Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][CH:13]=1.[C:20](=O)([O:23]C)[O:21][CH3:22].C(OCC)(=O)C>C1COCC1.CCCCCC>[C:18]([C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:20]([O:21][CH3:22])=[O:23])#[N:19]
Reactant: Cc1ccncc1C#N
Reactant: COC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccncc1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
1M LiHMDS (45 mL, 44.794 mmol) was added to a solution of 4-methylnicotinonitrile (2.52 g, 21.33 mmol) in THF (15 mL) at −78° C. and the resulting reaction mass was stirred at −78° C. for 1 hour. This was followed by the addition of dimethyl carbonate (1.98 mL, 23.464 mmol) and stirred the resulting reaction mass at −78° C. for 1 hour and further at 0° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with saturated NH4Cl solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25% ethyl acetate in hexane) afforded 530 mg of the product (14.10% yield).
Reaction SMILES: O[C@H](CC)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:27]([CH2:49][CH3:50])[C@@H:28]([N:32]([C:37]1C=CC(C2C=CC=CC=2)=CC=1)[C:33]([O:35]C)=[O:34])[C:29]([OH:31])=[O:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:35][C:33](=[O:34])[N:32]([CH3:37])[C@H:28]3[C:29](=[O:31])[O:30][C@@H:27]3[CH2:49][CH3:50])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC[C@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: CC[C@@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid (0.193 g, 0.56 mmol) in dry CH2Cl2 (25.0 mL), at 0° C., Et3N (0.235 mL, 1.69 mmol) and subsequently TBTU (0.217 g, 0.67 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy/AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.089 g, 57%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 343 [M−NH4]+; (ESI) m/z: 324 [M−H]−. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.38 Hz, 3H), 1.68-1.94 (m, 2H), 4.49-4.60 (m, 1H), 4.76 (dd, J=4.32, 8.08 Hz, 1H), 5.12 (s, 2H), 7.33-7.42 (m, 1H), 7.42-7.53 (m, 4H), 7.62-7.76 (m, 4H), 8.25 (d, J=8.09 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=[C:21]([Br:24])[Br:20])[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 52.45 g (200 mmol) triphenylphosphine in 200 ml CH2Cl2 was treated with 33.16 g (100 mmol) tetrabromomethane (the reaction heated up to reflux) and after 50 min with 32.06 ml (230 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 12.83 g (50 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 125 ml CH2Cl2 were added during 10 min. The solution was stirred for 16 h at RT, evaporated and filtered through silica gel (deactivated with hexane/0.5% Et3N) with hexane and then hexane/Et2O 4:1 to 1:1 as eluent to yield 13.28 g (67%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, mp: 93–99° C., dec.; MS: 396 (MH+, 2Br).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:20]=[CH2:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[O:7][C:8]1[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=1.C1COCC1>CO>[CH2:20]([C:3]1[C:2]([F:1])=[CH:17][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:21]
Reactant: C=Cc1cc(OC)c(Oc2cccnc2[N+](=O)[O-])cc1F
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(OC)c(Oc2cccnc2N)cc1F

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by 3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine (3.7 mmol, 1.1 g) and THF by methanol, the title compound was prepared as a white solid (800 mg; 80.5%) and used without further purification.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:15]=[CH:16][C:3]=12.S(=O)(=O)(O)[OH:27].N([O-])=O.[Na+]>O1CCOCC1.O>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][N:14]1[C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([OH:27])=[C:3]2[CH:16]=[CH:15]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1N
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To solution of ethyl 4-amino-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6 g, 14.8 mmol) in 1,4-dioxane (16 mL) at 0° C. was added dropwise a cold solution of sulfuric acid (16 mL, 300 mmol) in water (24 mL) followed by dropwise addition of a solution of sodium nitrite (4.2 g, 60.5 mmol) in water (12 mL) in 10 min. After stirring for 1 h at 0° C. and 3 h at RT for 3 h the mixture was cooled to 0° C. and more sodium nitrite (1.3 g) in water (3 mL) was added. After 2 h at RT cold water was added and the mixture was filtered washing with water. The solid was dissolved in MeOH and solid NaHCO3 was added. The mixture was stirred for 10 min then filtered and concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3/water and the organic phase was dried (Na2SO4), concentrated and dried in vacuo to provide ethyl 1-(3,4-difluorobenzyl)-4-hydroxy-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.02 g, 13.8 mmol, 93% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (t, J=7 Hz, 3 H), 2.86 (s, 3 H) 4.49 (q, J=7 Hz, 2 H), 5.40 (br s, 2 H), 6.66 (d, J=3.51 Hz, 1 H), 6.91-7.15 (m, 4 H), 12.82 (br s, 1 H); LCMS (m/z) ES+=347 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36](C)[C:37](=O)C(F)(F)F)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].O[Li].O>C1COCC1.O.C(Cl)Cl>[F:1][C:2]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][CH3:37])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5]
Reactant: CN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Yield: 45.5 %

