Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[Cl:20][C:21]1[CH:22]=[N+:23]([O-:41])[CH:24]=[C:25]([Cl:40])[C:26]=1[CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:40][C:25]1[CH:24]=[N+:23]([O-:41])[CH:22]=[C:21]([Cl:20])[C:26]=1[CH2:27][C@H:28]([O:18][C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)(=[O:10])=[O:11])=[O:19])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C=O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a stirred solution of (2S)-1-(4-formylphenyl)sulfonylpyrrolidine-2-carboxylic acid (283 mg, 1 mmol) in DMF (15 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (344 mg, 1 mmol), followed by DMAP (60 mg, 0.5 mmol) and EDC (385 mg, 2 mmol). The mixture was allowed to stir at room temperature for 18 hours and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in isohexane followed by 10% methanol in DCM, to afford the title compound as an off-white solid (333 mg, 55%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])[CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][CH2:25][CH3:26])[NH2:22]>>[CH3:18][O:19][C:20](=[O:27])[C@@H:21]([NH:22][C:14](=[O:16])[CH:12]([CH3:13])[NH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(Nc1cnc2ccccc2c1)C(=O)O
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCCC[C@H](NC(=O)C(C)Nc1cnc2ccccc2c1)C(=O)OC

Procedure:
Using General Procedure G, followed by hydrolysis set forth in General Procedure C, N-(quinolin-3-yl)-D,L-alanine was prepared. This compound was then coupled to L-norleucine methyl ester hydrochloride (Sigma) using General Procedure D to provide for the title compound as an oil. The latter reaction was monitored by tlc (Rf=0.76 in 10% methanol/methylene chloride and 0.07 in 1:1 EtOAc:Hexanes and the product was purified by flash chromatography using 10% methanol/methylene chloride as the eluent.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[CH3:15][C:13](=[CH2:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=C(C)C(=O)Nc1cccc([N+](=O)[O-])c1C

Procedure:
2-Methyl-N-(2-methyl-3-nitrophenyl)acrylamide was prepared as described in Example 1a starting from 2-methyl-3-nitroaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.97 (3H, s), 2.23 (3H, s), 5.56 (1H, s), 5.90 (1H, s), 7.40-7.46 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.71 (1H, s).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:15]=[S:16])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][NH:19][C:20](N)=[NH:21].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:21][C:20]1[N:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:5][CH:6]=2)[C:15]([SH:16])=[N:18][N:19]=1
Reactant: S=C=Nc1ccc(C2CC2)c2ccccc12
Reactant: N=C(N)NN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
Compound 3 (447 mg, 2.1 mmol) was dissolved in 3 mL of dimethylformamide, aminoguanidine hydrochloride salt (355 mg, 3.2 mmol) and diisopropyl ethylamine (0.56 mL, 3.2 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (10 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (4). (240 mg, 44% yield)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.ClCCN1CC[O:41]CC1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:41][CH2:31][CH2:30]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCCC4)c3)nn12
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCOCC4)c3)nn12

Procedure:
The title compound was prepared in analogy to the compound of Example 231 using 2-chlorethyl-morpholine hydrochloride instead of 1-(2-chlorethyl)pyrrolidine hydrochloride and with a second flash chromatography purification afterwards (tR 3.04 min (conditions 3), MH+=458.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.33 (d, 1H); 8.09 (m, 2H); 8.01 (d, 1H); 7.76 (d, 1H); 7.62 (m, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.28 (t, 2H); 3.50 (m, 4H); 2.72 (m, 2H); 2.39 (m, 4H)).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[C@H:27]2[CH2:32][C@@H:31]([NH:33]C(=O)OC(C)(C)C)[C:30](=O)[C@@H:29]([CH3:42])[CH2:28]2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:43]>CCO.N1C=CC=CC=1>[NH2:33][C@@H:31]1[CH2:32][C@H:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:18](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([F:43])=[C:12]([C:6]3[C:5]([F:4])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[N:17]=2)[CH2:28][C@H:29]([CH3:42])/[C:30]/1=[N:2]/[OH:3]
Reactant: NO
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)/C1=N\O
Reaction time: 16 h
Yield: 14 %

