Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:28]([CH:35]([C:41]([OH:43])=[O:42])[C@@H:36]([C:38]([OH:40])=[O:39])[NH2:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:37][C@H:36]([C:38]([OH:40])=[O:39])[CH:35]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:41]([OH:43])=[O:42])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
5.3 g (30 mmol) of t-butoxycarbonyl glycine was dissolved in 100 ml of purified THF and 4.6 ml (33 mmol) of triethylamine and 4.33 ml (33 mmol) of isobutyl chloroformate) were added thereto at -15° C. The mixture was stirred at this temperature for 10 minutes. To the resultant solution of a mixed acid anhydride was added a solution which had been prepared by dissolving 8.0 g (36 mmol) of β-benzyl-L-aspartic acid and 5.02 ml (36 mmol) of triethylamine in water and cooling to 0° C. The mixture was then stirred at 0° C. for 1 hour and further at room temperature for 15 hours. After removing the THF by concentration under reduced pressure, cold 10% citric acid was added thereto. The precipitate thus formed was extracted with ethyl acetate twice. The extracts were combined and washed 5 times with one fifth the volume of 5% citric acid and then 10 times with water (one tenth the volume thereof). The solution was dehydrated over anhydrous sodium sulfate and concentrated to dryness. Then the residue was dissolved in ether and precipitated with n-hexane. After repeating this precipitation procedure 3 times, the obtained product was dried, whereby 6.9 g of the titled compound was obtained.
Reaction SMILES: N.[F:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([CH2:34][CH2:35][OH:36])[CH:33]=1)[CH2:6][N:7]1[CH2:30][CH2:29][C:10]2([O:15][CH2:14][CH2:13][N:12](C(C3N=C(C4C=CC=CC=4)SC=3)=O)[CH2:11]2)[CH2:9][CH2:8]1>CO>[O:15]1[C:10]2([CH2:29][CH2:30][N:7]([CH2:6][C:5]3[CH:31]=[C:32]([CH2:34][CH2:35][OH:36])[CH:33]=[C:3]([F:2])[CH:4]=3)[CH2:8][CH2:9]2)[CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Agent: N
Solvent: CO
Product: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reaction time: 1.5 h

Procedure:
‘880’ Ammonia solution (5 mL) was added to a solution of 2,2,2-trifluoro-1-(9-(3-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone (example 41, step d) (2.2 g) in methanol (25 mL). The resulting mixture was stirred for 90 min and the solvent evaporated. The residue was azeotroped three times with acetonitrile and concentrated to give the subtitled compound as a clear gum. Yield 1.96 g.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[O:19][CH2:20][O:21][CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][C:12]=2[O:19][CH2:20][O:21][CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COCOc1cc(C#N)ccc1-c1cccc(CN(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCOc1cc(CN)ccc1-c1cccc(CN(C)C)c1
Reaction time: 0.17 h

Procedure:
3′-Dimethylaminomethyl-2-methoxymethoxy-biphenyl-4-carbonitrile (crude material from above) is dissolved in ether (10 mL). The resulting solution is slowly added to a suspension of LiAlH4 (100 mg, 2.6 mmol) in Et2O. After addition, the mixture is stirred for another 10 min before quenching with H2O and 5 N NaOH. After which, EtOAc is added and the organic layer is collected and washed with brine and dried over Na2SO4. Removal of the solvent provided the crude amine, which is used directly in the next step. MS (ESI): 301 (M+1)+1.
Reaction SMILES: [CH2:1]([S:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:2][S:3][CH2:4][C:5]([O:7]C)=[O:6]>Cl>[CH2:2]([S:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:1][S:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CSCCSCC(=O)OC
Agent: Cl
Product: O=C(O)CSCCSCC(=O)O
Temperature: 25 °C

