Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.Cl.[CH3:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([NH2:14])[CH2:10]2.[CH:15]([C:17]1[C:25]2[C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]([CH3:30])[N:18]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:30][N:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[C:25]=2[C:17]([CH2:15][NH:14][CH:9]2[CH2:8][CH:7]3[N:6]([CH3:5])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:18]1
Reactant: COC(=O)c1cccc2c1c(C=O)nn2C
Reactant: CN1C2CCC1CC(N)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1c(CNC1CC3CCC(C1)N3C)nn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (60%) (0.19 g) was added in portions to a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride and stirred at ambient temperature for 1 h. To the reaction mixture, methyl 3-formyl-1-methyl-1H-indazole-4-carboxylate (0.41 g, 1.9 mmol) from Step A of Example 6 in 1% acetic acid in dichloromethane (50 mL) was added and stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (1.2 g, 5.6 mmol) was added, and the resulting suspension was stirred for 16 h at ambient temperature. The solvent was removed under reduced pressure, and the crude material purified by column chromatography (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford methyl 1-methyl-3-((8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)methyl)-1H-indazole-4-carboxylate (0.54 g, 100%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=7.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38 (t, J=6.0 Hz, 1H), 5.49 (s, 1H), 4.26 (s, 2H), 4.04 (s, 3H), 3.96 (s, 3H), 2.99-2.89 (m, 1H), 2.45 (s, 3H), 2.10-1.85 (m, 6H), 1.74-1.62 (m, 4H); LC/MS (ESI+) m/z 343 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(F)c2)nc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)nc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of 2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-5-(methylsulfonyl)pyridine (0.166 g, 0.46 mmol) in CH2Cl2 (20 mL) was cooled to −78° C. BBr3 (0.18 mL, 1.86 mmol) was added dropwise. The reaction mixture was stirred at −78° C. to 0° C. for 2 h, poured into ice and aqueous NaHCO3 and extracted with EtOAc (60 mL×2). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a solid, which was triturated with hot hexanes containing 1% of CH2Cl2 and 1% of MeOH to give 0.115 g (93%) of 2-fluoro-4-[5-(methylsulfonyl)-2-pyridinyl]phenol as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 9.05 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, Ja=8.4 Hz, Jb=2.4 Hz), 8.03 (d, 1H, J=8.3 Hz), 7.92 (dd, 1H, Ja=12.6 Hz, Jb=2.2 Hz), 7.85-7.75 (m, 1H), 7.03 (t, 1H, J=8.6 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 268 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[C:6]1([CH:12]2[CH2:17][CH2:16][C:15]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C1=C(N2CCCC2)CCC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
36.8 g (0.517 mole) of pyrrolidine dissolved in 170 ml of n-hexane were added dropwise to 30.0 g (0.172 mole) of 4-phenylcyclohexanone dissolved in 860 ml of n-hexane, and the solution was cooled to 0° C. in an ice bath. 18.0 g (0.095 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane were added dropwise within one hour at 0° C.-10° C., stirred for a further two hours at RT, following which the suspension was filtered. The filtrate was concentrated by evaporation on a rotary evaporator (500 to 10 mbar), and the remaining oil was purified by distillation at a pressure of less than 1 mbar; the main fraction boiled at 135° C. 22.2 of crude product were obtained, which on account of incomplete conversion underwent, in the cold, the addition of 27.2 g (0.379 mole) of pyyrolidine dissolved in 125 ml of n-hexane and 13.1 g (0.069 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane, and the mixture was then heated under reflux for two hours. 20.2 g of 1-(4-phenylcyclohex-1-enyl)pyrrolidine (51.7% of theory) were obtained in this way.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:12])(=[O:11])[CH3:10]>>[C:3]1([CH:2]2[O:12][C:9](=[O:11])[CH2:10][CH2:1]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CC(=O)O
Product: O=C1CCC(c2ccccc2)O1
Temperature: 110 °C
Yield: 70 %

Procedure:
Styrene in the amount of 20 grams was dissolved in 100 milliliters of acetic acid containing 10% potassium acetate. Ceric acetate in the amount of 0.005 mole was added and the reaction mixture was heated in a sealed tube at 110° C. overnight. The lactone, gamma-phenyl butyrolactone, was obtained in 70% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[N:8][C:7]=1[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:5])C.[Na].[OH-].Cl>C1COCC1.CO>[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:13])=[N:8][C:7]=1[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: Cl
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)O)s1)c1ccncc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Compound 24 (840 mg, 2.45 mmol) was dissolved in THF (5 mL) and methanol (5 mL), and a 4 mol/L aqueous sodium of hydroxide solution (3 mL) was added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was allowed to cool down, and neutralized with 2 mol/L hydrochloric acid added thereto. The precipitated solid was collected by filtration to afford the entitled Compound 95 (411 mg, 53%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC[C@H](O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-((S)-3-hydroxypyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (390 mg, 1.61 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (244 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.40-4.33 (m, 1 H); 3.70-3.60 (m, 4 H); 3.44-3.34 (m, 1 H); 2.88-2.77 (m, 1 H); 2.73-2.52 (m, 3 H); 2.47 (dd, J=10.1, 5.2 Hz, 1 H); 2.30-2.12 (m, 2 H); 1.84-1.69 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:15](=[O:26])[N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:44][O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:23])[NH:63][C@H:47]([C:46]([O:45][CH3:44])=[O:64])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:15](=[O:26])[N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CN1C(=O)[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Yield: 72.5 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (2.9 g) was coupled to (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (1.5 g) following general procedure A to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (3.0 g). LC-MS (m/z) 878.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][CH:15]=[CH2:16])([CH3:13])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C>C1C=CC=CC=1>[CH2:14]([C:4]1([CH3:13])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:18])[CH:12]=[C:3]1[O:2][CH3:1])[CH:15]=[CH2:16]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: C=CCC1(C)C(OC)=CCc2ccccc21
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: C=CCC1(C)C(OC)=CC(=O)c2ccccc21
Yield: 24.9 %

