Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[S:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C>C1COCC1.[Ni]>[S:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:17][CH2:16]2)=[N:19]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 96 %

Procedure:
3-{4-[2-(4-Nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole (942 mg, 2.56 mmol) was dissolved in 50 mL of THF treated with triethylamine (0.3 mL) and with wet Raney nickel (0.14 g). The resulting mixture was placed on a shaker type hydrogenator, purged with hydrogen, pressurized (two re-pressurizations were needed to maintain the pressure between 3 and 17 psig) and shaken at room temperature for 64 hours. The resulting mixture was filtered to remove the catalyst then filtered a second time over celite before the filtrate was concentrated. The resultant white solid was dried in vacuo (830 mg, 2.45 mmol). Yield 96%; mp 154° C.; MS (APCI): 339 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+].OO>C1COCC1.O.CCOC(C)=O>[OH:20][C@@H:8]1[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC=C(c2ccccc2)C1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 22 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Add slowly over 35 minutes a 1M solution of borane tetrahydrofuran complex (137.35 mmol; 137.35 mL) to a solution of tert-butyl 5-phenyl-3,6-dihydro-2H-pyridine-1-carboxylate (137.35 mmol; 36.20 g) in anhydrous THF (362.00) at 0° C. under nitrogen and warm the mixture to 22° C. for 18 h. Then, add slowly a 2M aqueous solution of NaOH (54.94 mmol; 27.47 mL) at 0° C. and stir the mixture for 5 min. Add a 35% aqueous solution of hydrogen peroxide (274.70 mmol; 23.88 mL) at 0° C. and stir the mixture at 22° C. for 2 h, dilute with water (300 mL). Dilute the mixture with EtOAc (250 mL) and separate the organic layer. Extract the aqueous layer with EtOAc (250 mL). Wash the combined organic layers with sodium bisulfate (214.39 mL) and concentrate. Purify the residue by flash chromatography (750 g column; eluent:hexane/EtOAc 80:20 to 60:40; 400 mL fractions, charge in DCM (100 mL)) and then by chiral chromatography Chiralpak AD, 20 um, 8×25 cm; mobile phase: Isocratic 100% MeOH-0.2% DMEA Flow rate: 300 ml/min UV detection: 225 nm Loading: 3 g/6 min. Collect the first eluting isomer to give the title compound (11.85 g, 31%). MS (m/z): 222 (M-tBu+1) [Alpha]Na=−22.89 (in methanol, 25° C.)
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](C)[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2].[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>[O-2].[O-2].[Mn+4].O>[C:24]([C:11]1[CH:12]=[C:13]2[C:8]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[N:6][C:5](=[O:23])[N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:9][CH:10]=1)([OH:25])=[O:27]
Reactant: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: Cl
Solvent: O
Product: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C(=O)O)ccc23)c1

