Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)CCOc1ccc(Br)cc1-2
Product: Cn1cc(-c2c(C(N)=O)nc3n2CCOc2ccc(Br)cc2-3)cn1

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole similar to as described in Example 4 and triturated from water to give 90 mg of 10-bromo-3-(1-methylpyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 13.2 mg of 10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1-methylpyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benz oxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 392 (M)+. 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.29 (dd, J=8.5, 2.1 Hz, 1H), 7.05-7.00 (m, 2H), 5.43 (s, 1H), 4.46-4.40 (m, 2H), 4.31 (d, J=4.0 Hz, 2H), 3.90 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:33]([N:40]1[CH2:48][CH2:47][CH2:46][C@H:42]([C:43]([OH:45])=O)[CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C.[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63]([CH2:66][CH2:67][CH3:68])=[CH:62][C:61]=1[C:69]1[N:70]=[C:71]([NH2:74])[S:72][CH:73]=1>CN(C=O)C.CCOC(C)=O>[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63]([CH2:66][CH2:67][CH3:68])=[CH:62][C:61]=1[C:69]1[N:70]=[C:71]([NH:74][C:43]([C@H:42]2[CH2:46][CH2:47][CH2:48][N:40]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:41]2)=[O:45])[S:72][CH:73]=1
Reactant: CCCc1ccc(OC)c(-c2csc(N)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc(OC)c(-c2csc(NC(=O)[C@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
0.5 g of TBTU, 0.1 g of HOBT, 0.35 g of (S)-N-Boc-nipecotic acid and then 0.3 mL of DIPEA are added, at a temperature of 0° C., to a solution of 0.5 g of 4-(2-methoxy-5-propylphenyl)-1,3-thiazol-2-amine, obtained in preparation I.4, in 4 mL of DMF. The medium is stirred at room temperature for 3 hours and then diluted with EtOAc and washed 4 times with 10% Na2CO3 solution and then with saturated NaCl solution. After drying over MgSO4, the solution is concentrated and then purified by flash chromatography to give 0.56 g of a white solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:32])[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:20]=3)[C:15]([OH:17])=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:32])[CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:20]=3)[C:15]([OH:17])=[O:16])=[CH:33][CH:34]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3.08 g, 5.93 mmol) was dissolved in methanol (30 mL) and THF (30 mL). Triethylamine (2 mL) was added and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (200 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours LC-MS showed only 26% required product. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the flask containing the filtrate evacuated and purged with nitrogen (3 times). Fresh 10% Palladium on carbon (200 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for a further 16 hours LC-MS showed complete reaction. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, the filtrate concentrated in vacuo and dissolved in diethylether (50 mL), washed with water (20 mL), 1N citric acid (20 mL), saturated aqueous sodium chloride solution (20 mL) and dried (MgSO4) to give the title compound (2.16 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:17][C:7]2[C:8]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:2]([CH:3]1[CH2:17][C:7]2[C:8]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4]1)=[O:1]
Reactant: N#Cc1ccc2sc3c(c2c1)CC(CO)CC3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc2sc3c(c2c1)CC(C=O)CC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a room temperature suspension of 8-(hydroxymethyl)-6,7,8,9-tetrahydrodibenzo[b,d]thiophene-2-carbonitrile (0.24 g, 1 mmol) in 4 mL CH2Cl2 was added TFA (0.5 mL). To the resulting homogeneous solution was added Dess-Martin periodinane (0.243 g, 1 mmol). Precipitates were formed after reaction mixture was stirred for 10 minutes. The resulting suspension was cooled in ice water, and diluted with EtOAc (15 mL), then was treated with 10 mL of 1.25 N NaOH (aq.) solution. After stirring for a few minutes, the organic layer was collected, washed with water, then brine, then was dried over MgSO4), filtered, and concentrated. Purification by chromatography on silica gel (25% EtOAc in hexane) afforded 0.14 g (58%) of the title compound as a white solid: mp 172-173° C.; MS (ES) m/z=241 [M]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=O)C.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31](Cl)(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:31]([C:28]2[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][N:29]=2)(=[O:32])=[O:33])[N:10]([CH3:21])[N:9]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (3.80 g) in anhydrous pyridine (25 ml) at room temperature and under an atmosphere of nitrogen was added 4-dimethylaminopyridine (0.85 g) and 5-isopropyl-2-pyridinesulfonyl chloride (2.00 g). After being left to stir overnight, the reaction mixture was poured onto saturated citric acid solution (300 ml) and extracted with ethyl acetate (2×200 ml). The organic fractions were washed with brine (200 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To a solution of the residue (4.45 g) in ethanol (100 ml) was added sodium hydroxide solution (2.76 g in 10 ml water). The red solution which formed was stirred for 1 hour before being concentrated to approximately 20 ml under reduced pressure and partitioned between ethyl acetate (2×100 ml) and saturated citric acid solution (100 ml). Washing of the organic fractions with brine (100 ml), drying over magnesium sulfate, filtering and concentration under reduced pressure afforded a brown residue. Purification by column chromatography on silica gel (200 g), eluting in an isocratic fashion with dichloromethane:methanol (20:1) afforded the title compound as a brown foam (1.85 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH2:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: N[C@H]1CCc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1CCc2ccccc2C1

