Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[O:28][C:27]([Si](C(C)C)(C(C)C)C(C)C)=[N:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cnco2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
122 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(tri isopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine was dissolved in 1.2 ml of tetrahydrofuran, and 0.5 ml of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The reaction solution was stirred at room temperature for 20 min, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 60 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 45 mg of the objective compound as pale orange powder.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:21])[C:19]=2[OH:20])[CH2:16][CH2:15][O:14][C:13]23[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([O:30]C)=[O:29])[CH2:23][CH2:22]2)=[O:9])=[CH:4][CH:3]=1.N(C)C.CO>CN(C=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:21])[C:19]=2[OH:20])[CH2:16][CH2:15][O:14][C:13]23[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([OH:30])=[O:29])[CH2:23][CH2:22]2)=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)N1CCC2(CC1)OCCn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CNC
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)C(=O)N1CCC2(CC1)OCCn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 26.8 %

Procedure:
A solution of Example 28 (0.0147 g, 0.03 mmol) and 2M Me2NH/MeOH (0.10 mL, 0.2 mmol) in DMF (0.5 mL) was stirred at 80° C. in a sealed tube for 18 h and concentrated. The residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) and the resulting residue was triturated with hot MeOH to give the title compound as white solid (0.0037 g, 25%). 1H NMR (300 MHz, CDCl3) δ: 12.21 (1H, bs), 7.92 (1H, t, J=5.8 Hz), 7.29 (2H, dd, J=8.4, 5.5 Hz), 7.00 (2H, t, J=8.6 Hz), 4.63-4.49 (2H, m), 4.46-4.40 (1H, m), 4.19-4.14 (1H, m), 4.01 (4H, s), 3.44 (1H, td, J=13.3, 2.1 Hz), 3.02 (1H, td, J=13.3, 2.4 Hz), 2.25-2.09 (2H, m), 1.98-1.91 (2H, m). HRMS (M+H) calcd for C21H22FN4O7: 461.1473; found: 461.1533.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1.[CH3:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([S:59]([F:64])([F:63])([F:62])([F:61])[F:60])[CH:58]=1)[C:53](O)=[O:54])(=[O:49])=[O:48]>CN(C=O)C>[CH3:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([S:59]([F:64])([F:60])([F:61])([F:62])[F:63])[CH:58]=1)[C:53]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([CH3:25])=[C:27]([N:33]2[C:40]3[N:36]([N:37]=[C:38]([C:41]4[S:45][CH:44]=[N:43][CH:42]=4)[CH:39]=3)[CH:35]=[CH:34]2)[CH:28]=1)=[O:54])(=[O:49])=[O:48]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cncs3)cc12
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cncs3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
193 mg (0.51 mmol) of HATU and 62 mg (0.51 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added to a solution of 100 mg (0.34 mmol) of the compound of Example 89A and 122 mg (0.37 mmol) of the compound of Example 32A in 2 ml of DMF. The reaction was stirred at RT for 20 h. The reaction mixture was then purified directly by preparative HPLC (Method 16). This gave 86.4 mg (42% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O.NN>CCO>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 112.1 %