Procedure:
To a solution of Example 123B (7.72 g, 36.1 mmol) in benzene (400 mL) was added celite (15 g), pyridinium dichromate (54.3 g, 144.3 mmol) and tert-butylhydroperoxide (70% in water) (19.9 mL, 144.3 mmol). The resultant solution was stirred at room temperature for 1.25 hours, followed by filtering the solution through a plug of celite (20 g) which was rinsed with benzene (100 mL). The combined filtrate was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with a mixture of 20% ethyl acetate in hexane followed by 50% ethyl acetate in hexane to provide the title compound as a light yellow oil (2.05 g, 25%). 1H NMR (300 MHz, DMSO-d6): δ 1.53 (s, 3H), 2.77 (m, 2H), 3.82 (s, 3H), 4.75 (m, 2H), 5.02 (m, 1H), 5.84 (s, 1H), 7.42 (m, 1H), 7.65 (dt, J=8.1, 1.5 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.96 (dd, J=7.7, 1.5 Hz, 1H).
Reaction SMILES: C(OC([N:8]([C:12]1[S:13][CH2:14][C@@H:15]2[C@@H:20]([CH3:21])[O:19][CH2:18][C@:16]2([C:22]2[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:23]=2[F:29])[N:17]=1)C([O-])=O)=O)(C)(C)C.O.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(O)=O.[Na+].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[F:29][C:23]1[CH:24]=[CH:25][C:26]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:34]=2)=[CH:27][C:22]=1[C@:16]12[CH2:18][O:19][C@H:20]([CH3:21])[C@H:15]1[CH2:14][S:13][C:12]([NH2:8])=[N:17]2
Reactant: C[C@H]1OC[C@]2(c3cc(Br)ccc3F)N=C(N(C(=O)[O-])C(=O)OC(C)(C)C)SC[C@H]12
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: C[C@H]1OC[C@]2(c3cc(-c4cncc(C(F)(F)F)c4)ccc3F)N=C(N)SC[C@H]12
Temperature: 100 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
tert-Butyl[(4aS,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]imidodicarbonate (0.15 g, 0.34 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL). The resulting solution was heated to 100° C. and to it was added [5-(trifluoromethyl)pyridin-3-yl]boronic acid (0.32 g, 1.68 mmol), cesium carbonate (0.659 g, 2.02 mmol) and dichloropalladium-triphenylphosphane (0.047 g, 0.067 mmol) and the reaction was stirred at 100° C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 0-60% EtOAc in hexane). The purified product was dissolved in DCM (2 mL) and trifluoroacetic acid (2 L). After 1 hour, the solvents were removed in vacuo. The residue was neutralised with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic layers were dried (MgSO4), filtered and concentrated to give the title compound (35 mg, colourless solid).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1>C(O)C.Cl>[O:23]=[C:15]1[C:12]2([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C(c1ccccc1)N1CCC2(CC1)Cc1ccccc1C2=O
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2CC12CCNCC2
Yield: 77.4 %

Procedure:
A solution of 3.66 g (12.0 mmoles) 1'-benzoyl-1,3-dihydro-1-oxospiro-[2H-indene-2,4'-piperidine] in 90 ml ethanol and 30 ml 6N hydrochloric acid was heated at reflux for 42 hours. An additional 10 ml 6N hydrochloric acid was added and the solution was heated at reflux for 6 hours. The cooled solution was concentrated in vacuo to remove ethanol and the resulting aqueous solution was washed with 2×20 ml ethyl acetate. The aqueous layer was made basic with 10N sodium hydroxide and extracted with 3×75 ml ethyl acetate. The extract was washed with 20 ml water and brine, dried, and the solvent was removed in vacuo to give 1.87 g (77%) product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 36.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.8 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.6 g, 22.8 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.2 (M+). Found: 291.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NC(CO)CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=S(=O)(NC(CO)CO)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
After triethylamine (10.12 g, 100 mmol) was added dropwise to a solution of serinol (3.64 g, 40 mmol) in a mixture of dioxane (100 ml) and water (200 ml), the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 4-phenoxybenzenesulfonyl chloride (10.75 g, 40 mmol) in dioxane (100 ml) was added dropwise and this was stirred for 3 hours. Most of the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (10.62 g, yield 82%) as a white powder.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH:13][CH2:14]C(CO)O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.C1(=O)OCCC1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[C:14]([O:11][C:1](=[O:12])[C:2]=2[CH:10]=1)=[O:13]
Reactant: OCC(O)CO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Ti+4]
Agent: CC(=O)[O-]
Agent: CCCC[O-]
Solvent: O=C1CCCO1
Product: O=C(O)c1ccc2c(c1)C(=O)OC2=O

