Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][C:14]=1[N:15]([CH:25]([CH3:27])[CH3:26])[C:16]([CH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])=[O:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][C:14]=1[N:15]([CH:25]([CH3:26])[CH3:27])[C:16]([CH:18]1[CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20][CH2:19]1)=[O:17])=[O:9]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(=O)CC1)C(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Butyllithium (2.5 M, 0.9 mL, 2.280 mmol) was added to a cold solution (−78° C.) of methyltriphenylphosphonium bromide (939 mg, 2.630 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 1 h and then 3-[Isopropyl-(4-oxo-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. (700 mg, 1.754) in THF (5 mL) was added at −78° C. The reaction mixture was allowed to stir at room temperature for 12 h. The reaction was quenched by adding saturated solution of NH4Cl and diluted with ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:4) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (300 mg, 43%) as a solid. 1H NMR (CDCl3, 400 MHz): δ7.63 (d, 2H), 7.50-7.38 (m, 3H), 7.12 (s, 1H), 4.99 (m, 1H), 4.55 (d, 2H), 3.85 (s, 3H), 2.25 (m, 3H), 1.83-1.63 (m, 5H), 1.50 (m, 1H), 1.25 (d, 3H), 0.99 (d, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:8][C@@H:9]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
2,2-Dimethyl-propionic acid (R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propyl ester (81 g, 196 mmol) prepared in Step D was dissolved in dichloromethane (300 mL). 4N hydrochloric acid/1,4-dioxane solution (100 mL) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the solvent was thoroughly removed under reduced pressure. The residue was recrystallized from diethylether, and dried to give the title compound (68 g, Yield 95%).
Reaction SMILES: C([Cl:4])(=O)C.Cl.C(OC([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[O:21][C:20]2=[O:30])[CH2:15][CH2:14]1)=O)(C)(C)C>CO>[ClH:4].[CH:26]1[C:23]2[CH2:24][CH2:25][N:19]([CH:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]3)[C:20](=[O:30])[O:21][C:22]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3OC2=O)CC1
Agent: Cl
Solvent: CO
Product: O=C1Oc2ccccc2CCN1C1CCNCC1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Acetyl chloride (0.2 mL, 2.8 mmol) was added to 2 mL of methanol and stirred for 10 min. This solution of HCl in MeOH was added to 58 mg of 1-t-butyloxycarbonyl-4-(8,9-dihydro-7H-5-oxa-7-aza-benzocyclohepten-6-one-7-yl)-piperidine (Step A) and stirred for 2 hr. The reaction was concentrated in vacuo, the residue was diluted with EtOAc and the solution was concentrated again in vacuo leaving 46 mg of the title compound which was sufficiently pure for use in the next step. 1H NMR (500 MHz, CDCl3): δ2.06 (m, 2H), 2.35 (m, 2H), 3.02 (m, 4H), 3.5-3.8 (m, 4H), 4.35 (br s, 1H), 7.1-7.3 (m, 4H), 9.6 (br, 2H).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH:17]=[N:16]1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:3]3[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=3)[CH:22]=2)[CH:17]=[N:16]1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc3cn[nH]c3c2)[nH]c1=O
Temperature: 80 °C
Yield: 45.4 %

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (358 mg, 1.671 mmol) and 1-H-indazol-6-amine (222 mg, 1.671 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (227 mg, 45.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][N:24]([C:39](=[O:38])[CH2:40][OH:41])[CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(CO)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide, prepared as in Example 19 above (77.3 mg, 0.15 mmol) in CH2Cl2 (2 mL) was added pyridine (0.035 mL, 0.45 mmol, 3 equiv) and then acetoxyacetyl chloride (0.024 mL, 0.225 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 20 min and MeOH (2 mL) and K2CO3 (138 mg, 1.0 mmol) were added sequentially. The resulting mixture was stirred at room temperature for another 1 h. The resulting mixture was filtered and concentrated. The resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=C[CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24](=[N:27][CH3:28])SC)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(#[N:31])C>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]([NH:27][CH3:28])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]2[NH:4][CH:5]=[N:31][C:2]=2[CH3:7])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC#N
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)SC
Reactant: NCCSCc1ncccc1Br
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
A solution of 3-bromo-2((2-aminoethyl)thiomethyl)pyridine (5.0 g) and N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.4 g) in acetonitrile was heated under reflux for 24 hours. Concentration followed by recrystallisation afforded N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)CI
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(SCC(C)(C)C)cc1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