Procedure:
A mixture of 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (640 mg, 1.36 mmol) and hydrazine monohydrate (0.073 ml, 1.5 mmol) in EtOH (6 ml) was stirred for 1 hour. The precipitated materials were filtered off and washed with EtOH (2 ml×2), then the filtrate was evaporated under reduced pressure to give O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (519 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[Na+].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH:14]1([NH:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC[C@H](N)C(=O)OC
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC1CCCC1)C(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
Methyl (2S)-2-aminobutanoate 41b (18.74 g, 0.12 mol) was dissolved in 280 mL of dichloromethane. The reaction solution was cooled down to 0° C. in an ice-water bath followed by the addition of sodium acetate (5 g, 0.061 mol), cyclopentanone (10.78 g, 0.13 mol) and sodium triacetoxyborohydride (31 g, 0.16 mol) successively. The reaction solution was heated to room temperature and stirred for 4 hours. The reaction solution was poured into 150 mL of water, added dropwise with saturated sodium carbonate solution to adjust pH to 11 to 12 and seperated. The aqueous phase was extracted with dichloromethane (150 mL×2). The combined organic phase was washed with saturated brine (100 mL×2), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound methyl (2S)-2-(cyclopentylamino)butanoate 4k (17.42 g, yield: 77.1%) as a light yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:19][N:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2cn[nH]c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of tert-butyl 4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (700 mg, 3.14 mmol) in DMF (5 mL) was added NaH (251 mg, 6.28 mmol) at 0° C. and then MeI (669, 4.71 mmol). The mixture was then stirred at 25° C. for 4 hours after which the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to yield a residue which was used directly in the next step. 1H NMR (400 MHz, MeOD): δ 7.16 (s, 1H), 3.77 (s, 2H), 3.66 (s, 3H), 3.06 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3ccco3)nnc(Cl)c2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cc3ccco3)nnc(N3CCCC3)c2c1
Temperature: 60 °C
Yield: 74.6 %

Procedure:
A solution of 4-chloro-1-furan-2-ylmethyl-6-methoxy-phthalazine (500 mg, 1.82 mmoles), prepared as described in example 127, in DMF (10 ml) was added under stirring with pyrrolidine (0.91 ml, 10.92 mmoles), and heated at 60° C. overnight. The mixture was diluted with ethyl acetate, washed three times with water, anhydrified over Na2SO4 and dried. The residue was crystallised from ethyl ether/petrolatum 1:1 (10 ml) to give 420 mg of the title compound (yield: 75%). m.p.: 148-149° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)cccc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=410.0.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[Cl:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:18][C:19]1[C:24]([C:2]2[NH:6][CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.67 g), (2-chloropyridin-3-yl)boronic acid (2.00 g), sodium hydrogen carbonate (2.15 g) and tetrakis(triphenylphosphine)palladium (738 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (40 mL) and water (10 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1). The obtained pale-yellow oil was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), 8 mol/L aqueous sodium hydroxide solution (15 mL) was added dropwise at room temperature and the mixture was stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as brown crystals (yield 578 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[N+](=[CH2:28])=[N-]>CCOCC>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH3:28])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The acid from Step 1 (0.84 g) was dissolved in 10 mL of Et2O and a solution of diazomethane in Et2O was added portionwise until all the acid had been consumed. Excess diazomethane was removed by addition of 1 mL HOAc, the solvent was then removed and the residue chromatographed (hexane/EtOAc 4:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]2(OCC[O:8]2)[CH2:4][C:3]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])S(C1C=CC=CC=1)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[C:3]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]
Reactant: CC1(C)CCC2(CC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(=O)C=C1CCCCCCCCCCO
Yield: 78 %

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 400 mg of 4,4-dimethyl-1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-3-(phenylsulfonyl)-cyclohexane in 30 ml of chloroform and 6 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture, were added 10 ml of a saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 4,4-dimethyl-3-(10-hydroxydecyl)-2-cyclohexen-1-one was obtained in the form of a colorless oil. Yield: 78%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:23]1[CH2:24][CH2:25][C:20]([F:27])([F:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CCC(F)(F)CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(F)(F)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4,4-difluoro-cyclohexylamine following general procedure B to afford 4-(4,4-difluoro-cyclohexylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (192 mg). Thus obtained amino-ester (92 mg, 0.25 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 3-(3-chloro-phenyl)-1-(4,4-difluoro-cyclohexyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (69 mg). LCMS: m/z 472 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.24 (m, 1H), 7.06-7.14 (m, 2H), 6.48 (m, 1H), 5.09 (m, 1H), 4.08 (s, 3H), 2.84 (m, 2H), 2.23 (m, 2H), 1.80-2.00 (m, 4H) ppm.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].N(N([C:22]1C=CC=C[CH:23]=1)O)=O.[Al].[C:29]([OH:33])(=[O:32])[CH:30]=[CH2:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(O)(=O)=O>C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:29]([OH:33])(=[O:32])[CH:30]=[CH2:31].[C:29]([OH:33])(=[O:32])[CH:30]=[CH2:31].[CH2:22]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH3:2])[CH3:23]
Reactant: O=NN(O)c1ccccc1
Reactant: OCCOc1ccccc1-c1ccccc1O
Agent: [Mn+2]
Agent: C=CC(=O)O
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOc1ccccc1-c1ccccc1OCC
Reaction time: 2.5 h