Procedure:
To a solution of 2,6-difluoro-N-[3-(3-{2-[(3-{[methyl(trifluoroacetyl)amino]-methyl}phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]benzamide (70 mg, 0.11 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH.H2O (10 mg, 0.21 mmol). The solution was stirred at 50° C. for two h, then diluted with 25 mL DCM and washed with 1 M aqueous Na2CO3. The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography to generate 26 mg of the title compound as a yellow solid (0.05 mmol, 42% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.95 (s, 1H), 9.52 (s, 1H), 8.86 (d, J=7.0 Hz, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.73 (s, 1H), 7.46-7.62 (m, 4H), 7.36 (d, J=7.5 Hz, 1H), 7.12-7.28 (m, 4H), 6.92 (d, J=7.3 Hz, 1H), 6.53 (d, J=5.3 Hz, 1H), 3.59 (s, 2H), 2.26 (s, 3H). MS (ESI) m/z=562 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].I[CH3:24]>C(#N)C>[CH3:17][N:13]1[C:12]([CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:16][N:15]=[N:14]1.[CH3:24][N:14]1[N:15]=[N:16][C:12]([CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:13]1
Reactant: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CC#N
Product: Cn1nnc(CSc2ccc([N+](=O)[O-])cc2)n1
Product: Cn1nnnc1CSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (6.3 g) were added acetonitrile (315 ml), and then, to this solution was added potassium carbonate (4.5 g) and iodomethane (1.75 ml), and the mixture was stirred for 240 hours at room temperature. The solvent was removed under reduced pressure, and to the obtained residue was added ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 1-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole and 2-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole as mixture (3.87 g, 1:1).
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[O:6][C@H:3]1[CH2:4][CH2:5][C@H:1]([OH:7])[CH2:2]1)([CH3:19])([CH3:18])[CH3:17].[C:16]([Si:13]([CH3:15])([CH3:14])[O:6][C@@H:3]1[CH2:4][CH2:5][C@H:1]([OH:7])[CH2:2]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)C1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a mixture of 1,3-cyclopentanediol (5.0 g, 48.9 mmol) (cis/trans mixture, Aldrich) and imidazole (3.3 g, 48.5 mmol) in tetrahydrofuran (100 mL) at 0° C. was added tert-butyldimethylsilyl chloride (5.2 g, 34.3 mmol) (Aldrich) in portions (250 mg every 15 minutes). When all additions were completed the reaction mixture was allowed to slowly warn to room temperature. After stirring overnight the mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a silica gel column with a 0–20% ethyl acetate in hexanes gradient to give (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol as a colorless viscous oil, (Yield 4.23 g, 57%), and (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (Yield 420 mg, 6%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(Cl)Cl>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([NH:6][C:24](=[NH:25])[C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=2)=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: COc1cccc(C#N)c1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(C(=N)Nc2c(C(C)C)cc(Br)cc2C(C)C)c1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
One 2 L 3-neck flask was charged with 4-bromo-2,6-diisopropylaniline (19 g, 74.2 mmol) and toluene (200 ml). Trimethylaluminum (2M solution in toluene, 25 ml) was added dropwise into the reaction mixture at 0° C. After the addition was over, the ice bath was removed and reaction mixture was allowed to stir at room temperature (20-25° C.) for 3 hours. 3-methoxybenzonitrile (9.88 g, 74.2 mmol) in toluene (300 ml) was then added into reaction mixture. The reaction mixture was allowed to heated to 80° C. for 17 hours. The reaction mixture was poured slowly into a slurry of 200 gm of celite in 900 ml of a 2:1 mixture of DCM in methanol. The reaction mixture was then filtered and filtrate was evaporated to dryness, the residue was re-suspend with heptane and filtered to yield N-(4-bromo-2,6-diisopropylphenyl)-3-methoxybenzimidamide (19.73 g, 68%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])C.[N:14](C(Cl)=O)([CH3:16])[CH3:15]>>[C:6]([NH:5][NH:4][C:1](=[O:3])[N:14]([CH3:16])[CH3:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)NNC(=O)c1ccccc1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)NNC(=O)c1ccccc1