Procedure:
A mixture of 11.25 g. of 1-isopropyl-7-methyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone, 5.25 g. of sodium carbonate and 750 ml. of water is refluxed with 7.5 g. of potassium permanganate being added every half hour until a total of 52.5 g. of potassium permanganate is added. After refluxing for an additional 45 minutes, the reaction mixture is cooled, acidified on the slow addition of 263 ml. of 6N. hydrochloric acid and then treated with sodium sulfate until the manganese dioxide is eliminated. The resulting mixture is cooled and filtered to recover the precipitate which is washed with water, dried under vacuum (40° C.) and crystallized from hot glacial acidic acid to obtain 7-carboxy-1--isopropyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Cc1cc(Br)ccc1C#N
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: CCO
Product: Cc1cc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)ccc1C#N
Temperature: 90 °C
Yield: 59.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 4-bromo-2-methylbenzonitrile (0.301 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil which crystallised under high vacuum over 24 hours. Trituration with diethyl ether resulted in isolation of the title compound as a solid (0.11 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:14][CH3:15])[CH2:9]1)=O)(C)(C)C.Cl.CCO>>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[O:16][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH3:15]
Reactant: CC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH in mineral oil (60:40, NaH:mineral oil, 10 mg, 260 μmol) was slowly added to a mixture of (S)-3-((S)-1-hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol, 1 eq.) in DMF (680 μL, 8.7 mmol). The resulting mixture was stirred for 15 minutes, at room temperature. 2,4-Dichloro-1-fluorobenzene (76 μL, 3 eq.) was added and the mixture was heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL). DMF and MeOH was removed under reduced pressure, leaving the BOC-protected intermediate, (S)-3-[(S)-1-(2,4-dichlorophenoxyl)propyl]pyrrolidine-1-carboxylic acid t-butyl ester. Deprotection was carried out using 1.25 M HCl in EtOH (1.7 mL, 2.2 mmol). The mixture was stirred overnight at room temperature. The product was then purified by preparative HPLC to yield the title compound as a mono-TFA salt (41.5 mg). MS m/z: [M+H]+ calcd for C13H17Cl2NO, 274.07. found 274.0.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][C:17]=1[CH:18]=O.FC(F)(F)C(O)=O.[CH:34]([C:37]1[S:38][CH:39]=[C:40]([C:42]([N:44]2[CH2:49][C:48]3([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[O:47][CH2:46][CH2:45]2)=[O:43])[N:41]=1)([CH3:36])[CH3:35].C(O)(=O)C>CN1C(=O)CCC1.C(OCC)(=O)C>[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][C:17]=1[CH2:18][N:52]1[CH2:53][CH2:54][C:48]2([O:47][CH2:46][CH2:45][N:44]([C:42]([C:40]3[N:41]=[C:37]([CH:34]([CH3:35])[CH3:36])[S:38][CH:39]=3)=[O:43])[CH2:49]2)[CH2:50][CH2:51]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cc(CCO)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (0.339 g) was added to a stirred solution of 2-fluoro-5-(2-hydroxyethyl)benzaldehyde (example 40, step a) (0.135 g), (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.339 g) and acetic acid (0.046 mL) in NMP (7 mL). After 16 h, more 2-fluoro-5-(2-hydroxyethyl)benzaldehyde (example 40, step a) (0.135 g) was added followed by sodium triacetoxyborohydride (0.339 g). After 2 h, the reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:triethylamine, 10:1 to give the subtitled compound as a gum that contained NMP. The NMP was removed by applying the gum to a 10 g SCX cartridge eluting first with methanol and then 20% ‘880’ aqueous ammonia in methanol to collect the subtitled compound. The solution was evaporated to dryness and the resulting gum applied to a silica gel column eluting with ethyl acetate:triethylamine, 10:1 to give the subtitled compound as a gum. Yield 0.31 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)[CH3:31])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)[CH3:31])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cc1cc2ccccc2o1)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)Cc1cc2ccccc2o1)C(CN1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
To a solution of Example 31 (1.659 g, 2.66 mmol) in THF (25 mL) at room temperature was added TBAF (2.8 mL of a 1 M solution in THF, 2.8 mmol). The reaction was stirred for 2.5 hours, then diluted with saturated brine (100 mL) and extracted with dichloromethane (4×120 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in ethyl acetate:methanol (9:1) gave the product as an oil. 0.824 g, 61%.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=O.[NH2:12][C:13]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15]>C(Cl)Cl>[CH:16]([C:13]([CH3:19])([N:12]1[C:6](=[O:11])[C:7]2[C:2](=[N:1][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:5])[C:14]#[N:15])([CH3:18])[CH3:17]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=C1OC(=O)c2ncccc21
Solvent: ClCCl
Product: CC(C)C(C)(C#N)N1C(=O)c2cccnc2C1=O
Yield: 74.6 %

Procedure:
To a stirred solution containing 212 g quinolinic anhydride in 950 ml methylene chloride is added at a moderate rate 167 g of 2-amino-2,3-dimethylbutyronitrile. The mixture had reached the boiling point of the solution after about one quarter of the aminonitrile had been added and the rate of addition is adjusted to maintain this temperature. After the addition the solution is heated under reflux for a further 4 hours. The solution is cooled, filtered and concentrated to a thick oil. This oil is dissolved in 950 ml acetic anhydride, 6 g anhydrous sodium acetate added and the mixture distilled until the vapor temperature reached 118° C. when the heating was continued under reflux for 3 hours. The mixture is concentrated in vacuo the residue dissolved in 500 ml toluene and again concentrated. This is repeated. The residue is slurried with a mixture of ether and hexane and the crude product which crystallizes collected (349 g). This is dissolved in 700 ml methylene chloride and filtered through a column containing 700 g silica gel and the product eluted with methylene chloride. Concentration of the eluant gave 258 g of the desired product. An analytically pure sample with mp 95°-96° C. can be obtained by the recrystallization of the product from ether-methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])[CH3:2].[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26](O)[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:32]2)=[CH:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26]([O:6][C:5](=[O:7])[C:4]([O:3][CH2:1][CH3:2])([CH3:9])[CH3:8])[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[CH2:32]2)=[CH:19]1)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: CCOC(C)(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCOC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 1.15 g of 2-ethoxy-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 414 mg of a fraction containing the title compound. This fraction was usedin the next step without further purification.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8]([NH2:35])=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A mixture of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated amrnonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6) δ 7.84 (m, 4 H, Ar), 7.60-7.25 (m, 5 H), 7.53 (br s, 1 H, CONH), 7.15-6.8 (m, 4 H), 5.67 (t, 1 H, J=7.8 Hz), 5.04 (s, 2 H, OCH2), 3.75 (s, 3 H, OMe), 3.19 (d, 2 H, J=9, 16.5 Hz); 13C NMR (DMSO-d6) δ 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24].[C:25]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:27])[CH3:26]>CO>[C:25]([NH:28][C@H:29]([C:34]([O-:36])=[O:35])[CH2:30][CH:31]([CH3:32])[CH3:33])(=[O:27])[CH3:26].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)NCC2
Solvent: CO
Product: CC(=O)N[C@@H](CC(C)C)C(=O)[O-]