Procedure:
To a 2000 ml 3 neck round bottom equipped with an overhead stirrer, dean stark trap and temperature probe was added 2,2′-dihydroxyethoxy-biphenyl (368 g, 1.34 mole, 1.0 eq.), toluene (700 g), Prostab 5198 (0.023 g), aluminum N-nitrosophenylhydroxylamine (NPAL) (0.059 g), manganese acetate (0.023 g), acrylic acid (212.7 g, 2.95 mole, 2.2 eq), p-toluene sulfonic acid (pTSA, 23.1 g, 0.13 mole, 0.1 eq.) and heated to reflux. After 2.5 hours the reaction stalled with ˜45/45 product/intermediate and 10% starting material. The reaction was treated with acrylic acid (26 g) and pTSA (5 g) and continued refluxing. No additional conversion to product was observed. Acrylic acid (50 g) and methane sulfonic acid (5 g) were added. The Dean stark trap continued to collect water. Upon running the reaction overnight the product was ˜75% product and 7% mono acrylate. The reaction was washed 3 times with sodium chloride brine (200 ml), 3 times with brine with some 1N NaOH (200 ml), 3 times with sat. sodium carbonate (200 ml), dried over MgSO4 (5 g), filtered and concentrated in vacuo to recover the product. The product (500 g) was purified by series of 3 columns eluting with 50% hexane/chloroform to recover 220 g product at 92% purity (GC) and 3 other fractions of lesser purity. The refractive index of the (i.e. uncured) monomer was determined to be 1.559.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:6]([F:10])([F:9])[CH2:7][CH3:8])=[CH:4][F:5].S(=O)(=O)(O)[OH:14]>O>[F:5][CH2:4][C:3]([OH:14])([C:6]([F:9])([F:10])[CH2:7][CH3:8])[C:2]([F:11])([F:12])[F:1]
Reactant: CCC(F)(F)C(=CF)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCC(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol may be prepared by fluorinating 3-pentanone to form 3,3-difluoropentane which may then be dehydrogenated to form 3,3-difluoro-1-pentene. CF3 may then be reacted with the 3,3-difluoro-1-pentene to form 2-trifluoromethyl-1,3,3-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-pentene. The 2-trifluoromethyl-1,3,3-trifluoro-1-pentene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][C:11]([C:26](=[O:51])[NH:27][CH:28]([C:37](=[O:50])[N:38]([CH2:42][CH:43](OCC)OCC)[CH:39]([CH3:41])[CH3:40])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([CH3:25])[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([O:8][C:9](=[O:52])[NH:10][C:11]1([CH3:25])[C:26](=[O:51])[N:27]2[CH:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:37](=[O:50])[N:38]([CH:39]([CH3:40])[CH3:41])[CH2:42][CH:43]2[N:13]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])(=[O:16])=[O:15])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(C)(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Solvent: O=CO
Product: CC(C)N1CC2N(C(=O)C(C)(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Yield: 42.4 %

