Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([C:3]2[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.2 %

Procedure:
To a flask containing N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2.0 g, 8.9 mmol) and methyl acrylate (0.7 g, 8 mmol) in methylene chloride (100 mL) at 0° C. under an inert atmosphere was added TEA (0.90 g, 8.8 mmol). The reaction mixture was slowly warmed to ambient temperature, stirred for 20 h, quenched with water (30 mL), and extracted with methylene chloride (2×50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel, eluting with methylene chloride/methanol (100/1 to 95/5). The appropriate fractions were combined and concentrated in vacuo to give methyl 3-[3-(trifluoromethyl)phenyl]4,5-dihydroisoxazole-5-carboxylate (2.3 g, 100%): LCMS: 274.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 8.03 (s, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.59 (dd, 1H), 5.28 (dd, 1H), 3.86 (s, 3H), 3.71 (dd, 2H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([C:19]#[N:20])=[N:17]O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CC(C)=O>[O:7]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([C:19]#[N:20])=[N:17][O:4][CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Reaction time: 0.08 h
Yield: 108.2 %

Procedure:
Potassium carbonate (3.11 g, 0.023 mol) and acetone (60 ml) were added to 2-phenoxy-α-hydroxyiminobenzyl cyanide (E/Z=11/89)(7.15 g, 0.03 mol). The mixture was stirred for 5 minutes. Then dimethyl sulfate (5.68 g, 0.045 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting insoluble materials were removed. To the residue obtained after concentration under reduced pressure, toluene (60 ml) and 1N aqueous sodium hydroxide solution (60 ml) were added. The mixture was stirred at room temperature for 1 hour. After stirring, water (60 ml) was added. The mixture was extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromarography (ethyl acetate/n-hexane) to give 2-phenoxy-α-methoxyiminobenzyl cyanide (6.28 g, Yield: 83.0%, E/Z=7/93).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)([O:13]CC1C=CC=CC=1)=[O:12]>C1C=CC=CC=1>[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:29])=[CH:23][CH:22]=1)([OH:13])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxy-2-phenylethanamine (0.68 g) and 1-(4-carbobenzyloxyphenyl)propan-2-one (1.34 g) were refluxed in benzene (50 ml) in a Dean and Stark apparatus for 2 hours. The solvent was removed, tetrahydrofuran (50 ml), benzene (10 ml) and water (3 ml) were added followed by sodium borohydride (0.9 g). The reaction mixture was left at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between water and ether. The layers were separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound as the benzyl ester (1.67 g). This was dissolved in ethanol amd hydrogenated at 75 psi and 50° for 4 hours. Filtration and evaporation of the solvent gave the title compound mp 180°-190° (ethyl acetate-methanol). τ (TFA-d) 8.5 (3H, d, J=7 Hz), 5.85-7.45 (5H, m), 4.72 (1H, broad), 2.6 (7H, m), 1.8 (2H, d, J=8 Hz). τ (d6DMSO+D2O+NaOD) 9.05 (3H, d, J=7 Hz), 6.9-7.7 (5H, m), 2.85 (2H, d, J=8 Hz), 2.7 (5H, s), 2.17 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][OH:6].[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[Cl:13][C:11]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)=[O:12]
Reactant: O=C(Cl)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-dichlorobenzyl alcohol (0.201 g, 1.06 mmol) in CH2Cl2 (0.5 mL) was added phosgene (20% in toluene; 0.42 mL, 0.79 mmol), and the mixture was stirred at room temperature for 30 minutes to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[C:19]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)(=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CCC(=O)O)CC(C)(C)N1OC1CCCCC1
Yield: 90.6 %

Procedure:
A mixture of 12.8 grams (50.0 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 5.0 grams (50.0 mmol) of succinic anhydride and 15 ml of toluene is heated at reflux for five minutes. Solvent is evaporated and the residue is dissolved in hexane. Water is added and the resulting precipitate is washed with hexane to afford 16.1 grams (90% yield) of the title compound as the monohydrate as a white solid melting at 56°-60° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.C(Cl)Cl>CS(C)=O>[CH3:1][C:2]1([CH3:11])[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]=[O:10])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(CCO)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(CC=O)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 109.3 %