Procedure:
A solution of hydroxylamine-HCl (4.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3(sat.). The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5S,Z)-3-amino-4-(hydroxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=470.3 (MH+), Rt=0.60 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 10.49 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 8.02 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (t, J=8.0, 2H), 4.24 (m, 1H), 3.82-3.86 (m, 1H), 3.21-3.27 (m, 1H), 2.50-2.55 (m, 1H), 2.24 (d, J=12.0, 1H), 1.86 (d, J=16.0, 1H), 1.68 (q, J=12.0, 1H), 1.59 (q, J=12.0, 1H), 1.40 (d, J=8.0, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][C:10]=1CO)O.[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[Na+]>O=P(Cl)(Cl)Cl>[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[CH2:7]([C:15]1[N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:7]=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1cccc(CO)c1C(O)c1ccccn1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1c2ccccc2cc2cccc[n+]12

Procedure:
A mixture of 0.6 g (2.5 mmol) of 1-(2-pyridyl)-1-[2,6-di(hydroxymethyl)-phenyl]methanol and 10 ml of POCl3 was refluxed with 30 stirring for 4 hours. The mixture was cooled, poured onto ice, stirred and treated with a 20% sodium perchlorate solution. The resulting mixture was filtered, the resulting solid was washed with water, and dried to afford 0.58 g of 10-chloromethyl-benzo[b]quinolizinium perchlorate (Formula II: R1 =R2 =H; R7 =10-CH2Cl; X- =ClO4-).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(O)[C:31]#[CH:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[CH:32]=[CH:31][C:30]([C:27]4[CH:28]=[CH:29][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:25][CH:26]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:17][C:9]=3[CH:8]=2)[CH2:5][CH2:6]1
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCOCC2)cc1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1
Solvent: Cc1ccccc1
Product: C1=CC(c2ccccc2)(c2ccc(N3CCOCC3)cc2)Oc2cc(N3CCOCC3)c3ccccc3c21
Yield: 73.2 %

Procedure:
A solution of 4-morpholino-2-naphthol (1.5 g, 6.5 mmol) and 1(4-morpholinophenyl)-1-phenylprop-2-yn-1-ol (1.92 g, 6.5 mmol) in toluene (65 cm3) containing acidic alumina (Brockmann 1), (4.0 g) was refluxed for 60 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). Removal of the solvent from the filtrate gave an oil which solidified on standing at room temperature. Recrystallisation from EtOAc/hexane gave 6-morpholino-3(4-morpholinophenyl)-3-phenyl-3H-naphtho[2,1-b]pyran (yield=2.4 g, theoretical yield=3.3 g 73%, m.p.=187-188° C. (uncorrected), λmax in toluene=469 nm, i.e. red-orange).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8]S[N:10]=[C:6]2[C:5]([S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1>CC(O)=O.O.[Zn]>[NH2:10][C:6]1[C:7]([NH2:8])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:11]([NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c3nsnc23)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c(N)c2N)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the compound 39D (382 mg, 1.0 mmol) in AcOH/H2O (8 mL/3 mL) at 70° C. was added zinc powder (975 mg, 15 mmol) and the resulting suspension was stirred at 70° C. for 1 h. The solid was filtered off and washed with EtOAc. The filtrate was partitioned between satd. NaHCO3 and EtOAc. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give crude product 39E, which was confirmed by LCMS, and used in the next reaction without further purification. LC-MS: m/z 354.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:25]([CH3:39])[CH2:26][CH2:27][N:28]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:25]([CH3:39])[CH2:26][CH2:27][NH2:28])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: COc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (335 mg, 1.02 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (837 mg, 2.56 mmol) and then using general procedure D afforded 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (240 mg, 62% over 2 steps).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH3:20])[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3.[H][H]>O.CO.[Pd]>[NH2:2][CH2:3][C:4]1([CH3:20])[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]([CH3:18])[CH2:9]3.[ClH:1]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CN)O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C(C)C3)OC(C)(CN)C2
Yield: 80.6 %

Procedure:
A hydrochloric acid salt of 2-Aminomethyl-2,5,8-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.18 g, 4.0 mmol) was suspended in a mixture of water (200 ml) and methanol (40 ml), to which 10% palladium-on-carbon (1.2 g) was added. The mixture was then stirred in a bath at 80° C. for 16 hours in the atmosphere of hydrogen. Post-treatment and recrystallization (methanol-ether) were performed in a manner similar to that described in Example 280 to obtain 957 mg of the title compound as colorless crystals (80.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:20]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: O=c1cc(O)cc[nH]1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc2ccccc2c1
Yield: 69.1 %