Procedure:
was prepared by reaction of the commercially available (S)-7-amino-5,6,7,8-tetrahydro-naphthalene with acetic anhydride according to known methods.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:24]3[CH2:27][C@H:26]([CH2:28][O:29]S(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][O-].[Na+]>CO>[CH3:40][O:29][CH2:28][CH:26]1[CH2:25][CH:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[N:9]=2)[CH2:27]1
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Agent: [Na+]
Solvent: CO
Product: COCC1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (20 mg, 0.04 mmol) in MeOH (2 mL) was added 25% wt. NaOMe in MeOH (25:75, MeONa:MeOH, 13 uL). The resulting mixture was stirred at 50° C. overnight. Reaction was quenched with sat. aq. NaHCO3 solution, extracted with DCM and dried (Na2SO4). The solvent was removed under reduced pressure to give a residue which was then purified by flash chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 2.28-2.43 (m, 2H), 2.54-2.65 (m, 2H), 2.65-2.75 (m, 1H), 3.34 (s, 3H), 3.40-3.46 (m, 2H), 3.59-3.75 (m, 1H), 5.03 (s, 2H), 7.02-7.09 (m, 3H), 7.08-7.18 (m, 4H), 7.33-7.40 (m, 2H), 7.59-7.65 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:19](=[O:20])[O:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:13]([CH3:14])[CH:12]=1
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(C)c(Sc2ccccn2)c(C)c1
Reaction time: 6 h

Procedure:
4-(2-Pyridylthio)-3,5-dimethylphenol (161 g.), prepared in part A, and methylisocyanate (48 g.) was dissolved in dry toluene (1500 ml.) containing triethylamine (10 ml.) and the mixture was then stirred under reflux overnight. Further quantities of methyl isocyanate (22 g.) and triethylamine (10 ml.) were then added and refluxing was continued for a further 6 hours.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([S:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].ClC1N2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.C(N(CC)CC)C>CN(C)C=O.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]3[N:15]([C:14]([S:13][C:6]4[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=4)[NH2:3])=[N:18][N:19]=3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Reactant: N#CSc1ccc([N+](=O)[O-])c(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
342 mg of sodium borohydride are added to a mixture of 1.76 g of commercial 3-amino-4-nitrophenyl thiocyanate in 15 cm3 of N,N-dimethylformamide. The reaction is stirred at ambient temperature for 2 h and then 746 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine and 1.25 cm3 of triethylamine are added. The resulting mixture is then heated to 95° C. and then stirred for 1 h at 20° C. After the addition of demineralized water, the mixture obtained is extracted with 3×100 cm3 of ethyl acetate (a small amount of methanol is added due to solubility problems). The organic phases are combined and then dried over magnesium sulphate and concentrated to dryness, so as to give a brown solid which is chromatographed on a 25 g Merck cartridge of silica 15-40 μm (elution with ethyl acetate). 360 mg of 5-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-2-nitroaniline are thus obtained in the form of a green solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](N)[C@@H](O)c1ccccc1

Procedure:
As shown in the scheme above, (1R, 2S)-(−)- norephedrine is reacted with an optionally substituted benzaldehyde by refluxing in ethanol, and reducing the product of that reaction with sodium borohydride at ambient temperature to produce the desired norephedrine derivative compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].Cl.C(OCC)C>CC(O)C>[ClH:1].[N+:18]([C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(=O)O)n2)cc(OC)c1OC
Temperature: 90 °C
Yield: 62.3 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzoic acid (52 mg, 0.178 mmol) and 3,4,5-trimethoxyaniline (34 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for 30 hours. After the reaction was cooled to room temperature the mixture was filtered, and the solid was washed with 2-propanol, hexane, and ethyl acetate. The solid was then dried under vacuum to give 2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)-amino]pyrimidin-4-yl}amino)benzoic acid hydrochloride (53 mg, 63%) as a dirty orange solid. 1H NMR (DMSO-d6/D2O): δ 9.14 (s, 1H), 8.47 (m, 1 H), 8.02 (d, 1 H), 7.46 (m, 1 H), 7.26 (t, 1 H), 6.95 (s, 2 H), 3.69 (s, 3 H), 3.63 (s, 6 H); MS m/z 441 (M+1).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([N+]([O-])=O)=[C:12]([NH:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22](=[N:25]O)[CH2:23][OH:24])[N:11]=1>[OH-].[Na+]>[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]2[N:25]=[C:22]([CH2:23][OH:24])[C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[NH:20][C:12]=2[N:11]=1
Reactant: CCC(CC)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(CO)=NO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCC1(CC)Nc2nc(N)nc(O)c2N=C1CO
Yield: 2.8 %