Procedure:
275 g of a polyester of 1.0 mol of terephthalic acid, 0.38 mol of glycerol and 0.72 mol of glycol having a hydroxyl group content of about 6.0% by weight and catalytic quantities of lead acetate and butyl titanate at 150° C. After a final condensation for from 4 to 6 hours at from 200° to 220° C., 2724 g of a clear, pale reddish brown, brittle, solid resin having a resin content of 90.3% (according to DIN) and a viscosity of 22 070 mPa s as determined in a 50% solution of γ-butyrolactone at 20° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:12]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]([F:9])([F:10])[F:11])([O-:14])=[O:13]
Reactant: Cc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 15 °C

Procedure:
2 gms of 3-methyl benzotrifluoride is dissolved in 5 mls of methylene chloride and added dropwise with stirring at -20° C. to -25° C. to 6 gms of 98% HNO3 dissolved in 10 ml methylene chloride. After addition, the reaction was allowed to finish by warming the mixture to 15° C. After treatment with ice and water followed by sodium bicarbonate wash, near quantitative yield was recovered. Isomer distribution was as follows:
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])([O-])=O.[Na+].[Na+].[OH:40][C:41]([CH3:75])([CH3:74])[CH2:42][O:43][N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH:47]([O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][C:45]1([CH3:73])[CH3:72]>C(O)(C)(C)C>[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:75][C:41]([CH3:74])([OH:40])[CH2:42][O:43][N:44]2[C:49]([CH3:50])([CH3:51])[CH2:48][CH:47]([O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][C:45]2([CH3:73])[CH3:72])[C:25]([CH3:32])([CH3:33])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(O)CON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 4-octadecanoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated to obtain a mixture which includes 1-(2-hydroxy-2-methylpropoxy)-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine and the title compound. The title compound is separated from the mixture by high pressure liquid chromatography.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]3[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[C:10]2=[O:26])=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+]>ClCCl.C(=O)=O.CC(C)=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]3[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=3[O:12][C:11]([CH3:24])([CH3:25])[C:10]2=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)C(C)(C)Oc3cc(NS(C)(=O)=O)ccc32)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(O)cc2)C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 90.9 %

Procedure:
To a solution of N-[4-(4-methoxyphenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 14, 40 mg) in dichloromethane (5 mL) was added dropwise boron tribromide-dichloromethane solution (1.0 M, 0.32 mL) under cooling in dry ice-acetone bath. The reaction mixture was stirred at room temperature for 5.5 hours, and thereto was added an aqueous saturated sodium hydrogencarbonate solution. The mixture was extracted with chloroform and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=4/1→3/7) to give N-[4-(4-hydroxyphenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (35 mg) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)=[O:4].[Li+].[OH-].O>O1CCOCC1>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(2-oxopyrrolidin-1-yl)-biphenyl-3-carboxylic acid methyl ester (D10) (23 mg, 0.078 mmol) in dioxane (2 ml) was added LiOH (5 mg, 0.117 mmol) and water (1 ml) and stirred at room temperature for 2 hours. The solvent was then evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH=1. The product precipitated in the aqueous layer and was removed by filtration and dried in vacuo to afford D11 (10 mg) as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CCCC[Sn]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(CCCC)CCCC>C1COCC1.CN(C=O)C>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][N:30]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9.1 mmol) and 2-(1,1,1-tributylstannyl)pyridine (3.36 g, 9.11 mmol) in THF (80 mL) and DMF (10 mL) was degassed with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (200 mg, 3 mol %) was added, and the mixture was heated at reflux for 24 h. More 2-bromo-1-fluoro-4-nitrobenzene (0.60 g, 2.7 mmol) and catalyst (100 mg, 1.5 mol %) were added, and the mixture was heated as before for another 24 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 50% dichloromethane in isohexane, then 100% dichloromethane, then 100% ethyl acetate (UV detection). 2-(2-Fluoro-5-nitrophenyl)pyridine was isolated as a colourless solid (2.11 g, 100%). δH (400 MHz, CDCl3) 7.30-7.37 (2H, m), 7.80-7.87 (2H, m), 8.27 (1H, m), 8.78 (1H, m), 9.01 (1H, dd, J 3.1, 6.7); MS (ES+) m/z 219 [M+H]+.