Procedure:
Dimethyl 2,2′-(ethane-1,2-diylbis(sulfanediyl))diacetate (7.00 g, 29.4 mmol) was heated to reflux for two hours in 2 N HCl (50 mL). Cooling the mixture to room temperature gave a clear solution, which was concentrated to dryness in vacuo, giving Compound 3 as a white solid, 5.98 g (96.8%). 1H NMR (400 MHz, D2O) δ 3.47 (s, 4H), 2.95 (s, 4H). 13C NMR (101 MHz, D2O) δ 174.61, 33.28, 31.39.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:9]2=[O:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C=O)C.[CH2:32]([NH2:34])[CH3:33]>C(Cl)Cl.C1COCC1.[OH-].[Na+]>[CH2:32]([NH:34][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])[CH:14]=1)[CH3:33]
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (140 mg) in methylene chloride (3 ml) was added thionyl chloride (40 μl) and DMF (40 μl) and the solution heated to 40° C. for 35 minutes. The reaction mixture was cooled to room temperature and 2M ethylamine in THF (2.1 mL) was added and the reaction stirred at room temperature for 2 hours. The reaction was dissolved in 1N NaOH and washed with ethyl acetate. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate (×3). The organic layers were dried (magnesium sulfate) and concentrated to yield N-ethyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a solid (88 mg); NMR Spectrum: (DMSOd6) 1.11 (t, 3H), 2.09 (s, 3H), 3.30 (m, 2H), 6.66 (d, 1H), 7.11 (d, 1H), 7.25 (d, 1H), 7.49 (d, 1H), 7.60 (s, 1H), 7.61 (d, 1H), 7.77 (s, 1H), 7.89 (d, 1H), 8.47 (s, 1H); Mass Spectrum: M+H+ 323.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use heptylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as white powder (46% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.12, 7.82, 7.75, 7.65, 7.50-7.57, 7.35, 3.69-3.80, 3.45-3.60, 3.38-3.43, 3.28-3.34, 3.20-3.26, 3.06-3.17, 1.45, 1.15-1.28, 0.85.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].O.[Pd]>[C:11]1([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ncc(-c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (5.01 g) and phenylboronic acid (3.61 g) in ethylene glycol dimethyl ether (150 ml), 2M aqueous sodium carbonate solution (100 ml) and tetralcistriphenylphosphine palladium (1.42 g) were added and stirred for 5 hours at 80° C. To the reaction liquid aqueous sodium hydrogencarbonate solution was added, diluted with water and washed with diethyl ether. To the aqueous layer 10% aqueous phosphoric acid was added to drop pH of the system to 4, followed by extraction with ethyl acetate, washing with saturated saline, drying over anhydrous sodium sulfate and concentration under reduced pressure. Thus the title compound (3.66 g) was obtained as white crystals. ESI-MS Found:m/z 201[M+H]+ ESI-MS Found:m/z 199[M−H]−
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccccc2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH3:22])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCOCC1>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:17][C:12]=1[O:11][CH2:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:31]([CH:29]=[O:30])[CH2:32][O:1]2)=[CH:6][CH:7]=1
Reactant: C=CC=O
Reactant: CCCc1ccc(OCc2ccc(C=O)c(O)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1ccc(OCc2ccc3c(c2)OCC(C=O)=C3)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2-hydroxy-4-[(2-methoxy-4-propylphenoxy)methyl]benzaldehyde (120 mg) in dioxane (2.4 mL) were added K2CO3 (55.2 mg) and acrolein (0.267 mL) at 25° C. The reaction mixture was warmed to 100° C., followed by stirring at 100° C. for 15 hours. The reaction mixture was left to be cooled to 25° C., and then filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 7-[(2-methoxy-4-propylphenoxy)methyl]-2H-chromene-3-carbaldehyde (104.2 mg) as a colorless liquid.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[O:7][CH:8]=[C:9]([C:11]3([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]3)[N:10]=2)[CH2:5][CH2:4]1.Cl>O1CCCC1.O>[CH:3]1([C:6]2[O:7][CH:8]=[C:9]([C:11]3([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]3)[N:10]=2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C1(c2coc(C3CC3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
An aqueous solution of sodium hydroxide (4N, 5 mL) was added to a solution of ethyl 1-(2-cyclopropyloxazol-4-yl)cyclopropanecarboxylate (200 mg, 0.9 mmol) in tetrahydrofuran and water (4 mL, 1:1). The reaction mixture was stirred at room temperature for 12 h. The mixture was acidified with an aqueous solution of hydrochloric acid (4N), extracted with ethyl acetate, dried and concentrated under reduced pressure to afford the title compound (150 mg). MS (ES+APCI) (M+H) 194.1; LCMS retention time: 3.515 min (Method Q1).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
DMF and KOH (3.3 g, 58 mmol) were stirred together at rt for 5 minutes before adding 1,2,4-triazole (1 g, 14.5 mmol). After a further 30 minutes, the reaction mixture was cooled to 0° C. and 1-bromo-4-bromomethyl-benzene (7.2 g, 29 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to 60° C., then cooled to It, extracted with ethyl acetate and water, and subsequently dried over K2CO3. The solvent was evaporated to yield yellow-white crystals, which, upon repeated recrystallisation, (ethylacetate/isohexane) yielded 0.60 g of the sub-title compound as white crystals (62% isolated yield).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[CH2:11](Br)[C:12]#[CH:13].O=CC1C=CC(O)=C(OC)C=1>ClCCl>[CH3:8][O:7][C:5]([CH:4]1[CH2:9][CH2:10][N:1]([CH2:13][C:12]#[CH:11])[CH2:2][CH2:3]1)=[O:6]
Reactant: COC(=O)C1CCNCC1
Reactant: C#CCBr
Agent: COc1cc(C=O)ccc1O
Solvent: ClCCl
Product: C#CCN1CCC(C(=O)OC)CC1
Reaction time: 36 h

