Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[C:22]([F:23])=[C:21]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:20]=[CH:19][C:18]=3[N:32]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[N+](C1C=CC(S([O:45][CH2:46][C@H:47]2[CH2:49][C:48]2([F:51])[F:50])(=O)=O)=CC=1)([O-])=O>>[F:51][C:48]1([F:50])[CH2:49][C@@H:47]1[CH2:46][O:45][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[C:22]([F:23])=[C:21]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:20]=[CH:19][C:18]=3[N:32]=2)=[N:13][CH:14]=1
Reactant: CC(=O)N[C@@H](C)COc1ncc2nc(-c3ccc(OCc4ccccc4)cn3)oc2c1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: CC(=O)N[C@@H](C)COc1ncc2nc(-c3ccc(OC[C@H]4CC4(F)F)cn3)oc2c1F

Procedure:
Using N-((2S)-1-((2-(5-(benzyloxy)pyridin-2-yl)-7-fluoro[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step A of Example 4 and Example 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C1CCNC1
Reactant: CC#CCOc1ncnc(F)c1F
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
0.2 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine and 0.09 g of pyrrolidine were added to 0.3 ml of toluene, then the mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.19 g of 4-(2-butynyloxy)-5-fluoro-6-pyrrolidinopyrimidine (referred as the present compound (1) hereinafter).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22].[N:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=1)=[C:24]=[S:25]>ClC(Cl)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:5]2[N:4]([CH3:21])[C:3](=[O:22])[CH:2]([NH:1][C:24]([NH:23][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=3)=[S:25])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:6]=2[CH:16]=1
Reactant: CN(C)c1ccc(N=C=S)c2ccccc12
Reactant: CN1C(=O)C(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc(NC(=S)NC2N=C(c3ccccc3Cl)c3cc(Cl)ccc3N(C)C2=O)c2ccccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 8) (0.03 g, 1 mmol) in dichloroethane (5 ml) was added 4-isothiocyanato-N,N-dimethyl-1-naphthalenamine (0.025 g, 1 mmol). The reaction mixture was stirred at 70° C. for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (35 mg, 60%). 1H-NMR (CDCl3): δ 8.26 (d, J=8.4 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.93 (br s, 1H), 7.73-7.06 (m, 11H) 6.10 (d, J=7.6 Hz, 1H), 3.40 (s, 3H) and 2.92 (s, 6H). MS (ESI) (M+H)+=562.
Reaction SMILES: CO/[N:3]=[C:4]1/[C:5]([CH3:20])([CH3:19])[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8]/1.B>O1CCCC1>[NH2:3][CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][C:5]1([CH3:20])[CH3:19]
Reactant: CO/N=C1\CN(C(=O)OCc2ccccc2)CC1(C)C
Agent: B
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Yield: 67.2 %

Procedure:
To a solution of (Z)-benzyl 4-(methoxyimino)-3,3-dimethylpyrrolidine-1-carboxylate (3.17 g, 11.5 mmol) in tetrahydrofuran (10 mL), was added borane in THF (24.1 mL, 24.1 mmol) at rt. The reaction was heated at reflux overnight. The reaction was cooled, quenched with 6N aq. sodium hydroxide, then diluted by water, and extracted with ether. The organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography, eluting with 0-20% methanol in dichloromethane to give benzyl 4-amino-3,3-dimethylpyrrolidine-1-carboxylate (1.92 g, 67.4 yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.45-7.31 (m, 5H), 5.32 (s, 2H), 5.15 (s, 2H), 4.07-3.91 (m, 1H), 3.56 (dd, J=12.1, 6.4 Hz, 1H), 3.51-3.32 (m, 1H), 3.22-3.06 (m, 1H), 2.83-2.75 (m, 1H), 1.17 (s, 3H), 1.10 (s, 3H). MS (ES+) m/z: 248.2, 249.1 (M+H); LC retention time: 2.24 min (analytical HPLC Method I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: -20 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a stirred solution of 1-chloro-2-methoxy-4-nitrobenzene (20 g, 106.6 mmol) in dichloromethane (500 mL) at −78° C. under a flow of Nitrogen