Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[O:9])[CH2:2]1>CO>[O:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[O:9])[CH2:2]1
Reactant: O=C(NCC1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Solvent: CO
Product: O=C(NC[C@H]1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1

Procedure:
A racemic mixture of N-(4-{[tetrahydrofuran-3-ylmethyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide (250 mg) was dissolved in methanol and separated using SCF-LC with a ChiralPak AD-H 21×250 mm column to provide N-(4-{[(3R)-tetrahydrofuran-3-ylmethyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.57 (s, 1H), 8.38 (t, J=5.7 Hz, 1H), 7.75-7.79 (m, 2H), 7.64-7.69 (m, 2H), 7.30-7.39 (m, 4H), 4.78-4.79 (bs, 4H), 3.57-3.78 (m, 3H), 3.48 (dd, J=8.5, 5.3 Hz, 1H), 3.13-3.29 (m, 2H), 2.40-2.50 (m, 1H), 1.87-2.07 (m, 1H), 1.54-1.66 (m, 1H); MS (ESI(+)) m/e 366 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)(=[O:12])=[O:11].[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(CO)c2)c(C)c1
Reactant: BrCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(COCc3ccncc3)c2)c(C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethylphenyl)-3-(hydroxymethyl)-N-isobutylbenzenesulfonamide (50 mg, 0.144 mmol) and Sodium hydride (60% in Mineral Oil) (6.33 mg, 0.158 mmol) were dissolved in N,N-Dimethylformamide (DMF) (3 mL). To this solution was added 4-(bromomethyl)pyridine (24.75 mg, 0.144 mmol), and the reaction heated to 60° C. and left to stir for 30 min. The reaction solution concentrated on the Biotage V10 and then extracted the crude product to the organic phase of an aqueous work up between ethyl acetate (15 mL) and water (15 mL). The organic phase was separated (hydrophobic frit) and then concentrated in vacuo. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoprep on Sunfire C18 column using acetonitrile:water with a formic acid modifier. The solvent was evaporated in vacuo. The crude product was run through an NH2 SPE column (1 g) eluting with methanol, to remove the formic acid. The product was then dried under a stream of nitrogen on a Radleys blow down unit, to give the final product, 13.5 mg.
Reaction SMILES: [CH2:1]([C:5]1[N:13]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]#[N:27])=[CH:19]3)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:13]([C:14]2[C:15]3[C:20](=[CH:19][C:18]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]4[NH:38][N:37]=[N:36][N:27]=4)=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C#N)ccc12
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3-c3nnn[nH]3)ccc12
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[5-(2-butyl-imidazo[4,5-b]pyridin-3-yl)-naphthalen-2-yl]-benzonitrile (85 mg, 0.21 mmol) and trimethyltin azide (108 mg, 0.50 mmol) in xylene (2.5 mL) was heated under reflux for 17 hours. The reaction mixture was cooled to 23° C. and the solvent was removed in vacuo. The crude residue was dissolved in EtOH (5 mL) and 2N NaOH (5 mL) was added. After 0.5 hour, the reaction mixture was concentrated in vacuo. The residue was dissolved in saturated aqueous NaCl (2 mL) and neutralized with concentrated HOAc. The aqueous solution was extracted with CHCl3 (3×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was azeotroped with heptane, diluted with EtOAc (1 mL) and hexanes (25 mL). The solid that precipitated was filtered and dried. 