Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccnc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
The mixture of 2-[(quinoline-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (49) (220 mg, 0.61 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (50) as a pale yellow solid (98 mg, 48%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:16].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:15]#[N:16])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ccc(CC#N)cc2)s1
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
5-Bromo-thiophene-2-sulfonic acid tert.-butylamide (0.6 g) was suspended in toluene (5 mL) under an Ar-atmosphere. To the suspension (4-cyanomethylphenyl)boronic acid (486 mg), Na2CO3 (533 mg), water (2.5 ml) and EtOH (2.5 mL) was added. To this suspension 2′-(dimethylamino)-2-biphenyl-palladium (II) chloride dinorbornylphosphine complex (23 mg) was added and the mixture was stirred for 18 h at 80° C. After that the suspension was cooled to 25° C., evaporated to ⅓ of the original volume and treated with EtOAc (30 mL). The organic layer was washed with aqueous HCl (1N, 10 mL) and brine. The organic layer was dried over Na2SO4, filtrated and evaporated to dryness. The crude material was purified by flash chromatography (eluent CH2Cl2, 2N NH3 in methanol) to yield 5-(4-cyanomethyl-phenyl)-thiophene-2-sulfonic acid tert-butylamide (268 mg, 40%) as a light yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[ClH:27].[CH2:28](O)[CH3:29]>>[ClH:27].[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:28][CH3:29])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CCCNCCCO)Cc1c2ccccc2cc2ccccc12
Reactant: CCO
Agent: Cl
Product: CCOCCCNCCCN(CC)Cc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A solution of compound 18 (200 mg, 0.57 mmole) was dissolved in absolute ethanol (13 mL) and stirred at 0° C. for 10 minutes. A 4N HCl solution (22 mL) was added to the reaction mixture dropwise and stirred at 0° C. for 20 minutes and then at room temperature overnight. The solution was concentrated in vacuo to give 20 as a yellow solid in 95% yield. 1H NMR (D2O) δ 8.50 (s, 1H), 8.06 (m, 4H), 7.73 (m, 2H), 7.62 (m, 2H), 4.98 (s, 2H), 3.64 (t, 2H), 3.39 (q, 2H), 3.13 (t, 2H), 2.90 (t, 2H), 2.76 (t, 2H), 1.79 (q, 2H), 1.44 (m, 5H); 13C NMR (D2O): δ 133.8, 133.4, 132.4, 130.8, 128.3, 125.1, 121.8, 61.4, 52.4, 52.1, 52.0, 48.0, 47.0, 30.5, 23.4, 11.3. HRMS (FAB) calcd for C23H3ON2O.2HCl (M+H−2HCl)+ 351.2431, Found 351.2428.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].FC1C=CC2[N:27]3[CH2:44][CH2:43][C:42]4[C:28]3=[C:29]([CH:39]=[CH:40][CH:41]=4)[C:30](N3CCN(C)CC3)=NC=2C=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1.[NH2:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[N:27]1[C:28]2[C:29](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:30][CH2:43][CH2:44]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Product: Cc1ccc(N2CCCc3ccccc32)c(N)c1
Product: Cc1ccc(N2CCCc3ccccc32)c([N+](=O)[O-])c1

Procedure:
Starting with 1,2,3,4-tetrahydroquinoline and 2-fluoro-5-methylnitrobenzene and following the steps of 1a to 1f of Example 2, one may obtain, in sequence, 1-(4-methyl-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline, 1-(2-amino-4-methylphenyl)-1,2,3,4-tetrahydroquinoline, N-[2-{1-(5-methylphenyl)-1,2,3,4 -tetrahydroquinolin-1-yl}]-4-methyl-1-piperazine carboxamide, and 10-methyl-7-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-quino-[1,8-ab][15]benzodiazepine.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[OH:28][C:29]1[CH:46]=[CH:45][C:44]2[C@:43]3([CH:47]=O)[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[CH2:38][C@H:37]([OH:49])[CH2:36]4)[CH2:33][CH2:32][C:31]=2[CH:30]=1.CS(C)=O.O>C(OCC)(=O)C>[CH:47]([C@:43]12[CH2:42][CH2:41][C@@:39]3([CH3:40])[C@@H:35]([CH2:36][C@@H:37]([OH:49])[CH2:38]3)[C@@H:34]1[CH2:33][CH2:32][C:31]1[CH:30]=[C:29]([OH:28])[CH:46]=[CH:45][C:44]2=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12