Procedure:
To a solution of methyl isonipecotate 3.5 g (24.4 mmol, 3.30 mL) in 100 mL dichloromethane was added TEA (1.5 eq, 36.6 mmol, 5.1 mL), propargyl bromide (3.0 eq, 73.2 mmol, 6.5 ml), at room temperature for 36 hrs. The reaction was quenched with 35 mL water to yield to provide a clear solution. The solution was extracted with dichloromethane 2×25 mL, dried with Na2SO4, and the solvent evaporated to provide a yellow oil. r.f. (40% EtOAc/Hexanes) 0.26 stains faint white with Vanillin, starting material r.f. 0.05 stains yellow with Vanillin. The product appeared pure after extraction.
Reaction SMILES: [CH3:1][NH2:2].CO.O.[O:6]1[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7]1>>[CH3:1][NH:2][CH2:7][CH:8]([OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC1CO1
Reactant: CN
Solvent: O
Solvent: CO
Product: CCCCCCCCCCC(O)CNC
Reaction time: 24 h
Yield: 85.3 %

Procedure:
Two-thousand one-hundred and seventy grams of methylamine were introduced into 4550 ml of methanol at room temperature, whereupon there were dropped in 1288 grams of 1,2-epoxydodecane within 30 minutes at 20° C with stirring and water cooling and the mixture was allowed to stand for 24 hours with occasional stirring. After drawing off the excess methanol the residue was rectified. There were obtained 1284 grams (85.3% of theory) of N-methyl-N-(2-hydroxydodecyl) amine having a boiling point at 0.4 mm Hg of 130° C and a melting point of 67°-68° C.
Reaction SMILES: [CH2:1](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)[CH:2]=[CH2:3].[F:19][C:20]([F:36])([F:35])[C:21]([NH:23][C@@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[C@H:26]([OH:34])[CH2:25]1)=[O:22]>>[CH2:3]([O:34][C@H:26]1[C:27]2[C:32](=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C@@H:24]([NH:23][C:21](=[O:22])[C:20]([F:35])([F:36])[F:19])[CH2:25]1)[CH:2]=[CH2:1]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: Cc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Product: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(C)ccc21
Yield: 58 %

Procedure:
Step BK (1): 2,2,2-Trifluoro-N-((1S,3R)-3-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)acetamide (from Preparation BJ) was O-allylated by a procedure analogous to Step X(1) to afford 0.96 g (58% yield) of N-((1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide. LC-MS (M+H)+=260.09; 1H NMR (500 MHz, CDCl3) δ ppm 7.31 (d, 1H) 7.25 (bs, 1H) 7.18 (d, 1H) 6.87 (bs, 1H) 5.93-5.88 (m, 1H) 5.40-5.21 (m, 3H) 4.81 (d, 1H) 4.08 (bs, 2H) 2.69-2.65 (m, 1H) 2.37 (s, 3H) 2.08 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([O+](CC)CC)[CH3:20]>CCOCC>[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:1]([N+:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[O:13][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: O=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Product: CCOC1=[N+](Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-benzylpyrrolidinone (2.18 g, 12.4 mmol) in 25 mL of ether was added at 0° C. triethyloxonium tetrafluoroborate (2.15 g, 11.3 mmol). The reaction was allowed to warm to ambient temperature and stir for 30 minutes, during which a solid product precipitated from the reaction. The ether was decanted off, and the remaining residue washed three times with ether. Residual solvent was removed in vacuo to provide 1-benzyl-5-ethoxy-3,4-dihydro-2H-pyrrolium tetrafluoroborate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[Li+:14].[OH-:15]>>[Li+:14].[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[C:7]([C:9]2[O:11][CH:3]=[N:8][C:7]=2[C:9]([O-:11])=[O:15])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Reactant: [OH-]
Agent: [Li+]
Product: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1