Dissolve 4-methyl-benzenethiol (1.5 g, 12.08 mmol) in anhydrous DMF (6 mL). Cool the solution to 0° C., add sodium hydride (435 mg, 17.21 mmol, 95%) and stir the mixture under nitrogen atmosphere for 15 mm. Add 1-iodo-2,2-dimethylpropane (1.93 mL, 14.5 mmol), stir the mixture for 1 h at 0° C., warm to room temperature and stir overnight. Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (1.476 g, 63% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NOCC1CCO[C@H](c2ccccc2)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CCO)c(=O)n(C)c1=O
Yield: 87 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O—((S)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1H) 11.97 (s, 1H) 7.80 (dd, J=10.11, 1.77 Hz, 1H) 7.58 (d, J=8.84 Hz, 1H) 7.15 (t, J=8.59 Hz, 1H) 4.90 (d, J=4.29 Hz, 1H) 4.38 (t, J=5.05 Hz, 1H) 3.74-3.86 (m, 2H) 3.56-3.66 (m, 1H) 3.45-3.53 (m, 2H) 3.21 (s, 3H) 2.96 (s, 3H) 1.35-1.56 (m, 2H). [M+H] calc'd for C17H20FIN4O6, 523; found, 523.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:35](Cl)(Cl)=[O:36].[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:35]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([Cl:39])=[CH:41][CH:42]=2)=[O:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)NCc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2′-Ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester (0.172 g, 0.5 mmol) and diisopropylethylamine (0.43 mL, 2.5 mmol) were combined in CH2Cl2 (2.5 mL) and cooled to 0° C. Phosgene (20% in toluene; 0.40 mL, 0.75 mmol) was added, and the mixture was stirred for 1 hour. 4-Chlorobenzylamine (0.012 mL, 1.0 mmol) was added, and the reaction was stirred for 1 hour. The mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was dried, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]1([CH2:20]Br)[CH2:19]O[CH2:17]1.Cl.[CH3:23]N(C)C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:17][C:16]3([CH2:20][CH2:23][CH2:19]3)[CH2:15]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: BrCC1(CBr)COC1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=S(=O)(c1ccc(F)cc1)N1CC2(CCC2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
To a cooled (ice-water bath) solution of 4-fluoro-benzenesulfonamide (320 mg, 1.83 mmol) in N,N-dimethylformamide (5 mL), was added sodium hydride (150 mg, 60% dispersion, 3.75 mmol) portion-wise. After the mixture was stirred at 0° C. for 10 minutes, a solution of 3,3-bis-bromomethyl-oxetane (440 mg, 1.8 mmol) in N,N-dimethylformamide (3 mL) was added. The resulting mixture was stirred at room temperature overnight, then neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzenesulfonyl)-2-aza-spiro[3.3]heptane (120 mg, 26%) as a white solid (reference: Blizzard T. A. et al., Bioorg. Med. Chem. Lett. 14 (2004) 3861-3864), MS cald, for C12H14FNO2S 255, obsd. (ESI+) [(M+H)+] 256.
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1)([O-:9])=[O:8]>CN(C)C=O>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][N:2]([CH3:4])[CH3:1])=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride, suspended in mineral oil, and the mixture is treated with 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>C(Cl)Cl.N1C=CC=CC=1>[CH3:2][N:3]([O:4][CH3:5])[C:7]([C:6]([N:3]([CH3:2])[O:4][CH3:5])=[O:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C(=O)N(C)OC
Temperature: -78 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A mixture of 48.0 g (0.49 mol) of N,O-dimethylhydroxylamine HCl in 250 mL of 3:2 v/v CH2Cl2/pyridine was cooled to −78° C. and treated with 17.4 mL (0.2 mol) of oxalyl chloride maintaining the internal temperature at less than −70° C. The resulting mixture was allowed to warm to rt and stirred for 20 h. The reaction was quenched with 250 mL of sat'd NaCl and the quenched mixture was extracted with 3×400 mL of CH2Cl2. The extracts were combined, dried over MgSO4 and concentrated. Recrystallization from 250 mL of methyl t-butyl ether afforded 24.28 g (69%) of the title compound: 1H NMR (500 MHz) δ 3.25 (s, 6H), 3.75 (s, 6H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]2[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=2[N:23]=1>CN(C=O)C.CCOC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:21][C:22]2[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=3[N:23]=2)[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A suspension of 1-isopropyl-1,3-dihydro-benzoimidazol-2-one (0.79 g, 4.5 mmol) and Cs2CO3 (4.40 g, 13.5 mmol) in DMF (50 mL) was stirred for 30 minutes then 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (1.34 g, 4.5 mmol) was added and the mixture stirred for 5 h at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was evaporated to dryness and the residue taken up in EtOAc (100 mL), washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, hexanes:EtOAc 3:1 to 1:1) to give 1.71 g (95%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-:20].[NH4+].[Cl-].[Li+]>CN(C)C=O>[ClH:20].[NH:16]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]3[CH:13]=[N:14][CH:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)=[N:2][N:18]=[N:17]1
