Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClCCCl.O>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][NH:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH3:35]
Reactant: CCOC(=O)C=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.105 g, 0.26 mmol) in 1,2-dichloroethane (2 mL) was added ethyl glyoxylate (0.050 mL, ˜0.5 mmol, 50% solution in toluene), acetic acid (0.016 mL, 0.28 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol). The reaction was stirred at ambient temperature for 18 hours. Additional ethyl glyoxylate (0.050 mL, ˜0.5 mmol, 50% solution in toluene) and acetic acid (0.016 mL, 0.28 mmol) were added and the reaction was warmed to reflux for 3 hours. The reaction was then cooled to ambient temperature, sodium cyanoborohydride (˜0.030 g, 0.48 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.085 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: N#Cc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1

Procedure:
A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalladium (0) (83.15 mg, 0.0908 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N)([O-:3])=[O:2].C1(N)C=CC=CC=1N.FC1C=CC=CC=1[N+]([O-])=[O:34]>>[OH:34][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Nc1ccccc1N
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1O

Procedure:
N-2-nitrophenyl-o-phenylendiamine, M.p. 95°-98° C. by reaction between o-phenylendiamine and 2-fluoronitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:24][N:25]([CH3:27])[CH3:26])=[C:15]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOCCc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1CN(C)C
Yield: 28 %

Procedure:
A solution of EXAMPLE 182A (360 mg, 1 mmol), dimethylamine hydrochloride (164 mg, 2 mmol), 37% formaldehyde (0.5 mL) in acetic acid (5 mL) was heated at 100° C. for 5.5 hrs. The solvent was evaporated. The residue was dissolved in water (5 mL). The pH of the water solution was adjusted to 9 with 2 N NaOH. The precipitate was filtered, washed with water and dried to give the product as white powder (115.4 mg, 28% yield): mp 152-153° C.; MS m/e, 420, 418 (M+)
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: CC1(C)CCNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC1(C)CCN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 34 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-dimethyl-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (34%) as amorphous yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH:13](O)=O.C=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 150 °C
Yield: 90.9 %

Procedure:
A mixture of 2-(4-bromophenyl)pyrrolidine (0.5 g, 2.2 mmol), formic acid (0.11 mL, 2.42 mmol), formaldehyde (0.2 mL, 2.42 mmol, 37% in water), water (4 mL) in a sealed tube was heated to 150° C. under microwave for 5 minutes. After cooling to room temperature the reaction mixture was extracted with EtOAc (3×15 mL), the combined organic phase was washed consecutively with saturated NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product (0.48 g, 91%), which was used directly in the next step. LC-MS (ESI) m/z: 240 (M+1)+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O.O1CCOCC1>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:10]1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(F)cc3)[C@@H](CO)O2)cc1F
Temperature: 35 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
A 7.5 g quantity of potassium hydroxide was dissolved in a mixture of 300 ml of water and 80 ml of dioxane. To the solution were added 2.00 g of 2'-deoxy-5-fluorouridine and 4.9 ml of 4-fluorobenzyl chloride, and the resulting mixture was stirred at 35° C. for 2 days. After the reaction, the same subsequent procedure as in Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.57 g of the title compound in a yield of 20%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([I:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)cc1I
Yield: 96.8 %

Procedure:
A mixture of compound 489B (4.60 g, 16.8 mmol), tetrahydrofuran (75 mL), ethanol (100 mL), ammonium chloride solution (1.51 g, 28.3 mmol, dissolved in 100 mL of water), and iron (325 mesh, 4.21 g, 75.4 mmol) was mechanically stirred. The reaction mixture was heated to reflux for 3 h or until all starting material was consumed. The reaction mixture was cooled, filtered through Celite and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with 1N sodium hydroxide (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 3.97 g (97%) of compound 489C as a dark solid. HPLC: 95% at 1.877 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 245.13 [M+H]+.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C[O-].[Na+].C[C:12](C)([C:16]([O-:18])=[O:17])[C:13]([O-:15])=O.[F:20][C:21]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[CH:26][C:22]=1C(Cl)=O>O.CN(C)C=O>[F:20][C:21]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[CH:26][C:22]=1[C:13]([CH2:12][C:16]([O:18][CH3:1])=[O:17])=[O:15]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: Cc1ccccc1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
A 500 ml, three-necked flask was set up in a heating mantle and equipped with a mechanical stirrer, an equilibrating type addition funnel, a thermometer, an inert gas (argon or nitrogen) inlet, and a distillation head set for downward distillation. The flask was charged with 100 ml of toluene, 2 ml of dimethylformamide, and 2.84 g (0.0525 mol) of anhydrous sodium methoxide. The slurry was heated with stirring to 110° C., and dimethylmalonate (7.1 g, 0.0538 mol) was added dropwise from the addition funnel over 15 to 20 minutes. A total of 20 ml of distillate was collected at a vapor temperature of 50°-105° C. A fluid slurry was obtained. After five minutes at 105° C. (vapor), the mixture was cooled to 18°-20° C., and 5.3 g (0.025 mol) of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise with good stirring. The mixture was stirred for three hours at ambient temperature. Water (250 ml) was added with stirring and the aqueous layer was removed and acidified to a pH of 2-3 with 2N HCl. The organic product was extracted with two 50 ml portions of methylene chloride. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was distilled under reduced pressure (0.2-0.3 mm of Hg) to remove dimethyl malonate (pot temperature 85°-105° C., vapor 35°-39° C.). A gas chromatographic analysis of the residue indicated that it contained 94-97% of the desired product. The oily residue was mixed with 140 ml of water and refluxed for 1.5 hours. The mixture was cooled to room temperature and extracted with two 50 ml portions of methylene chloride. The organic layer was washed with 20 ml portions of 2.4N ammonium hydroxide solution till the aqueous extracts showed a pH of 9. The methylene chloride layer was dried over magnesium sulfate, concentrated to dryness, and triturated with cold n-hexane. The product was collected and dried under vacuum to yield 3.25 g (45-50%) of methyl 2,3,4,5-tetrafluorobenzoylacetate, mp 68°-72° C., which was 98% pure by gas chromatographic analysis. A pure sample was prepared by recrystallization from n-hexane, mp 71°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][N:8]1[C:9](=[O:10])[C:4]2[C:5](=[CH:11][CH:12]=[C:2]([Br:1])[CH:3]=2)[C:6]1=[O:7]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN1C(=O)c2ccc(Br)cc2C1=O
Temperature: 25 °C