Procedure:
Prepared starting from 6-trifluoromethyl-pyridine-2-carboxylic acid following sequentially general procedures M and E (using LiOH). LC-MS-conditions 02: tR=0.80 min; [M+H]+=259.12.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][NH2:12])[CH2:2]1.[F:13][C:14]([F:30])([F:29])[C@@H:15]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1.[BH4-].[Na+].[ClH:33]>C(Cl)Cl.CO>[ClH:33].[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][NH:12][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C@H:15]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:14]([F:29])([F:30])[F:13])=[CH:21][CH:20]=2)[CH2:2]1
Reactant: NC[C@H]1COc2cccnc2O1
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](c1ccc(CNC[C@H]2COc3cccnc3O2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
Combine [(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-YL]methanamine (9.71 g, 58.4 mmol), N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (16.43 g, 58.4 mmol) and MeOH (292 mL). Add 4 Å Molecular Sieves (30 mL) and stir the mixture at ambient temperature under a nitrogen atmosphere for 1 h. Add sodium borohydride (8.84 g, 233.7 mmol) portionwise and stir at ambient temperature for 10 minutes, monitoring the reaction via MS and 1H NMR. Slowly add H2O to quench the reaction and filter through Celite®. Collect the filtrate; remove solvents under reduced pressure; and purify via flash column chromatography using a gradient of 0-100% of (5% (2N NH3/MeOH) in DCM) in (5% MeOH/DCM) to elute the product. Combine the product fractions, and remove solvents under reduced pressure to afford the free base as a residue. Dissolve the residue in DCM, and add HCl (1N in Et2O; 87.7 mL, 87.7 mmol) while stirring. Stir for 10 minutes after the addition is complete, then remove the solvents under reduced pressure to provide the title product (12.9 g, 47.3%) as a white solid. MS (m/z): 432 (M-Cl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH3:23])[C:10]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: COC(=O)C(C)I
Product: COC(=O)C(C)N1CCSCC(NC(=O)OC(C)(C)C)C1=O
Yield: 81.5 %

Procedure:
The above-named compound is prepared from 6-t-butoxycarbonylamino-perhydro-1,4-thiazepin-5-one (0.1 g) and methyl iodopropionate (0.11 g) according to the procedure described in Example 4. The product (0.11 g) is obtained after chromatography. The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][N:15]=[CH:14][C:13]=3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][N:15]=[N:16][C:17]=3[O:19][CH2:36][CH3:37])[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2]
Reactant: CC[O+](CC)CC
Reactant: CCOC(=O)C1=C(C)Nc2cn[nH]c(=O)c2C1c1ccc(C#N)cc1OC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1=C(C)Nc2cnnc(OCC)c2C1c1ccc(C#N)cc1OC
Reaction time: 1 h

Procedure:
50 mg (0.136 mmol) of ethyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate are mixed under an argon atmosphere with 5 ml of abs. dichloromethane and 51.8 mg (0.273 mmol) of triethyloxonium tetrafluoroborate. After a reaction time of 2 hours at room temperature, the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 1 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent:acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 15 mg (27.8% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(=S)=S>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:17](=[O:18])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a stirred solution of thioanisole (380 mL, 3.2 mol) and 4-fluorophenylacetyl chloride (300 g, 1.6 mol) in carbon disulfide (1.2 L), cooled to 5° C., was added anhydrous aluminum chloride portionwise at such a rate that the internal temperature did not rise above 15° C. The reaction was stirred at room temperature for 16 hours. The solution was cautiously poured into 2 L of ice and water. The aqueous solution was extracted with methylene chloride (6×150 mL), the combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 800 mL of ether and cooled to 0° C. whereupon crystals of pure product formed which were isolated by filtration on a Buchner funnel and air dried to provide the ketone (199.6 g, 48%): mp 135°-138° C. 1H NMR (CDCl3 /TMS) 300 MHz 8.00 (d, J=8.7 Hz, 2H), 7.40-7.30 (m, 4H), 7.13-7.03 (m, 2H), 4.34 (s, 2H), 2.56 (s, 3H). Mass spectrum M+ =260.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[N:15][NH2:16])[CH3:6]
Reactant: CON=C(C(C)=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CON=C(C(C)=NN)c1ccccc1
Yield: 56 %

Procedure:
2.5 g (0.014 mol) of 1-phenylpropane-1,2-dione 1-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 1.45 g (0.029 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with diethyl ether and the crystals are filtered off. 1.5 g (55.6% of theory) of 2-hydrazono-1-phenylpropan-1-one O-methyl oxime of melting point 132° C. are obtained.