Reactant: N#CCCCCc1cccc2cncn12
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: c1cc(CCCCc2nnn[nH]2)n2cncc2c1

Procedure:
A mixture of 5-(4-cyanobutyl)-imidazo[1,5-a]pyridine (4.0 g), sodium azide (1.88 g), ammonium chloride (1.57 g) and lithium chloride (10 mole %) in 14 ml of dry dimethylformamide is heated at 125° for 17 hours. The reaction mixture is cooled, filtered and evaporated to a residual oil which is redissolved in 50 ml of water and extracted with ethyl acetate (50 ml). The aqueous phase is adjusted to pH=2 and extracted with ethyl acetate and then adjusted to pH=5. The resulting solid is collected by filtration and converted to its hydrochloride salt which is recrystallized from acetone/methanol to yield 5-[4-(5-tetrazolyl)butyl]-imidazo[1,5-a]pyridine monohydrochloride, m.p. 159°-161°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([CH3:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[N:20]([CH3:32])[C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([CH3:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc3c(c2)c(C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
12.36 g (3173 mmol) 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-methyl-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 15, were dissolved in 158 mL N,N-dimethylformamide. 1.62 g (40.61 mmol) sodium hydride (as a dispersion in mineral oil) were added and the mixture stirred for 20 minutes. 2.37 mL (38.08 mmol) methyl iodide were added and the mixture stirred for 2.5 hours. The solvent was distilled off under vacuum and the residue was taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Purification with column chromatography afforded 5-(3,5-dicyano-1,2,6-trimethyl-1,4-dihydro-pyridin-4-yl)-3-methyl-indazole-1-carboxylic acid tert-butyl ester (10.56 g, 82.5%). 1H-NMR (DMSO-D6): δ=8.06 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 4.56 (s, 1H), 3.22 (s, 3H), 2.54 (s, 3H), 2.25 (s, 6H), 1.64 (s, 9H) ppm. MS (ES+): 404.45 (M++1, 75%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:21]Br>CCOCC>[Br:21][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)C(C)c1cccc(C(C)=O)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(C)c1cccc(C(=O)CBr)c1

Procedure:
To a cooled vigorously stirred mixture containing ethyl 2-(m-acetyl phenyl)propionate (0.1 mole) dissolved in dry ether (100 ml) and a pinchful of aluminum chloride is added dropwise 0.1 mole bromine.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-2].[Mg+4].[O-2]>CC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(Oc2ccccc2)cn1
Agent: [Mg+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1ccc(Oc2ccccc2)cn1
Yield: 73.6 %

Procedure:
(5-Phenoxy-pyridin-2-yl)-methanol (300 mg, 1.5 mmol) described in Manufacturing Example 121-1-2, magnesium(IV) oxide (1.3 g, 15 mmol), and acetone (10 mL) were stirred under reflux for 20 minutes. More magnesium (IV) oxide (1.5 g, 17 mmol) was then added, which was stirred under reflux for another 20 minutes. The reaction solution was filtered through a Celite pad, and then the filtrate was concentrated under a reduced pressure to obtain the title compound (220 mg, 74%).
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16]1([CH2:22][CH2:23][CH2:24][CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Reactant: O=CCCCc1ccccc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=342.3 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and 4-phenyl-butyraldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([O:14][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (1-20 g) in dichloromethane (50 mL) at 0° C., triethylamine (0.61 mL) and methanesulfonyl chloride (0.31 mL) were added and the mixture stirred overnight at room temperature. The resulting solution was evaporated under reduced pressure and purified on Biotage Horizon® system (silica, gradient 10-20% ethyl acetate in dichloromethane) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.CO[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([NH2:19])=N.[CH2:23]([OH:25])C.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:17]([CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:22]([O:25][CH3:23])=[CH:21][CH:20]=2)[N:19]=1
Reactant: COc1cccc(OCC(=N)N)c1
Reactant: N#Cc1nccnc1N
Reactant: CCO
Solvent: CN(C)C=O
Product: COc1ccc(OCc2nc(N)c3nccnc3n2)cc1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 9.8 g (0.082 mole) of 3-amino-2-pyrazinecarbonitrile and the above solution of 2-(3-methoxyphenoxy)acetamidine in absolute ethanol. Refluxing time: 2 hours. Yld: 5.5 g (24%), m.p. 238°-240° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CNCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.38 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[2-(naphthalen-2-yloxy)-ethyl]amine, solid, m.p. 94° C. (yield 0.61 gm, 90.3%).