Procedure:
8.68 g (20 mmol) of pentyltriphenyl-phosphonium bromide+sodium amide (1 g contains 2.3 mmol of pentyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 ml DMSO are introduced into a reaction flask that was rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at 60° C. After the reaction is completed, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing of the organic phase with water and concentration by evaporation until a dry state is reached.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:33])/[CH:19]=[C:20](\[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)/[C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=1[CH3:34]>O1CCCC1>[CH2:1]([S:8][C:20]([C:25]1[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1)([C:21]([F:22])([F:23])[F:24])[CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[C:13]([CH3:34])[CH:14]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(SCc2ccccc2)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 43 %

Procedure:
Benzylmercaptan (0.18 g) and a solution of sodium hydroxide (0.1 eq) were added to a solution of (E)-1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (0.5 g) in tetrahydrofurane (11.4 mL). The solution was stirred at room temperature for 19 hours then heated at 80° C. for 4 hours. Then, more benzylmercaptan (0.5 mL) was added and the solution was stirred at 80° C. for 16 hours. More sodium hydroxide (20 mg) was added and after 90 minutes, the reaction was quenched by the addition of a saturated solution of sodium chloride, and then extracted with diethyl ether. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 3-Benzylsulfanyl-1-(4-bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butan-1-one (276 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14]C(OC)OC.[CH3:20]O>CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:20][O:12][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([O:14][CH3:13])[CH3:11]
Reactant: CO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(C)(OC)c1ccc([N+](=O)[O-])cc1
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of 1-(4-nitrophenyl)ethanone (5 g, 30 mmol) in MeOH was added trimethoxymethane (3.2 g, 30 mmol) followed by 4-methylbenzenesulfonic acid (29 mg, 0.15 mmol). The mixture was stirred for 72 h and quenched by adding solid Na2CO3 (16 mg, 0.15 mmol). Stirring was continued for 30 min and the mixture was filtered through a neutral alumina pad. The filtrate was concentrated and the crude product was re-crystallized with MeOH to afford the title compound as a white solid (6.4 g, 100%). MS (ESI) m/z [M+H]+212.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1.O>CO.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1
Reactant: Brc1cnc(C#CCCn2ccnn2)cn1
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: Brc1cnc(CCCCn2ccnn2)cn1

Procedure:
2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine (2.50 g, 9.0 mmol) is dissolved in methanol (700 ml) and hydrogenated for 2 h at r.t. in the presence of platinum(IV) oxide ×H2O (0.840 g, 3.40 mmol). The reaction mixture is filtered and concentrated in vacuo to yield 2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine as a colorless solid. Yield 1.63 g (64%)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)[C:16](O)=[O:17])=[CH:11][CH:10]=1.[F:34][C:35]([F:51])([F:50])[C:36]1[CH:37]=[C:38]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:27]1([NH:26][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[C:16]([NH:49][S:46]([C:38]3[CH:37]=[C:36]([C:35]([F:51])([F:50])[F:34])[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=3)(=[O:47])=[O:48])=[O:17])[CH2:24][CH2:23]2)=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(NC1CCCCC1)C1CCN(C(C(=O)O)c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCCCC1)C1CCN(C(C(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
140 mg of triethylamine and 0.32 ml of 50% propylphosphonic acid anhydride (solution in DMF) are added to a solution of 150 mg of (4-chlorophenyl)-(4-cyclohexylcarbamoyl-piperidin1-yl)-acetic acid, 174 mg of 3,5-bis(trifluoromethyl)-benzenesulfonamide and 24 mg of DMAP in 6 ml of anhydrous DMF at 10°. The mixture obtained is stirred for ca. 60 hours at RT, solvent is evaporated off and the evaporation residue obtained is treated with EtAc and H2O. Two phases obtained are separated and the organic layer obtained is washed, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel. 1-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-(4-chloro-phenyl)-ethyl]-piperidine-4-carboxylic acid cyclohexylamide is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:11]=2)=[C:6]([F:23])[CH:5]=[CH:4][C:3]=1[OH:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC(C)=O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:11]=2)=[C:6]([F:23])[CH:5]=[CH:4][C:3]=1[O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)phenyl]methylamino]phenol (250 mg, 0.76 mmol, 1.0 eq) in acetone (3 mL) was added Cs2CO3 (297 mg, 0.912 mmol, 1.2 eq). The resulting mixture was stirred for 40 min at room temperature then ethyl bromoacetate (139.4 mg, 0.84 mmol, 1.1 eq) was added. The resulting mixture was stirred overnight then partitioned against water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 1:0 to 20:1) to give the title compound as an oil (270 mg, 86%).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO.O.C(O)(=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:32])=[O:3])[CH:21]=1
Reactant: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cncc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)c1
Yield: 88.6 %