Procedure:
Under an argon atmosphere, to a mixture of 2-(4,4-dimethylcyclohexyl)ethanol (25.3 g) and DCM (200 mL) were added DMSO (50 mL) and TEA (100 mL), and a sulfur trioxide-pyridine complex (77.7 g) was added in small divided portions while maintaining the inner temperature to 10° C. or lower under ice-cooling. After stirring at room temperature for 2 hours, to the reaction mixture was added ice water, followed by concentration under reduced pressure and then extraction with chloroform. The organic layer was washed sequentially with 1 M hydrochloric acid and brine. To the organic layer was added MgSO4, followed by stirring. Then, the mixture was filtered and concentrated under reduced pressure to obtain (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[Cl:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2Cl)N=C(N)OCC1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2Cl)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-chloro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-3) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=406.3 [M+H]+.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.[NH2:38][C:39]1[CH:54]=[CH:53][C:42]2[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([CH2:49][OH:50])([OH:48])[CH2:46][O:47][C:41]=2[CH:40]=1>C(O)(C)C>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])=[N:22][C:17]([NH:38][C:39]2[CH:54]=[CH:53][C:42]3[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([OH:48])([CH2:49][OH:50])[CH2:46][O:47][C:41]=3[CH:40]=2)=[N:18][CH:19]=1
Reactant: CCN1CC(O)(CO)COc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCC(O)(CO)CN3CC)ncc1Cl

Procedure:
10-Camphorsulfonic acid (107 mg, 0.462 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (142 mg, 0.420 mmol), and 3-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.100 g, 0.420 mmol) in Isopropyl alcohol (3.0 mL) and the mixture was irradiated in a CEM microwave (120° C., 40 min). The reaction mixture was then purified by HPLC and lyophilized to afford 2-[5-Chloro-2-(9-ethyl-7-hydroxy-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a yellow lyophilate (2 mg, 1%). LCMS: 541.31 (M+H); 1HNMR (CDCl3): 9.33 (s, 1H), 8.02 (s, 1H), 7.46 (d, J=5.32 Hz, 4H), 7.33 (s, 1H), 6.97 (s, 1H), 6.65 (d, J=7.80 Hz, 1H), 4.05 (m, 4H), 3.87 (s, 2H), 3.51 (s, 2H), 3.13 (s, 2H), 1.12 (t, J=7.04 Hz, 3H);
Reaction SMILES: C([O:9][C:10]1[C:11]([C:22]([O:24]C)=O)=[N:12][C:13]([C:20]#[N:21])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCOCC>C1(C)C=CC=CC=1>[C:20]([C:13]1[N:12]=[C:11]([C:22]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=2[O:27][CH3:26])=[O:24])[C:10]([OH:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)#[N:21]
Reactant: COC(=O)c1nc(C#N)c2cccnc2c1OC(=O)c1ccccc1
Reactant: COc1cccc(CN)c1OC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cccc(CNC(=O)c2nc(C#N)c3cccnc3c2O)c1OC

Procedure:
To a solution of methyl 8-(benzoyloxy)-5-cyano-1,6-naphthyridine-7-carboxylate (264 mg, 0.792 mmol) in anhydrous toluene (12 ml) was added 2,3-dimethoxybenzyl amine (132 mg, 0.79 mmol) and the solution was stirred at reflux under argon overnight. The solvent was removed under reduced pressure to give a brown syrup which was subsequently taken up into ether (10 ml). After stirring for 4 hours the solids were collected by vacuum filtration and dried overnight on an aberhalden to give an off white solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1C(=O)Cn1cncn1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 57, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (71 mg, 55%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.59-7.52 (m, 2H), 7.49-7.15 (m, 6H), 7.05-6.90 (m, 4H), 5.25 (q, 2H), 4.60-4.49 (m, 1H), 3.92-3.79 (m, 1H), 2.97-2.73 (m, 3H), 2.30-1.88 (m, 2H). MS (EI) for C28H25FN5O3. found 533.9 (MH+).
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2)(=O)C.Cl.[OH-].[Na+]>>[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CN(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CC1CCc2cc(N)ccc2C1
Yield: 36.4 %

Procedure:
6-Acetylamino-2-(N,N-dimethylamino)methyltetralin hydrochloride (0.879 g; obtained in Reference Example 31) was added to 2 N hydrochloric acid. The reaction mixture was heated under reflux for 90 minutes, and then an aqueous solution of 1 N sodium hydroxide was added thereto to thereby make the resulting mixture have pH of 9. Then, this was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate/hexane=1/1) to obtain the entitled compound (0.231 g).
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH2:8])[CH:6]=[CH2:7].[CH3:9][C:10]1[N:15]=[C:14](SC)[NH:13][C:12](=[O:18])[C:11]=1[CH2:19][CH2:20][CH3:21]>O>[CH2:5]([NH:8][C:14]1[NH:13][C:12](=[O:18])[C:11]([CH2:19][CH2:20][CH3:21])=[C:10]([CH3:9])[N:15]=1)[CH:6]=[CH2:7]
Reactant: C=CCN
Reactant: CCCc1c(C)nc(SC)[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: C=CCNc1nc(C)c(CCC)c(=O)[nH]1
Temperature: 130 °C

