzene, 0.075 g (0.52 mmol) copper(I) bromide and 0.54 g (3.9 mmol) K2CO3 in 10 mL anhydrous N-methylpyrrolidinone was heated to reflux overnight with stirring. The reaction was allowed to cool and was then poured into 200 mL of water. The aqueous solution was shaken with 200 mL ethyl acetate, the combined aqueous and organic phases were filtered, and the organic phase was separated. The aqueous phase was extracted once more with 200 mL ethyl acetate and the combined organic phases were washed with brine and concentrated. The crude product was chromatographed on silica (5–7% EtOAc-hexane as elutant) to afford 0.505 g (44% yield) of 1,5-bis-(4-trifluoromethoxy-phenyl)-1H-indole.
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:9]([N+:27]([O-])=O)[CH:8]=1)[CH:2]([CH3:4])[CH3:3]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:27][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:6]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reaction time: 7 h

Procedure:
N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzamide (2.9 g) in solution in an ethyl acetate/ethanol mixture (100 ml), and 10% palladium on carbon (290 mg) are added together in an autoclave. After stirring for 7 hours under a hydrogen atmosphere (3 bars), the catalyst is eliminated by filtration on Celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (2.5 g, 92% yield).