Procedure:
5-{2-[5-Chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic acid ethyl ester (90 mg) was hydrolysed in methanol (3 mL) and 2N sodium hydroxide (2 mL) at 60° C. with stirring for 2 hrs. The reaction mixture was then reduced down to ˜1 mL, diluted with water (10 mL) and treated with a few drops of glacial acetic acid to make the solution ˜pH5. The product was then extracted twice with dichloromethane (10 mL) dried (magnesium sulphate), and evaporated to give the title compound (75 mg).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:34][O:35]C(C)=O)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:33])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([O:29]C(C)=O)[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C1(C)C=CC=CC=1.[OH-].[K+]>C(O)C>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:34][OH:35])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:33])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 66.6 %

Procedure:
In a glass duplicated reactor, equipped with a shaft stirrer, reflux condenser, inlet tube and blow valve, 2.00 kg of betulin diacetate of example 5 was dissolved under stirring in the mixture of 10 l of toluene and 8 l of ethanol containing 700 g of potassium hydroxide. The reaction mixture was refluxed for 2 hours, then under heating filtered through a PP cloth and the filtrate was inoculated with pure betulin crystals. After cooling down, the crystallized betulin was filtered off on a processing filter, washed with 3 l of ethanol, 3 l of 50% ethanol and 30 l of boiling water and finally 5 l of boiling distilled water. The crystalline betulin was dried in a hot-air oven at the temperature of 70-75° C. for the period of 48 h. 1.12 kg (66%) of betulin in the form of fine crystalline power was obtained, having the m.p. 256-258° C., [α]D+16 (10% v/v CH3OH in CHCl3; 0.35 g/100 ml), which has the HPLC purity of 98.9-99.1%. 1H NMR spectrum of the obtained betulin measured in CDCl3 with the addition of 10% v/v CD3OD is as follows: 0.76 s, 0.83 s, 0.97 s, 0.98 s, 1.02 s, 1.68 s, 6×3H (6×CH3); 2.39 ddd, 1H (J′=10.98, J″=10.8, J′″5.8, H-19β); 3.19 dd, 1H (J′=11.1, J″=5.2, H-3α); 3.33 dd, 1H (J′=11.0, J″=1.2, H-28a); 3.80 dd, 1H, (J′=10.8, J″=1.8, H-28b); 4.58 m, 1H (ΣJ=6.5, H-29E); 4.68 m, 1H (ΣJ=2.9, H-29Z). 13C NMR spectrum of the obtained betulin measured in CDCl3 with the addition of 10% v/v CD3OD is as follows: 14.74, 15.34, 15.96, 16.09, 18.28, 19.07, 20.81, 25.19, 27.02, 27.37, 27.97, 29.15, 29.73, 33.95, 34.21, 37.14, 37.29, 38.69, 38.84, 40.90, 42.70, 47.77, 47.77, 48.74, 50.38, 55.27, 60.53, 78.97, 109.68, 150.46. By concentrating the mother liquor to the final volume of 8 l was after inoculation and cooling down obtained a second fraction of the crystalline betulin, which was also filtered on a processing filter and washed in the same way as the first fraction. After drying in the hot-air oven at the temperature of 70-75° C. for the period of 48 h further 0.46 kg (27%) of the second fraction of betulin was obtained, having the m.p. 256-257° C., [α]D+16 (10% v/v CH3OH in CHCl3; 0.35 g/100 ml), which, according to HPLC analysis, has the purity of 98.7-99.0%. The overall yield of the hydrolysis is thus 1.58 kg of betulin (93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17](/[CH:25]=[CH:26]/[C:27]3[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][C:28]=3[C:29]([OH:31])=[O:30])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([CH:25]3[CH2:26][C:27]4[C:28](=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[C:29](=[O:31])[O:30]3)[CH:18]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)O)cc(-c2cccnc2OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2cccnc2OCc2ccccc2)cc(C2Cc3ccc(NS(C)(=O)=O)cc3C(=O)O2)c1
Temperature: 0 °C