gas, a solution of BBr3 (747 mmol) in dichloromethane was added dropwise. The reaction was stirred overnight at −20° C., then for 1 h at 4° C. To the reaction, 10 mL of MeOH and 100 mL of water were added dropwise. The resulting mixture was made basic with 10% NaOH solution. The aqueous layer was then made acidic and was extracted with chloroform. The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo to afford the yellow solid 2-chloro-5-nitrophenol (12.5 g, 68%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]3[CH3:25])=[CH:15][N:14]=2)[C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1.[O:26]1[CH2:29][C:28](=O)[CH2:27]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[Br:2][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH:28]4[CH2:29][O:26][CH2:27]4)[CH2:21][C@@H:20]3[CH3:25])=[CH:15][N:14]=2)[C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1
Reactant: O=C1COC1
Reactant: C[C@H]1CNCCN1c1ccc(Nc2cc(Br)nn3ccnc23)nc1
Agent: Br
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)nn3ccnc23)nc1
Temperature: 50 °C
Yield: 22.1 %

Procedure:
To a mixture of (S)-6-bromo-N-(5-(2-methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrobromide 115d (1.05 g, 2.24 mmol), oxetan-3-one (483 mg, 6.7 mmol), and ZnCl2 (914 mg, 6.7 mmol) in methanol (30 mL) was added NaBH3CN (421 mg, 6.7 mmol). The reaction mixture was heated at 50° C. for 14 h and concentrated under reduced pressure. Water (30 mL) was added to the residue and the resulting mixture was extracted with dichloromethane (% X 30 mL). The combined organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 115e as a yellow solid (220 mg, 22%). MS-ESI: [M+H]+ 444.1
Reaction SMILES: [CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([OH:24])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH:40]=[CH:39]1>C(Cl)(Cl)Cl>[CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([O:24][C:38](=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1[C@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)C1CC1
Reactant: O=C1C=CC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1[C@H](OC[C@@H](CNC(C)(C)Cc1ccc2ccccc2c1)OC(=O)/C=C\C(=O)O)C1CC1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
(2R)-1-[(1R)-(Cyclopropyl)-(2-methylphenyl)methoxy]-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propan-2-ol (1.25g) was dissolved in chloroform (10 ml) and, under ice-cooling, pyridine (0.485 ml) and maleic anhydride (294 mg) were added and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the obtained residue. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (1.40 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O>CO>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:19]=1[OH:20]
Reactant: Cc1cc(C(=O)CCCCCC(=O)O)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCCCCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid. To a cooled (-5° C.) solution of 103 parts of ethyl 6-chloroformyl hexanoate in 100 parts by volume of ethylene chloride is rapidly added with stirring 133 parts of granular anhydrous aluminum chloride. To this mixture is next added a solution of 88 parts of 2-methyl-6-t-butylphenol in 500 parts by volume of ethylene chloride. The reaction mixture is stirred at -5° C. for 5 hours and then allowed to slowly attain room temperature overnight. At the end of this time the material is poured over ice, rendered acidic with 6 N hydrochloric acid and extracted with ether. The combined extracts are successively washed with water, dilute aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution. After drying over sodium sulfate, the solvent is removed under reduced pressure to yield ethyl 6-(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoate, which is saponified with excess potassium hydroxide in methanol. After acidification of the reaction mixture, the solid, comprising 6 -(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoic acid, is subjected to a Clemmenson reduction as modified by Martin [J.A.C.S. 58, 1438 (1936)]to yield 7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid which is esterified with ethanol and p-toluenesulfonic acid to yield the corresponding ethyl ester.