Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=O)[N:4]=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][NH2:25]>CO>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][N:25]=[CH:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[O:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Reactant: NOCc1ccc(Cl)cc1Cl
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCc2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
5.2 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde and 3.8 g of 2,4-dichlorobenzyloxyamine were dissolved in 100 ml of methanol and the solution was stirred at room temperature for 2 hours. After the methanol was distilled out under reduced pressure, the resulting residue was recrystallized from isopropyl ether to obtain 8.1 g of O-(2,4-dichlorobenzyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.
Reaction SMILES: C([O:3][C:4]([C:6]1([OH:20])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].C1COCC1>CO>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:9]1[CH2:10][CH2:11][C:6]([OH:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1(O)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)(C(=O)O)CC1

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-1-hydroxy-cyclohexanecarboxylic acid ethyl ester (Intermediate 78, 1.35 g) was hydrolyzed to an acid by adding it to 45 ml of a solution of 1M LiOH in 1:1 THF:MeOH: at room temperature. The pH was adjusted to 3 and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. MS MH+ 275.4
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9]C)=O)[CH2:2][CH3:3].C(O)C.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([NH:17][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:16][CH2:15]1
Reactant: CCC[C@H]1O[C@@H]1C(=O)OC
Reactant: NC1CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.8 %

Procedure:
Methyl (2S,3R)-3-propyl-2-oxiranecarboxylate (0.26 g, 1.8 mmol), ethanol (1 ml) and cyclopropylamine (1.03 g, 18 mmol) were mixed, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with 1 N HCl (5 ml) and water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a pale yellow solid (0.17 g, yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)n1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
Heat a mixture of 2-chloro-6-methylpyridine (5.46 g, 42.8 mmol), NBS (8.38 g, 47.08 mmol), and benzoyl peroxide (500 mg, 2.06 mmol) in carbon tetrachloride (80 mL) for 20 h at 85° C. Cool to ambient temperature, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/toluene (4:3) to provide the title compound as a white solid (3.64 g, 41%).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH3:4])[CH2:32][CH2:33]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: CCCI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCNCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN1CCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzamide (0.145 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.109 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.87 (t, 3H), 1.48 (m, 2H), 2.12 (s, 3H), 2.28 (t, 2H), 2.50 (m, 4H), 2.84 (m, 1H), 3.27 (m, 4H), 7.45 (s, 1M), 7.50 (d, 1H), 7.62 (s, 2H), 7.80 (s, 1H), 7.87 (d, 1H), 8.06 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1=[O:20])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C:5]1=[O:20]
Reactant: CC(C)(C)OC(=O)CN1CCCCCC(N=[N+]=[N-])C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCCCC(N)C1=O