Procedure:
Sodium dithionite was added portionwise to a warm solution of 2-amino-4-hydroxy-6-(1,1-diethyl-3-hydroxy-2-hydroxyiminopropylamino)-5-nitropyrimidine (II) (450 mg) in 0.1M sodium hydroxide until the colour changed from red to very pale yellow. A solid product was not obtained either on cooling or on adjusting the pH. In order to separate the product from inorganic material the solution was evaporated and the product extracted with ethanol and the inorganic material was filtered off. This extraction was repeated and the combined extracts were evaporated to dryness in vacuo. The residue was dissolved in the minimum quantity of water and placed on a column of Amberlite (C.G.50) ion exchange resin (2.5 × 28 cm). Elution with water gave two main fluorescent bands. Evaporation of the solution containing the first band gave the 6-carboxaldehyde derivative of the title compound (10 mg. yield 3%) as a bright orange powder, whilst the second band gave the 7,8-dihydropteridine (I) (160 mg. yield 44.5%%) as a bright yellow powder, m.p. >300° decomp.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[C@H:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(=O)CC.O.N>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCN1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Agent: N
Solvent: O
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Product: CCCCN1CCCCC1C(=O)Nc1c(C)cccc1C
Yield: 96.9 %

Procedure:
A stirred mixture of (S)-bupivacaine (0.140 g, 0.49 mmol) and propanoic acid (3.5 ml) was heated to reflux under a nitrogen atmosphere for 7 hours. The resulting solution was cooled and then poured into a mixture of distilled water (20 ml) and ethyl acetate (20 ml). Aqueous ammonia (28% w/v) was added until the pH of the aqueous layer was 10. The organic layer was separated and the aqueous layer extracted with ethyl acetate (20 ml). The combined organic extracts were washed with distilled water (20 ml), dried (MgSO4) and concentrated under reduced pressure to give racemic bupivacaine (0.137 g, 98%). ##STR1##
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:18][C:19](=O)[CH2:20][CH3:21]>C(O)C>[CH2:20]([C:19]1[N:6]([O:5][CH:2]([CH3:4])[CH3:3])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:21]
Reactant: CC(C)ON
Reactant: CCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCc1nc2cnc3ccccc3c2n1OC(C)C
Temperature: 25 °C
Yield: 94.9 %

Procedure:
O-isopropylhydroxylamine hydrochloride (2.5 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)propionamide (3.1 g, 1.0 eq) in ethanol (150 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 3.2 g of 2-ethyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: Nc1ccc(-n2cccc2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(-n3cccc3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of 3-fluoro-4-(1H-pyrrol-1-yl)aniline (0.80 g, 4.55 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (23 mL, 23 mmol, 1 M in heptane) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (785 mg, 5.0 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:2) to give the title compound as a pale yellow solid (450 mg, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[C:11]2[C:16]([C:17]=1[O:18]CC1C=CC=CC=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(-c2ccc(C)cc2)c2ccccc2c1OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(-c2ccc(C)cc2)c2ccccc2c1O

Procedure:
Synthesized from (4-benzyloxy-1-p-tolyl-isoquinoline-3-carboxylic acid butyl ester in analogy to Example D-78 d) (EtOAc was used as the solvent); MS-(+)-ion: M+1=336.2.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[CH3:26][NH2:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:27][CH3:26])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNc1nc(N(C)c2ccc(OC)c(OC)c2)c2ccccc2n1
Temperature: 90 °C
Reaction time: 41 h

Procedure:
A suspension of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (106 mg; 0.289 mmol), methylamine hydrochloride (198 mg; 2.93 mmol) and sodium carbonate (340 mg; 3.21 mmol) in i-PrOH (4 mL) was heated at 90° C. After 41 h, the suspension was concentrated then water (5 mL) was added. The product was extracted into chloroform (3×2 mL) and the combined extracts washed with water (3×2 mL) and brine (2×3 mL). This solution was dried (MgSO4), filtered through silica and washed with 100:10:1 CHCl3:MeOH:concentrated NH4OH, concentrated then purified by MPLC (12 g SiO2/0-30% (20:1 MeOH:concentrated NH4OH) in CHCl3 gradient). Product was obtained as an oil, which solidified to a pale yellow solid under high vacuum (74 mg; 79%). 1H NMR (CDCl3) δ 7.46 (m, 1H), 7.38 (m, 1H), 6.90 (m, 1H), 6.84 (m, 1H), 6.76-6.65 (m, 3H), 3.91 (s, 3H), 3.78 (s, 3H), 3.53 (s, 3H), 3.12 (d, 3H); LC-MS (ESI−; 325 ([M+H]+)).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.467 g, 1.16 mmol) (from example 33, step 1) was dissolved in MeOH (4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.047 g, 1.16 mmol) dissolved in water (0.4 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.071 mL, 1.16 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6 mL, 36.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.432 g, quant.) as a yellow oil. MS m/z 371 (M+H)+