Procedure:
A mixture of allylamine acetate (12 g) and 6-methyl-2-methylthio-5-propylpyrimid-4(3H)-one (6 g) was heated at 130° C for 45 minutes. The mixture was cooled and water was added. The precipitated product was collected, washed with water, dried and recrystallised from petroleum (b.p. 80°-100° C) giving 2-allylamino-6-methyl-5-propylpyrimid-4(3H)-one (formula VII, R1 = CH3, R = C3H7, R6 = H, R7 = CH2CH=CH2) having a melting point of 152°-153° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:6]1[N:7]=[CH:8][C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1ccc(C#N)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 30.3 %

Procedure:
5-Cyano-2-methylthiopyridine (2.26 g, 15.0 mmol) and methyl thiosalicylate (5.05 g, 30.0 mmol) were dissolved in toluene (100 ml), and triethylamine (6.3 ml, 45.0 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (1.30 g, 31%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24].[K+].[Br-]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolate Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm−1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C15H15NO5S: C, 56.07; H, 4.70; N, 4.36. Found: C, 55.65; H, 4.67; N, 4.10.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].[CH2:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:38].C(=O)([O-])O.[Na+]>O1CCCC1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH2:37][CH3:38])[CH2:40][CH2:41]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)nc3s2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (284 mg, 0.547 mmol) produced in Example C15(i), 1-ethylpiperazine (114 μL, 0.901 mmol) triethylamine (125 μL, 0.901 mmol) and tetrahydrofuran (5 mL) was stirred at 60° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and filtered through a pad filled with basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to give the title compound (138 mg, 51%) as white crystals.
Reaction SMILES: [O:1]1[C@:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[CH2:2]1.[NH3:21]>CO>[NH2:21][CH2:2][C@:3]1([OH:1])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:4]1
Reactant: N
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CO4)C3)c2c1
Solvent: CO
Product: N#Cc1ccc2ncn(C[C@H]3CCC[C@@](O)(CN)C3)c2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A suspension of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH (1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a microwave at 100° C. for 3 h. The reaction mixture was cooled to RT and blown down to dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile which was used without further purification. A solution of 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in three 20 mL microwave vials and heated with microwave at 160° C. for 3 h. The combined reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid was then filtered and washed with 2×10 mL of water. The solid was air-dried under house vacuum overnight. The compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-{[(5S,7S)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an off-white solid (856 mg, 97% yield). The aromatic region of the NMR spectra showed that the product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:18])=[N:15][C:16]([Cl:17])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O)(C)(C)C>C(Cl)Cl.CO>[Cl:17][C:16]1[N:15]=[C:14]([Cl:18])[N:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)nc(Cl)c2C1CCc1ccc(C(F)(F)F)cc1
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCC2NCCn3c(Cl)nc(Cl)c32)cc1

Procedure:
According to the general procedure (GP13), Boc-deprotection of 1,3-dichloro-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (185.7 mg; 0.400 mmol) and purification by FC (DCM/MeOH/25% aq. NH4OH=150/10/1) gave the expected product 1,3-dichloro-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine as a yellow oil (121 mg; 0.332 mmol; 83%). LC-MS: tR=0.79 min.; [M+H]+=364.11 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g, 0.04 mol) in MeOH (150 mL) and water (50 mL) is added LiOH (1.9 g, 0.08 mol). The resulting reaction mixture is stirred at RT for 0.5 hour. After most of the MeOH is removed, the mixture is acidified with concentrated aqueous HCl until a white solid precipitates. The solid is collected by filtration and washed with water (5 mL) to give the desired product (8.7 g, 93% yield). MS (m/z): 234.0 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O.[Cl-].[Na+]>N1C=CC=CC=1.Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=2)[NH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Methanesulphonyl chloride (0.23 ml) was added to an ice cooled, stirred solution of 2-[2-[5-(aminomethyl)-1H-indole-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.84 g) in dry pyridine (25 ml). After 20 h at room temperature, a further portion of methanesulphonyl chloride (0.14 ml) was added. The mixture was stirred for 2 h, water (10 ml) was added and the solution was stirred for a further 1 h. The solution was diluted with hydrochloric acid (2N; 250 ml) containing sodium chloride (30 g) and ice. The product was extracted into ethyl acetate (2×80 ml) and the extract was washed with brine (2×60 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow foam (0.85 g).