Procedure:
step b—A solution of 199a, TFA (3 mL), H2O (1 mL) and DCM (10 mL) was heated at reflux for 3 h, cooled and diluted with a ice-water mixture. The pH of the solution was adjusted to ca. 3 with sat'd. NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried, filtered and evaporated to afford N-{3-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-phenyl]-1-oxo-isochroman-7-yl}-methanesulfonamide (199b)
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH:31]([NH2:34])([CH3:33])[CH3:32]>ClCCl.CCOCC.Cl>[CH:31]([NH:34][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:3]=1[CH:1]=[O:2])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: O=Cc1c(O)cccc1OCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)CCCCOc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-(2-Formyl-3-hydroxyphenoxy)pentanoic acid (595 mg, 2.5 mM) was dissolved in dry dichloromethane (7.5 ml) under nitrogen with stirring, and immersed in a cooling bath kept at -10° C. To this solution was added dropwise from a syringe triethylamine (0.35 ml, 2.5 mM). After 5 minutes was then similarly added ethyl chloroformate (0.25 ml, 2.5 mM). After 15 minutes was then similarly added isopropylamine (0.215 ml, 2.5 mM). The reaction mixture was allowed to warm to room temperature and then stirred at room temperature (1/2 hr). After diluting with ether (50 ml) and 1 N hydrochloric acid the aqueous phase was removed and the organic phase washed with dilute sodium bicarbonate solution and then quickly extracted with 2 N sodium hydroxide solution (1×25 ml). The layers were separated and the aqueous phase immediately acidified with dilute hydrochloric acid and extracted with ether/ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution, water, dried (sodium sulphate) and evaporated to give N-isopropyl 5-(2-formyl-3-hydroxyphenoxy)pentanamide, m.p. 92°-93° C. from ethyl acetate/petrol.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C)C=O.C(OCC)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
8.0 g (0.18 mol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed twice with hexane and suspended in 250 ml of dimethylformamide. A solution of 31 ml (0.16 mol) of ethyl diethylphosphonoacetate in 50 ml of dimethylformamide was then added, with ice-cooling, to the suspension, and the resulting mixture was stirred at room temperature for 40 minutes. At the end of this time, the mixture was ice-cooled and a solution of 27 g (0.13 mol) of 2-t-butyl-5-formyl-1-nitrobenzene [prepared as described in step (i) above] in 50 ml of dimethylformamide was added thereto over a period of 30 minutes, after which the mixture was stirred for 1 hour. The reaction mixture was then diluted with diethyl ether, and the diluted solution was washed with a 10% w/w aqueous solution of hydrochloric acid and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.6 g of the title compound as crystals, melting at 77-78° C. (from ethyl acetate-hexane).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2].C(Cl)(Cl)[Cl:17]>CO.CCOCC.O=[Pt]=O>[ClH:17].[NH2:2][CH2:1][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C#N)c1cccc(OC)c1
Reactant: ClC(Cl)Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(CN)c1cccc(OC)c1
Product: Cl
Reaction time: 24 h

Procedure:
The compound obtained in Step A (34.32 g; 0.1672 mol) is dissolved in 150 ml of methanol. The solution is poured into an autoclave and then 50 ml of chloroform and platinium oxide (10% by weight) are added to the solution. The autoclave is placed under hydrogen pressure (60 bars) at ambient temperature and stirred magnetically for 24 hours. After removal of the catalyst by filtration, the solution is evaporated under reduced pressure. The oil obtained is taken up in ether. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title product in the form of a white solid.