Procedure:
Dissolve 9.5 g. 3-azido-1-t-butoxycarbonylmethylperhydroazocin-2-one in 85 ml. ethanol. Hydrogenate at 40 psi hydrogen pressure at room temperature using 1.0 g. 10% palladium on charcoal as catalyst. Filter the reaction and concentrate the filtrate to obtain 3-amino-1-t-butoxycarbonylmethylperhydroazocin-2-one.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([Br:14])[N:10]=[C:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[C:11]([Br:14])[N:10]=[C:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(Br)c(Br)n2Cc2ccccc2)c(F)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Fc1cc(F)cc(-c2c(Br)nc(-c3ccc(F)cc3F)n2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
Reflux a mixture of 1-benzyl-4,5-dibromo-2-(2,4-difluoro-phenyl)-imidazole (0.386 g, 0.90 mmol), 3,5-difluorophenyl boronic acid (0.15 g, 0.945 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.065 g, 0.09 mmol), 2 M sodium carbonate (0.90 mL), methanol (1.5 mL) and toluene (10 mL) for 18 hours, then cool to ambient temperature. Dilute with ethyl acetate and wash with saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate, filter and remove solvents under reduced pressure. Purify the residue on silica gel eluting with hexane/ethyl acetate mixtures to provide 1-benzyl-4-bromo-5-(3,5-difluoro-phenyl)-2-(2,4-difluoro-phenyl)-1H-imidazole (0.19 g). MS(ES+): m/z=461.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[OH-].[Na+].O>CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoroaniline (11.1 g, 100.0 mmol) in 100 ml of dry ether cooled in an ice bath is added ethyl chloroformate (7.1 ml, 8.1 g, 75.0 mmol). After addition, the mixture is allowed to warm to RT and is stirred at RT for 3 hours. Then a 10% sodium hydroxide solution (54 ml, 2.8M, 150.0 mmol) is added, followed by another 7.1 ml of ethyl chloroformate. The mixture is stirred at RT for 3 hours, and is then poured into water and ether. The organic layer is separated, washed with 5% HCl and with brine, and dried. The solvent is removed to give ethyl N-(2-fluorophenyl)carbamate.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>>[CH3:17][N:18]1[C:22](=[O:23])[CH2:21][CH:20]([O:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:19]1=[O:24]
Reactant: CN1C(=O)C=CC1=O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: CN1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
The procedure for Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 2.78 g (25 mmole) of N-methylmaleimide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].Cl.O>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12](=[O:13])[NH:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cccc(I)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc(-c2cccc(I)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
3-Iodobenzohydrazide (1.00 g, 3.82 mmol) obtained in Step 1 of Example 52 was dissolved in THF (19 mL), and the mixture was stirred at room temperature for 1 hour after adding 1,1′-carbonyldiimidazole (681 mg, 4.18 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (20 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-iodophenyl)-1,3,4-oxadiazol-2(3H)-one (779 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22]>>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:21]=[O:22])=[CH:3][CH:4]=3)=[O:7])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: O=Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
This material was prepared analogous to the procedure described for Example 1(a). 4-Bromo-N-quinolin-7-yl-benzamide, Example 27, (327 mg, 1 mmol) reacted with 2-formylphenyl boronic acid (183 mg, 1.1 mmol, Aldrich) to give the title compound as a yellow solid. Mp 258-260° C. MS (ESI, pos. ion) nz/z: 353 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][C@@H:37]([CH3:41])[CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][C@@H:37]3[CH3:41])=[O:20])=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Reactant: C[C@H]1CN(c2ccccc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccccc2)CCN1C(=O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [[(2S)-2-[[(5-chloro-1-benzofuran-2-yl)carbonyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (150 mg), (S)-1-phenyl-3-methylpiperazine (79 mg), 1-hydroxy-benzotriazole (55 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (79 mg) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (15 ml), and washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol 10:1) to give the title compound as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[N:13]([CH3:29])[NH:14][CH:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)(C)[CH3:2].[ClH:32]>C(O)C>[ClH:32].[CH2:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[N:13]([CH3:29])[NH:14][CH:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NN(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NN(C)C(=O)N1CCC[C@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of N-(1-carboethoxy-3-phenylpropyl)-α-azaalanyl-(L)-proline t-butyl ester (16S) in absolute ethanol was saturated with hydrogen chloride. After one hour, the solution was evaporated to dryness and the product purified by chromatography on LH-20 (in methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:26][CH2:25][CH2:23][OH:24])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Reactant: NCCO
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(C)cccc3c21
Yield: 72.2 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (1.0 g) and ethanolamine (3.0 g) were heated to 150° C. for 3 hours. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from ethyl acetate/petroleum ether yielded 1-(2-methylphenyl)-4-(2-hydroxyethylamino)-6methylpyrrolo[3,2-c]quinoline (0.78 g), m.p. 187°-188°.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C@@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(O)(C)C.CO>[ClH:1].[NH2:9][CH2:10][C@@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
15 ml of a solution of hydrochloric acid in isopropanol having a concentration of 5-6N are added dropwise to a solution of 3.8 g (10.4 mmol) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 50 ml of methanol. The reaction medium is stirred at 40° C. for 3 h, concentrated under vacuum then taken up in diethyl ether. The product precipitates, is filtered, rinsed with diethyl ether then dried under vacuum. 3 g (97%) of methyl (R)-3-amino-2-(4-methanesulphonylpiperazin-1-yl)propanoate hydrochloride are obtained in the form of a beige solid.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1
Reactant: CCOC(=O)c1csc(Nc2ccc(C)cc2O)n1
Agent: Br
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nc(CO)cs2)c(O)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
0.02 mole of the product obtained in Example 2 is added in small portions at room temperature to a suspension of 0.05 mole of lithium aluminium hydride in 100 ml of anhydrous THF. Stirring is maintained for 1 hour at room temperature, the mixture is cooled and the excess hydride destroyed by adding water, the solid is allowed to drain and the filtrate is evaporated under vacuum on a water bath. The oily residue is then crystallized in ether and recrystallized in a methanol/ether mixture. (M.p. 188°-90° C.). Yield: 30%.
Reaction SMILES: [SH:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]([NH:11][C:12](=[O:17])[CH2:13][CH:14](C)[CH3:15])[CH3:10])=[N:4][N:3]=1.C(NC(C)C(=O)C(OCC)=O)(=O)CC(C)C>>[SH:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH3:15])[CH3:10])=[N:4][N:3]=1
Reactant: CC(C)CC(=O)NC(C)c1nnc(S)[nH]c1=O
Agent: CCOC(=O)C(=O)C(C)NC(=O)CC(C)C
Product: CCCC(=O)NC(C)c1nnc(S)[nH]c1=O