Procedure:
Using 1.00 g of 4-hydroxy-2-pyridone and 2.57 g of β-naphthoyl chloride and following the general procedure of Example 18, 1.65 g of the title compound was produced in a yield of 69%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([CH:17]=1)[CH:15]=[CH:14][CH:13]=[CH:12]2.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([C:17]=1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Cc1cc2ccccn2c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2ccccn2c1C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 74.8 %

Procedure:
4.54 ml (32.52 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 3.56 g (27.14 mmoles) of 2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 5.53 g (29.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 18 h at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 5.69 g of a yellow solid are obtained.
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[CH:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29]C(OCC1C=CC=CC=1)=O)=[N:18]C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2].[ClH:40].[H][H]>[Pd].CO.C(OCC)(=O)C>[ClH:40].[C:1]([O:4][CH:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[CH:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:29])=[NH:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 71 %

Procedure:
A methanol/ethyl acetate (1:1/5 mL:5 mL) solution of compound 40 (420 mg, 0.78 mmol) and 1N HCl (0.76 mL), containing 10% palladium on carbon, was shaken in a Parr hydrogenator at 45 psi hydrogen pressure for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 170 mg (71%) of the title product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:11]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1Br

Procedure:
Following a procedure similar to that described in Example 35, but using 1-(4-fluorophenyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 34) and N-bromosuccinimide as starting materials, the title compound was obtained as a white powder (yield 30%), melting at 158-159° C.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13]=2[N:14]=1)[CH3:3].C(N(CC)CC)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[CH2:2]([C@@H:4]1[CH2:8][N:7]([C:42]([C:33]2[CH:34]=[N:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]=2)=[O:43])[CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]=2[N:14]=1)[CH3:3]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1CN(C(=O)c2cnc3ccccc3n2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (73 mg) in dicloromethane (2 mL) was added triethylamine (62 mg) and 2-quinoxaloylchloride (40 mg) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via CombiFlash flash chromatography eluting with 24% MeOH/methylene chloride provided the title compound. 400 MHz 1H NMR (CDCl3) δ 12.78-12.62 (m, 1H), 9.41 (d, J=7.5, Hz, 1H), 8.18-8.00 (m, 3H), 7.87-7.73 (m, 2H), 4.84-4.81 (m, 1H), 4.55-3.86 (m, 6H), 3.61-3.53 (m, 2H), 3.38-3.31 (m, 1H), 2.75 (m, 1H), 2.39-2.34 (m, 2H), 1.93-1.89 (m, 2H), 1.58-1.56 (m, 1H), 1.63-1.50 (m, 1H), 1.01-0.88 (m, 3H). MS: (M+H m/z 474.2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]3[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:24]=1.C(=O)([O-])[OH:26].[Na+]>O1CCOCC1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:24]=[C:3]([CH2:2][OH:26])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: Fc1ccccc1C1=NCc2nc(CCl)cn2-c2ccc(I)cc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 1.2 g of 2-chloromethyl-6-(2-fluorophenyl)-8-iodo-4H-imidazo [1,2-a][1,4]benzodiazepine in 20 ml of dioxan was treated with a solution of 0.4 g of sodium hydrogen carbonate in 10 ml of water and the mixture was stirred at 80° C. for 2 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethanol. There was obtained 0.6 g of amorphous 6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol which was converted into the crystalline hydrochloride (m.p. 274-276° C.),
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: N#CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.6 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidine-4-carbonitrile (3.03 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carbonitrile (6.86 g, 93%) as a cream crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 78 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) was converted using aminomethylcyclopropane instead of 2,2,2-trifiuoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 142 mg, 78%) which was obtained as a white foam. MS: m/e=364.3 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)#[N:33].O[CH:42]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)[CH2:43]1>O1CCCC1>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:46]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[CH2:45]2)=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(O)cc1
Reactant: OC1CCN(c2ccncc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCN(c3ccncc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
A solution of diethyl azodicarboxylate (1.73 ml) in dried tetrahydrofuran (10 ml) was added dropwise to a stirred mixture of triphenylphosphine (3.15 g), 4-cyanophenol (1.31 g) and 4-(3-hydroxy-1-pyrrolidinyl)pyridine (1.64 g) in dried tetrahydrofuran (45 ml), under an atmosphere of argon, at 5-7° C. The resulting solution was stirred at ambient temperature for 16 hours. The solid, which had separated, was filtered off and washed with diethyl ether to give 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (823 mg) as an off-white solid, mp 182-185° C.