1H NMR (250 MHz, d6 -DMSO): d 8.13 (m, 3 H), 7.96 (s, 1 H), 7.65 (m, 6 H), 7.30 (m, 1 H), 7.12 (dd, 1 H), 6.86 (d, 1 H), 2.55 (m, 2 H), 1.63 (m, 2 H), 1.22 (m, 2 H), 0.74 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NS(=O)(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cold (ice/water) solution of {2-chloro-4-[(2-aminophenyl)amino]phenyl}(2-methylphenyl)methanone (0.67 g, 2.0 mmol)(disclosed in WO 98/32730) in pyridine (10 mL) was added benzenesulfonyl chloride (0.32 mL, 2.5 mmol). The reaction mixture was warmed to room temperature. After stirring for 48 h, the reaction mixture was poured into ice water. The precipitate was filtered off, washed with water, and diethyl ether to afford the crude product. Crystallization from acetic acid afforded the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](Br)=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C([Li])CCC.CCCCCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=1[CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:38]
Reactant: COCCc1cc(OCOC)cc(OCOC)c1Br
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCc1cc(OCOC)cc(OCOC)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
3,5-Bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)-benzene (5.3 g, 16 mmol) obtained in Example 1, Step 4 was dissolved in tetrahydrofuran (0.10 L). After the solution was cooled to −78° C., a 1.6 mol/L solution of n-butyllithium in hexane (30 mL, 48 mmol) was added thereto, followed by stirring for 5 minutes. Benzaldehyde (6.4 mL, 62 mmol) was added to the reaction mixture, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (30 mL), and the mixture was extracted with ethyl acetate (0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 53%). Then, [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 8.4 mmol) was dissolved in dichloromethane (50 mL), and Molecular Sieves 4 Å (7.9 g) and pyridinium dichromate (7.9 g, 21 mmol) were added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl=phenyl=ketone (2.9 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C(#N)C.O1CCCC1>[CH3:11][S:8]([NH:7][CH2:6][C:5]1[CH:12]=[CH:13][C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
N-(4-Aminobenzyl)methanesulfonamide (352 mg, 1.76 mmol) was dissolved in acetonitrile (3 mL) and tetrahydrofuran (4 mL). The reaction mixture was added pyridine (0.17 mL, 2.11 mmol) and phenyl chloroformate (0.23 mL, 1.85 mmol) and stirred at room temperature for 3 h under nitrogen atmosphere. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 4-(methylsulfonamidomethyl)phenylcarbamate (438 mg, 78%).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.C(OC([N:69]1[CH2:74][CH2:73][N:72]([CH2:75][C:76]2[CH:81]=[CH:80][C:79]([CH:82]=O)=[C:78]([O:84][CH3:85])[CH:77]=2)[CH2:71][CH2:70]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:82]([C:79]3[CH:80]=[CH:81][C:76]([CH2:75][N:72]4[CH2:73][CH2:74][NH:69][CH2:70][CH2:71]4)=[CH:77][C:78]=3[O:84][CH3:85])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 10 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-formyl-3-methoxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester were reacted to produce a material which following treatment with trifluoroacetic acid at 40° C. for four hours, followed by concentration and neutralization afforded the title compound (10%). 1H NMR (d-4 methanol): 8.30 (d, J=7 Hz, 1H), 8.11 (s, 1H), 7.40 (s, 1H), 7.27 (d, J=7 Hz, 1H), 6.47 (m, 2H), 5.09 (m, 1H), 4.34 (m, 2H), 4.13 (s, 3H), 3.73 (s, 1H), 3.56 (s, 4H), 3.44 (s, 4H), 3.07 (s 1H), 3.02 (s, 1H), 2.75 (s, J=8 Hz, 1H), 2.18 (m, 2H), 1.87 (s, 1H), 1.58 (d, J=8 Hz, 1H), 1.30 (s, 1H). MS: 508.2 (M+H). HPLC retention time: 1.66 minutes (G Method).