Procedure:
In a similar manner was prepared N-[1-(3-mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]3-methylbutyramide (10.0 g) m.p. 195°-196° (from ethyl acetate) from ethyl 3-isovaleramido-2-oxo-butyrate, thiosemicarbazone (16.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCN1CCC(CCN)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCN1CCC(CCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(1-ethylpiperidin-4-yl)ethanamine (15.6 mg, 0.12 mmol). The title compound was obtained as a solid (26.1 mg, 53% yield). MS m/z: 489.06, 491.06 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S:6]([CH3:9])(=[O:8])=[O:7])([CH3:5])[C:3]#[N:4].C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:32])=[C:20](/[C:22](=[N:25]/[S@@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])/[CH2:23][F:24])[CH:21]=1.B(F)(F)F.CCOCC>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:32])=[C:20]([C:22]([NH:25][S@@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])([CH2:23][F:24])[CH2:9][S:6]([C:2]([C:3]#[N:4])([CH3:5])[CH3:1])(=[O:8])=[O:7])[CH:21]=1
Reactant: CC(C)(C)[S@@](=O)/N=C(\CF)c1cc(Br)ccc1F
Reactant: CC(C)(C#N)S(C)(=O)=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC(CF)(CS(=O)(=O)C(C)(C)C#N)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (1.654 g, 11.24 mmol) in THF (14 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol) dropwise via syringe. After 30 minutes at −78° C., a 0° C. solution of (R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62 mmol) at 0° C. for 15 minutes, was added dropwise via cannula. The reaction was stirred for 2 hours at −78° C., and then quenched with saturated aqueous ammonium chloride at −78° C. and diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica-gel chromatography, eluting with 25% ethyl acetate in hexanes followed by 40% ethyl acetate hexane to provide the title compound. The product was isolated as a 2:1 mixture of diastereomers. LC/MS (ESI+) m/z=485, 487 (M+H; 2 bromine isotopes).
Reaction SMILES: C(OCOC([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[B:16]1[O:20][C:19]([CH3:22])([CH3:21])C(C)(C)[O:17]1)(C)C)C.Cl>C1COCC1>[CH3:22][C:19]1([CH3:21])[O:20][B:16]([OH:17])[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]1=2
Reactant: CCOCOC(C)(C)c1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution of compound 2-(2-(2-(ethoxymethoxy)propan-2-yl)-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.2 mmol) in THF (100 mL) was added 6 N HCl (381 mL). The reaction mixture was stirred at rt overnight, and the obtained mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give 3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (6.87 g; yield 51.2% over 2 steps) as a white solid. MS: m/z=177.1 (M+1, ESI+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21](C=O)[CH2:20][C:19]1=[O:26])=[O:6])[CH:2]=[CH2:3].Cl.[Na]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:26])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C=O)CC1=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNCC1=O
Temperature: 5 °C
Yield: 49.6 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxopiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (14.2 g) in methanol (60 ml) was added conc. hydrochloric acid (12.2 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 10 hours. The mixture was cooled to 5° C. and 28% sodium methoxidemethanol solution (28.2 ml) was added to it. The mixture was filtered, and the filtrate was evaporated in vacuo. To the residue was added chloroform. The mixture was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(2-oxopiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (6.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]=[N:7][C:6]([NH:14][C:15]([NH:17][CH2:18][C@@:19]1([OH:27])[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]1)=S)=[CH:5]2.C(=NC(C)C)=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]=[N:7][C:6]([NH:14][C:15]1[O:27][C@:19]3([CH2:18][N:17]=1)[CH:24]1[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]1)[CH2:20]3)=[CH:5]2
Reactant: COc1cc2cnc(NC(=S)NC[C@]3(O)CN4CCC3CC4)cc2cc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2cc1Cl
Reaction time: 240 h
Yield: 24.2 %

Procedure:
To a solution of (S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea (140 mg, 0.344 mmol) in DMF (2.5 mL) was added a solution of N,N′-methanediylidenedipropan-2-amine (101 mg, 0.800 mmol) in DMF (0.5 mL) and the resulting mixture was allowed to stand at room temperature for 10 days. The solvent was then evaporated in vacuo. The residue was dissolved in ˜5 mL MeOH (some white solid was filtered off, 09) and subjected to preparative HPLC purification followed by silica gel chromatography in 1% NH4OH/9% MeOH/90% CHCl3 to give 31 mg (24%) (R)—N-(6-chloro-7-methoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine LCMS RT 1.04 min, MH+=373.2, 375.2 1H NMR (500 MHz, MeOD) δ ppm 8.78-8.89 (1H, m), 7.90-8.01 (1H, m), 7.14-7.23 (1H, m), 4.01 (3H, s), 3.95-3.99 (1H, m), 3.62-3.71 (1H, m), 3.19-3.25 (1H, m), 3.06-3.13 (1H, m), 2.90-3.00 (2H, m), 2.76-2.89 (2H, m), 2.10-2.21 (2H, m), 1.69-1.83 (2H, m), 1.56-1.68 (1H, m).