Procedure:
50.3 g of 4-bromophthalimide, 92.0 g of potassium carbonate, and 24.5 ml of methyl bromoacetate were added to 888 ml of acetone. The resultant mixture was heated to reflux temperature for 24 h, and then cooled to room temperature. The mixture was filtered through a fine glass frit to remove all solid material, and the solution was then concentrated under vacuum to provide 66 g of the desired product, a white solid; 1H NMR (CDCl3): δ=3.76 (s, 3H), 4.43 (s, 2H), 7.71-7.75 (m, 1H), 7.85-7.90 (dd, 1H), 8.00 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[NH4+].C([O-])(=O)C.[Na+].C([BH3-])#[N:26].[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:26])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [BH3-]C#N
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To 2 g (10.29 mmol) of 3,4-dimethoxyphenyl acetone was added 10 mL of methanol, 7.9 g (102 mmol) of ammonium acetate, 844 mg (10.2 mmol) of sodium acetate and 970 mg (15.4 mmol) of sodium cyanoborohydride. The pH of the reaction was adjusted to between 6-7 by addition of glacial acetic acid. The reaction mixture was allowed to stir at room temperature 18 hours and concentrated under reduced pressure. To the residue 100 mL of water was added, and the pH of the reaction was adjusted to 14 using 6 N NaOH. The aqueous layer was extracted with 6×30 mL of chloroform. Organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give 2 g (10.24 mmol, 99%) of 3A as a light yellow gum (M+H, 196).
Reaction SMILES: NO.[CH:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Zn][CH2:13][CH3:14])C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CCCCCC.CCOCC.C1(C)C=CC=CC=1>[C:15]([O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:13][CH3:14])(=[O:17])[CH3:16]
Reactant: CCCCCC=O
Reactant: CC[Zn]CC
Reactant: CC(=O)OC(C)=O
Agent: NO
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCC(CC)OC(C)=O
Reaction time: 72 h
Yield: 66 %

Procedure:
To a vial containing aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added a solution containing freshly distilled hexanal (0.30 g, 3.0 mmol), toluene (3.0 mL), and 1 M diethylzinc in hexane (6.0 mL). After 3 days at room temperature, acetic anhydride (1.2 mL, 13 mmol) was added. After 2 additional days, the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 95% hexane and 5% ethyl acetate as eluant. The product (+)-3-octyl acetate (0.34 g, 66%) was isolated as a colorless liquid by distillation of the solvent at reduced pressure. Anal. for C10H20O2. Calcd: C, 69.72; H, 11.70; found: C, 70.08; H, 11.86. 1H NMR (CDCl3/TMS): δ0.86 (t, 6 H, J=7), 1.22-1.33 (br m, 6 H), 1.45-1.60 (m, 4 H), 2.03 (s, 3 H), 4.80 (m, 1 H). 13C NMR (CDCl3/TMS): δ9.58, 14.00, 21.25, 22.57, 25.02, 26.98, 31.62, 33.60, 75.57, 170.97. [α]D25=+7.0, c=2.01 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 100° C. on Cyclodex B stationary phase (J & W Scientific) indicated that the enantiomeric excess of the product was 86%.
Reaction SMILES: [C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16](Cl)[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2].[F:22][C:23]([F:28])([F:27])[C@@H:24]([OH:26])[CH3:25]>>[C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)COC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 63c, using 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide (Example 63b) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (9 mg, 18%) as light brown solid; MS (ESI, m/z): 388.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]([CH2:5][OH:6])([F:4])[F:3].C(O)(C)(C)C.[OH-].[K+].[C:14](=[C:17]([Br:19])[F:18])([F:16])[F:15]>O>[Cl:1][C:2]([CH2:5][O:6][C:14]([CH:17]([Br:19])[F:18])([F:16])[F:15])([F:4])[F:3].[C:2](=[CH:5][O:6][C:14]([CH:17]([Br:19])[F:18])([F:16])[F:15])([F:4])[F:3]
Reactant: FC(F)=C(F)Br
Reactant: OCC(F)(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: FC(Br)C(F)(F)OCC(F)(F)Cl
Product: FC(F)=COC(F)(F)C(F)Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %
Yield: 89 %