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH3:6][C:7](=[CH2:10])[CH2:8][OH:9].CC(N=NC(C#N)(C)C)(C#N)C>C(O)(=O)C>[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=C(C)CO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Product: CCP(=O)(O)CC(C)CO
Yield: 92.1 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 114 g (1 mol) of 2-methyl-2-propen-1-ol are initially charged in 200 ml of glacial acetic acid in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% solution of AIBN in glacial acetic acid are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 153 g of ethyl-(2-methyl-3-hydroxypropyl) phosphinic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10]([CH3:12])=O)=[C:5]2[C:4](=[O:20])[CH2:3]1.[OH-].[Na+].SC[CH2:26][OH:27]>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10][CH2:12][CH2:26][OH:27])=[C:5]2[C:4](=[O:20])[CH2:3]1
Reactant: OCCS
Reactant: CS(=O)c1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC(=O)c2c(SCCO)sc(-c3ccccn3)c2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
6,6-Dimethyl-3-methanesulphinyl-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (160 mg, 0.5 mmol) was suspended in ethanol (5 mL) and 4M sodium hydroxide solution (138 μL, 0.55 mmol) was added. 2-Mercaptoethanol (43 mg, 0.55 mmol) was added and the suspension was stirred at 20° C. for 2 h. After this time, further 2-mercaptoethanol (10 mg, 0.12 mmol) and 4M sodium hydroxide solution (35 μL, 0.12 mmol) was added and the mixture stirred for a further 2 h. The mixture was then diluted with ethyl acetate and 1M HCL (1 mL) was added. The ethyl acetate layer was washed with water, dried (Na2SO4), then evaporated to dryness. The residue was purified by chromatographed on silica gel, eluting with ethyl acetate, to yield the title compound as a pale yellow solid (58 mg, 36%). mp 175-177° C. Found: C, 61.18; H, 5.62; N, 3.97%. C17H19NO2S2 requires: C, 61.26; H, 5.70; N, 4.20%. 1HNMR (360 MHz, CDCl3)δ 1.08 (6H, s), 2.45 (2H, s), 2.93 (2H, s), 3.33 (2H, t, J=7.2 Hz), 3.98-4.02 (2H, m), 7.16-7.20 (1H, m), 7.46-7.49 (1H, m), 7.72-7.76 (1H, m), 8.64-8.66 (1H, m). MS (ES+) 334 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:21][C:18]2[CH:17]=[N:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)=[O:38])=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)cn2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2cnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cn2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7s) (350 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=7/1) to give Compound 11s (478 mg, 869 μmol, 74.8%) as a yellow foamy solid. Rf=0.19 (n-hexane/ethyl acetate=6/1); 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 6H), 0.19 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.66 (s, 2H), 6.75-6.82 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 7.17-7.24 (AA′BB′, 2H), 7.93-8.00 (AA′BB′, 2H), 8.90 (d, 1H, J=1.4 Hz), 9.28 (d, 1H, J=1.4 Hz), 10.99 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.8, 17.9, 25.46 (3C), 25.47 (3C), 41.8, 119.6 (2C), 120.2 (2C), 127.5 (2C), 128.2, 129.2, 130.4 (2C), 134.9, 138.7, 146.3, 147.0, 153.8, 156.2, 170.3; IR (KBr, cm−1) 417, 517, 575, 638, 681, 708, 781, 806, 839, 914, 1009, 1051, 1103, 1167, 1260, 1354, 1416, 1468, 1508, 1545, 1605, 1670, 2857, 2886, 2930, 2955, 3034, 3063; HRMS (ESI+) m/z 550.2930 ([M+H]+, C30H44N3O3Si2+ requires 550.2916).