Procedure:
A solution of 80 mg (0.1 mmol) of benzyl[1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)-1-methylethyl]carbamate in 1.5 ml of HCOOH (99%) is stirred at 60° C. for 24 h. The reaction solution is concentrated in vacuo, and the crude product is purified by chromatography (4 g of SiO2, eluent EtOAc/heptane (gradient 0-50%)). 30 mg of the desired product are obtained as a white solid. MW (calculated, monoisotopic)=706, measured value: (M+H)+=707
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)Cl>[Br:17][C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(N)n1
Solvent: ClC(Cl)Cl
Product: CCc1nc(N)ccc1Br
Reaction time: 0.75 h
Yield: 68.3 %

Procedure:
A 0° C. solution of 6-ethylpyridin-2-amine (3.37 g, 27.6 mmol) in CHCl3 (30 mL) was treated portion-wise with NBS (4.91 g, 27.6 mmol) over 30 min, stirred for 45 min, then concentrated to dryness. The residue was treated with EtOAc (8 mL), filtered to remove solids and purified via silica gel chromatography (EtOAc/Hex) to afford 5-bromo-6-ethylpyridin-2-amine (3.79 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 7.43 (d, J=8.6 Hz, 1 H), 6.21 (d, J=8.7 Hz, 1 H), 6.03 (s, 2 H), 2.61 (q, J=7.5 Hz, 2 H), 1.11 (t, J=7.5 Hz, 3 H);
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C@@H:11]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C@@H:12]([OH:25])[CH2:13][C:14]1([CH3:24])[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][CH2:16][S:15]1(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH:27]1([CH2:26][C@H:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C@@H:12]([OH:25])[CH2:13][C:14]2([CH3:24])[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][CH2:16][S:15]2(=[O:22])=[O:23])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC1(C[C@H](O)[C@@H](N)CC2CCCCC2)S(=O)(=O)CCCS1(=O)=O
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C[C@H](O)[C@H](CC2CCCCC2)NC(=O)Nc2ccccc2)S(=O)(=O)CCCS1(=O)=O
Reaction time: 5 h

Procedure:
A mixture of 1.19 g of phenyl isocyanate, 3.67 g of 2-[(2S,3S)-3-amino-4-cyclohexyl-2-hydroxybutyl ]-2-methyl- 1,3-dithiane 1,1,3,3-tetroxide, 1.01 g of triethylamine and 60 ml of dichloromethane is stirred at 20° for 5 h. The usual working up gives 2-[(2S,3S)-4-cyclohexyl-2-hydroxy-3-(N'-phenylureido)-butyl]-2-methyl-1,3-dithiane 1,1,3,3-tetroxide, m.p 238°-240°, FAB 487.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[NH2:2].[CH:13]([O-])=[O:14].[Na+].C(OCC)=O.C(O)=O>C(O)C>[CH:13]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)=[O:14]
Reactant: O=C[O-]
Reactant: NNc1ccc(CC(=O)O)cc1
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Solvent: O=CO
Product: O=CNNc1ccc(CC(=O)O)cc1
Yield: 56.7 %

Procedure:
p-Hydrazinophenylacetic acid (3.32 g, 0.02 M), sodium formate (2.72 g, 0.04 m), ethyl formate (49 g), formic acid (10 ml) was refluxed for one hour in ethanol (100 ml). The residue was removed by filtration and the filtrate on concentration afforded light-yellow crystals (2.2 g, 55 percent).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]O)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][S:33]([CH3:32])(=[O:35])=[O:34])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 100 mL round bottom flask containing 50 mL dichloromethane at 0° C. was placed 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (4.62 g, 13.26 mmol). To this solution was added triethylamine (2.77 mL, 19.90 mmol) followed by dropwise addition of methanesulfonyl chloride (1.23 mL, 15.9 mmol). The reaction was then warmed to room temperature and stirred for 3 hours at which time the reaction was diluted with 100 mL dichloromethane. The organic layer was then washed two times each with 50 mL of water, 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield 4.45 g of crude title compound as a white solid which was used directly in Preparation 2. (79%).