Procedure:
In a 50 ml glass reactor equipped with PTFE valve and magnetic stirring, 2.4 g (0.02 moles) of ClCF2—CH2—OH, 5 ml of tert-butyl alcohol, 1.1 g (0.02 moli) of KOH and 3.5 g of CF2═CFBr (0.022 moles) are fed. The reaction mixture is left under stirring at room temperature for three hours. The organic phase is then diluted with water, separated, washed twice with slightly acid water by HCl and anhydrified. 5 g of a mixture having the following composition: 89% ClCF2—CH2—O—CF2CFHBr and 11% CF2═CH—O—CF2CFHBr are obtained.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[O:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: COc1ccc(OC)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(OC)c(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (152 mg, 1 mM) and p-dimethoxybenzene (0.21 ml, 1.5 mM) were dissolved in dichloroethane (2 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 4 hours. Using the same procedure as in Example 1, 2',5'-dimethoxylbenzoin was obtained as an oil (219.4 mg, 79.2% yield).
Reaction SMILES: O[C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:24])C>>[CH3:15][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]1=[O:24]
Reactant: CC(C)(O)C#CC(=O)c1ccc(C#N)cc1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2ccc(C#N)cc2)=CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of crude 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.2 g, 5.60 mmol) in ethanol (12 mL), a solution of diethyl amine (0.58 mL, 5.60 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 1 h. The ethanol was removed and the mixture then diluted with EtOAc (50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g) as a light green semi solid which was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([OH:10])[CH3:9].[CH3:11]CCCCC.[Li]CCCC.C[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25]([C:32](Cl)=[O:33])=[N:26][NH:27]2>C1COCC1.CN1CCN(C)C1=O>[CH3:11][N:27]1[C:28]2[C:24](=[CH:23][CH:31]=[CH:30][CH:29]=2)[C:25]([C:32]([O:10][CH:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])[CH3:9])=[O:33])=[N:26]1
Reactant: CC(O)C1CCCCN1C
Reactant: Cc1cccc2[nH]nc(C(=O)Cl)c12
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CC(OC(=O)c1nn(C)c2ccccc12)C1CCCCN1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(1-Methyl-2-piperidyl)-1-ethanol (4.5 g, 31 mmol) was dissolved in dry THF (70 ml) and 1,3-dimethyl-2-imidazolidinone (20 ml) was added. The solution was ice-cooled and a hexane solution of n-BuLi (1.6M, 20 ml) was added dropwise. The reaction solution was stirred at room temperature for 20 minutes, to which was added dropwise a solution of 1 methylindazole-3-carboxylic acid chloride (5.4 g, 28 mmol) dissolved in a mixed solution of dry THF (70 ml) and 1,3-dimethyl-2-imidazolidinone (20 ml). The mixture was stirred overnight at room temperature, the reaction solution was concentrated under reduced pressure and a 5% sodium bicarbonate solution was added. It was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue. Separation and purification of the residue by silica gel column chromatography (110 g SiO2, chloroform:methanol=100:1) and further silica gel column chromatography with a different solvent (100 g SiO2, hexane:ethyl acetate=1:1) gave the title compound, 0.52 g of a high polar isomer and 0.64 g of a low polar isomer, respectively.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23])C1C=CC=CC=1.C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[OH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:12][C:13]1[C:14]([CH3:23])=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][C:18]=1[CH3:19]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1O
Yield: 95.4 %

Procedure:
A solution of 4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.65 g), TFA (3.5 mL) and thioanisole (2.2 mL) were stirred for 4 h. The reaction was partitioned between ethyl acetate and water, the organic layer dried over sodium sulfate and concentrated in vacuo. Flash chromatography afforded 4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.2 g) as a yellow oil.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH:5]=[C:6]2[C@:11]([C:13]([O:15][CH3:16])=[O:14])([CH2:12]\1)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7]2.O.O.O.C([O-])(=O)C.[Na+].[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(O)(=O)C.ClCCl>[C:33]1([N:39]2[C:4]3[CH:5]=[C:6]4[C@:11]([C:13]([O:15][CH3:16])=[O:14])([CH2:12][C:3]=3[CH:2]=[N:40]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:8][CH2:7]4)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)[C@]12C/C(=C/O)C(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@]12Cc3cnn(-c4ccccc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g, 3.23 mmol) was suspended in acetic acid (20 mL), and sodium acetate trihydrate (0.265 g, 3.23 mmol) and phenylhydrazine (0.318 ml, 3.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then water (20 mL) and dichloromethane (20 mL) were added and the phases were separated via a phase separator. The solvent was removed to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-6-tert-butyl 4a-methyl 1-phenyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (694 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.48 min, m+H=410.