Reaction SMILES: Br.[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1.[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].[NH4+].[NH4+]>CS(C)=O>[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2.[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: N=C(C1CC1)C1CC1
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of dicyclopropylmethanimine hydrobromide (0.200 g, 1.05 mmol) in 5.0 ml of dimethyl sulfoxide was added 0.139 g (1.05 mmol) of ammonium sulfate. The mixture was heated with stirring at 100° C. for 2 hours. The solvent was distilled out in vacuo and isobutyl alcohol was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.10 g (Yield: 62%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:10]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1Cl
Yield: 49.5 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(2-chloro-4-methylphenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.069 g; 0.166 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane furnished 0.033 g (44%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:8][OH:9]>F[B-](F)(F)F.C[N+](C)(C)C>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:8])=[O:2]
Reactant: CO
Reactant: O=CN1CCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCN1C=O
Yield: 86.7 %

Procedure:
In the same manner as indicated in Example 5 there are electrolyzed 17.7 g of N-formylpyrrolidine and 57.2 g of methanol in the presence of 0.29 g of tetramethylammonium tetrafluoroborate as conducting salt. In this case, however, the current is switched off after the throughput of already 2.0 Faraday per mol of N-formylpyrrolidine. The calculated mean cell voltage is 28.8 volts. Work-up of the electrolysis solution gives 20.0 g of 1-formyl-2-methoxypyrrolidine (boiling point 39°-40° C./0.1 mbar; nD25 = 1.4700), which corresponds to a product yield of 86.6% and a current efficiency of 86.6%.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]2[CH:26]3[CH2:27][CH2:28][CH:23]2[CH2:24][CH2:25]3)=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]3[CH:26]4[CH2:25][CH2:24][CH:23]3[CH2:28][CH2:27]4)=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC1C2CCC1CC2)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for ten minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole-2-yloxy)propane.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:24])(=[O:23])[CH2:18][CH2:19][C:20]([CH3:22])=O.Cl>C(OC(C)C)(C)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:20]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)([CH3:22])[CH2:19][CH2:18][C:17]([OH:24])=[O:23])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CC(CCC(=O)O)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 16.3 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (4.77 g, 20.0 mmol) in isopropyl ether (50 mL) was added levulinic acid (1.16 g, 10.0 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was heated under reflux over 10 days. The solvent was distilled off from the reaction mixture, and the resulting residue was purified by a flash column chromatography (filler: manufactured by Kanto Kagaku, K.K., 60Nmesh40-100, developing solvent:n-hexane/ethyl acetate (volume ratio)=5/1 to 2/1) to give 4,4-bis(3,5-di-t-butyl-4-hydroxyphenylthio)pentanoic acid (yield 935 mg and 16%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]1[CH:13]2[CH:9]([O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12]2)[CH:8]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[O:7]1.O.[OH-].[Li+].C(O)(=O)C>O1CCCC1>[CH2:35]([NH:34][C:32](=[O:33])[NH:31][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[C:28]=1[N:29]=[CH:30][N:22]2[CH:8]1[CH:9]2[O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]2[CH:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])[O:7]1)[CH3:36]
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CCC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CCC(=O)O)C2OC(C=Cc3ccccc3)OC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
3-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl}-propionic acid methyl ester (5.0 g, 10 mmol) was dissolved in tetrahydrofuran (300 mL). Water (100 mL) was added, followed by lithium hydroxide (1.0 g, 25 mmol). The solution was allowed to stir 16 h at room temperature. It was acidified to pH 5 with acetic acid, concentrated in vacuo, then extracted with chloroform (300 mL). The organic extract was evaporated, redissolved in ethyl acetate and precipitated with heptane to afford the final product (3.9 g, 80%). 1H-NMR (300 MHz, d6 DMSO) δ1.14 (t 3H, J=7 Hz), 1.90 (m, 2H), 2.19 (m, 2H), 3.26 (q, 2H, J=6 Hz), 4.17 (m, 1H), 4.93 (ψt, 1H, J=6 Hz), 5.43 (dd, 1H, J=3 Hz, 7 Hz), 5.84 (d 1H, J=6 Hz), 6.24 (d, 1H, J=3 Hz), 6.28 (dd, 1H, J=7 Hz, 13 Hz), 6.90 (d, 1H, J 16 Hz), 7.35 (m, 3H), 7.51 (d, 2H, J=7 Hz), 8.56 (s, 1H), 8.61 (s, 1H), 9.30 (t, 1H, J=6 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.CN(C=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3.000 g (16.65 mmol) of 4-acetoxybenzoic acid and 5 ml of thionyl chloride were mixed together and stirred for two hours at 50° C. after the addition of a drop of DMF. After thionyl chloride was removed by distillation under the reduced pressure, 5 ml of NMP was added in an ice bath. After stirring for 10 minutes in the ice bath after the addition of 1.784 g (16.65 mmol) of 2-aminotoluene, then the solution was poured into 400 ml of iced water. Precipitate formed was thoroughly washed to yield 3.634 g of 4-acetoxy-2′-methylbenzanilide shown in the structural formula 9 above in colorless solid (Yield: 81.04%).