Reaction SMILES: Cl.N[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.N([O-])=[O:26].[Na+]>Cl.O1CCOCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:3](=[O:26])[NH:4][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc(N)c1C(=O)OCC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a mixture of 90 ml of 2% hydrochloric acid and 60 ml of dioxane was dissolved 3.50 g (10 mmol) of 2-amino-3,4-diethoxycarbonyl-6-phenylpyridine hydrochloride. A solution of 0.83 g (1.2 eq.) of sodium nitrite dissolved in 3 ml of water was added dropwise thereto. The mixture was stirred at room temperature for 4 hours and left standing overnight. The solvent was distilled off. The resulting crystals were collected by filtration with water. The crystals were recrystallized from ethanol, to give pale yellow prisms.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: Oc1cccc2ccoc12
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc2ccoc12
Yield: 14 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 7-hydroxybenzofuran, the desired product is obtained in the form of a white solid with a yield of 14%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[CH3:40][Zn]C.C1(C)C=CC=CC=1>>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][N:13]([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:40])[N:7]=3)=[C:9]([C:21]3[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: C[Zn]C
Reactant: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(N3CCS(=O)(=O)CC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.325 mmol) and 2N dimethylzinc in toluene (0.325 mL, 0.649 mmol), the title compound was obtained as a solid (110 mg, 59% yield). MS (ESI): 596 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=[O:4].[CH3:29][NH2:30].[K+].[Br-]>C(O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH:30][CH3:29])=[O:4])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: CN
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 2.1 g (0.005 mole) of 8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid methyl ester and 20 ml of a 28% solution of methylamine in ethanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give a tan solid. Recrystallization from ethanol gave off-white prisms with mp 224°-227°. Uv λ max 218 mμ (ε=51,400) infl 245 (26,000) sh 275 (12,000); ir (KBr) 3410 cm-1 (NH) 1668, 1527 (CON).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]#[CH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[CH:20]=[C:19]([CH2:18][NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
A solution of ethyl chlorooximidoacetate (10 g, 66 mmol) in THF (200 ml) was added dropwise over 3 hours to a mixture of N-(tert-butyloxycarbonyl)propargylamine (20.5 g, 131 mmol) and triethylamine (11.2 ml, 80 mmol) in tetrahyrofuran (100 ml). The mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with isohexane/diethyl ether (80:20 then 50:50) to give the title compound (10.6 g, 60%). NMR (DMSO): 1.3 (t, 3H), 1.38 (s, 9H), 4.35 (m, 2H), 6.62 (s, 1H), 7.55 (s, 1H); m/z 269 (M−H)—.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:11][CH2:12]2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CN
Solvent: CO
Product: CNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 2-chloro-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]benzimidazole (Example 1, 69.3 mg, 0.17 mmol) in 40% MeNH2 solution in MeOH (5 ml) was stirred in autoclave at 110° C. for 6 h. After cooling down to room temperature, the solvent was evaporated and the residue was purified by preparative TLC (0.5 mm plate×3, CH2Cl2/MeOH:10/1) to give 56.9 mg(83%) of title compound as pale brown amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:13]2[CH2:12]1)(C)(C)C.[Cl:45]CCl.[ClH:48]>CO>[ClH:45].[ClH:48].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([C:19]1[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[N:14]2[CH2:15][CH2:16][N:11]([C:10](=[O:33])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:12][C:13]=12)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 95.2 %

Procedure:
(R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.10 g, 0.16 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (pyridin-2-yl)amide dihydrochloride 31(80 mg, yield 95.2%) as a white solid.
Reaction SMILES: [CH3:1][Mg]I.[CH2:4]([O:11][CH2:12][C:13]([CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:16][CH2:17][CH3:18])[CH:14]=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(OCC)C>[CH2:4]([O:11][CH2:12][C:13]([CH2:19][S:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH2:16][CH2:17][CH3:18])[CH:14]([OH:15])[CH3:1])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]I
Reactant: CCCC(C=O)(COCc1ccccc1)CSCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCC(COCc1ccccc1)(CSCc1ccccc1)C(C)O
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (4.0 ml, 3M solution in ether) was added to a solution of 2-benzyloxymethyl-2-benzylthiomethyl-pentanal (2.6 g.) in dry diethyl ether (50 ml.) at 0°. The mixture was refluxed, with stirring for 2 hours. The mixture was cooled and poured into 1N hydrochloric acid in ice. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica, eluting with diethyl ether. 3-Benzyloxymethyl-3-benzylthiomethylhexan-2-ol was obtained as a colourless oil (0.7 g.).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]1[C:37]2[O:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].O>CN(C)C=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[C:37]3[O:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCN3CCN(c4ccccc4Cl)CC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound. was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.O.[NH2:20][NH2:21].CCOCC.O>N1C=CC=CC=1>[NH:20]([C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2)[NH2:21]
Reactant: O=c1[nH]c2ccc(Cl)nc2cc1-c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Temperature: 160 °C

Procedure:
A mixture of 6-chloro-3-phenyl-1,5-naphthyridin-2(1H)-one (7-1) (1.4 g, 5.61 mmol) and hydrazine hydrate (2 g, 40 mmol) in pyridine (18 mL) was heated under microwave irradiation at 160° C. for 1.5 hours. To the mixture was added Et2O and water, and the resulting solid was collected by filtration to give 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)one (7-2) as orange solid.