Procedure:
18.9 g. (57.4 mmol) (±)-7-Hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline are dissolved at 60° C. in 70 ml. methanol and mixed with a solution of 9.94 g. (57.4 mmol) N-acetyl-L-leucine in 50 ml. methanol, also heated to 60° C. The solution obtained is concentrated by evaporating in a vacuum. After the addition of isopropanol/diethyl ether and recrystallisation from the same solvent mixture, there is obtained the N-acetyl-L-leucinate of (-)-7-hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline; m.p. 179°-186° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24].C(Cl)(Cl)Cl>C(#N)C.O>[CH2:23]([NH:25][C:26](=[O:27])[NH:2][CH2:3][CH2:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH3:24]
Reactant: COc1ccc2c(c1)[C@H](CCN)CC2
Reactant: CCN=C=O
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCC[C@@H]1CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a suspension of (S)-1-(2-aminoethyl)-6-methoxyindan hydrochloride (0.10 g, 0.44 mmol) and triethylamine (61 μl, 0.44 mmol) in acetonitrile (3 ml) was added ethyl isocyanate (35 μl, 0.44 mmol). The mixture was stirred for 30 min at room temperature, then diluted with water and the product was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from ethyl acetate and isopropyl ether to afford the titled compound (79 mg, yield 69%), m.p. 104-105° C. [α]Hg365 +48.80 (c 0.5, CHCl3)
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:13]C(=O)C)([O-:3])=[O:2].C[O-].[Na+].O>CO>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:13])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Yield: 93 %

Procedure:
To a solution of N-(2,3-dinitrophenyl)acetamide (3.0 g) in methanol (200 mL) was added sodium methoxide (72 mg). The stirred solution was heated at reflux for 3 hours. Water was added to the solution (300 mL) and the yellow solid precipitate was collected and dried to give the desired product (2.27 g, 93%). Chemical Formula: C6H5N3O4 Molecular Weight: 183.12; MS (ES) m/z 184
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3]O.Cl>[OH-].[Na+]>[C:5]1([C:2](=[CH2:3])[C:1]([OH:12])=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)C(CO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=C(C(=O)O)c1ccccc1
Yield: 72.9 %

Procedure:
Tropic acid (4.1 g, 25 mmol) in 50 ml 10N NaOH was stirred at 100° C. for 16 h. Upon cooling on ice, 50 ml conc. HCl was added slowly. The formed white crystals were isolated and dried to give 2.7 g 2-phenyl-acrylic acid. M.p. 97°-99° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([C@H:10]([CH2:17][CH3:18])[C@@H:11](C)[CH2:12][N:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.N[C@H]([C:25](O)=[O:26])CCSC>CS(O)(=O)=O>[CH3:14][N:13]([CH3:15])[CH2:12][C@H:11]([O:26][CH3:25])[C@@H:10]([C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=1)[CH2:17][CH3:18]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Product: CC[C@H](c1cccc(O)c1)[C@H](CN(C)C)OC
Temperature: 77.5 °C
Reaction time: 18 h
Yield: 105.3 %

Procedure:
In 28 mL of methanesulfonic acid, (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine HCl (6.0 g, 0.022 moles) is dissolved, and methionine (4.7 g, 0.031 moles) is added to the solution. The reaction is stirred at the temperature of 75-80° C. for 16-20 hours. It is then cooled to 15-25° C. and the following is added: purified water (20 mL), slowly at this temperature. The pH is brought to the value of 10-11 by means of the addition of 28% NaOH (about 35 mL), maintaining the temperature below 50° C. Then, ethyl acetate (30 mL) is added to the mixture. The mixture is then stirred for 30 minutes and the organic phase is separated. The organic phase, with dark color, is filtered over a silica panel and washed with 30 mL of ethyl acetate. A yellowish transparent solution is obtained. The solvent is removed under vacuum, obtaining about 5.5 g of oil which, left at ambient temperature, solidifies.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22](COCC[Si](C)(C)C)[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(CO)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(CO)ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
194 mg of 4-{[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 25 ml of DCM. After cooling to 0° C. using an ice bath, 1.9 ml of TFA are added and the mixture is stirred at RT for 2 h 30 min. It is concentrated under RP and the solid obtained is taken up in 50 ml of water, neutralized with 2.5 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/NH4OH mixture (90/10/1 by volume). This gives 28 mg of 4-{[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide. 1H NMR: 1.60-1.73 (m, 2 H) 2.05-2.16 (m, 2 H) 2.62-2.73 (m, 2 H) 3.46 (d, J=11.2 Hz, 2 H) 3.64-3.76 (m, 1 H) 4.63 (d, J=5.4 Hz, 2 H) 5.34 (t, J=5.9 Hz, 1 H) 5.75 (s, 1 H) 5.91 (d, 1 H) 6.70 (s, 2 H) 7.32 (t, 2 H) 7.59 (s, 1 H) 7.61-7.71 (m, 1 H) 7.84 (dd, 1 H) 8.35 (d, J=8.3 Hz, 1 H) 12.66 (s, 1 H).