Procedure:
Synthesis and isolation were same as 1-acetyl-2-benzoylhydrazine, using 1.5 g (11.2 mmol) of benzoylhydrazide, 1.2 g (11.2 mmol) of (CH3)2NCOCl and 1.11 g of TEA. Yield was 0.9 g (39%). 1H NMR (200 MHz, d6-DMSO) δ 2.90 (s, 6H), 7.50 (m, 3H), 7.90 (d, 3H), 8.45 (s, 1H), 10.05 (s, 1H); MS (EI, m/e, relative intensity %) calcd for C10H13N3O2 207, found 207 (M, 13.2); mp 199-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CCCN(c2ccc(Br)cc2)C(=O)C1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C(N2CCOCC2)=CCCCN1c1ccc(Br)cc1

Procedure:
N-[4-bromophenyl]-3-oxocaprolactam (0.37 g, 1.13 mmol), morpholine (0.25 mL, 2.81 mmol), and p-toluenesulfonic acid (catalytic amount) were refluxed with 30 mL benzene using a Dean Stark apparatus under N2 for 12 h. The solvent was removed in vacuo and the residue was dried under vacuum to give 1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-one. LRMS (AP+): 351.0, 353.0, (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)[Cl:22].C([O-])(O)=O.[Na+]>CCO>[OH2:25].[Cl:22][CH2:21][CH:23]([OH:25])[CH2:24][N:16]1[CH2:15][CH2:14][N:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)[CH2:18][CH2:17]1.[Cl:22][CH2:21][CH:23]([OH:25])[CH2:24][N:16]1[CH2:15][CH2:14][N:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)[CH2:18][CH2:17]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O
Product: OC(CCl)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reaction time: 20 h
Yield: 26.3 %

Procedure:
4-Chlorobenzhydrylpiperazine (14.34 g, 50 mmol) in EtOH (150 mL) was added to epichlorohydrin (3.92 mL, 50 mmol) in ethanol (25 mL) and NaHCO3 (4.2 g, 50 mmol) over 45 min at 0° C. under nitrogen. After 20 h, the EtOH was removed in vacuo and the residue eluted through silica gel using 50% methanol: methylene chloride to give the pure product (3.40 g, 18.3%) as a white solid, mp 72°-74° C. DCI/MS (M+1) 379. 400 MHz 1H NMR (CDCl3) δ: 7.5-7.35 (m, 9H), 4.2 (s, 1H), 3.65 (m, 2H), 2.9 (m, 2H), 2.7-2.6 (m, 8H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 43 mg (0.13 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (5 mL) was added NaH (9 mg, 0.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (22 mg, 0.16 mmol) in DMF (1 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 48 mg (86%) of the title compound as a colorless oil. ES-MS m/e: 436.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C1=CCNCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,2,3,6-tetrahydropyridine (82 mg) in tetrahydrofuran (2 ml) was added 4-fluorophenyl-isocyanate (0.112 ml) at ambient temperature. After stirring at ambient temperature for 10 hours, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with diisopropyl ether to give 1-(4-fluorophenylcarbamoyl)-1,2,3,6-tetrahydropyridine (117 mg).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([N+:13]([O-:15])=[O:14])[N:6]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:7]=1.[N:16]([O:18]CCC(C)C)=O>>[Cl:1][C:10]([CH3:12])([CH3:11])[CH:9]([N:16]=[O:18])[CH2:8][N:6]1[CH:7]=[C:3]([CH3:2])[N:4]=[C:5]1[N+:13]([O-:15])=[O:14]
Reactant: Cl
Reactant: CC(C)CCON=O
Reactant: CC(C)=CCn1cc(C)nc1[N+](=O)[O-]
Product: Cc1cn(CC(N=O)C(C)(C)Cl)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Concentrated HCl (20 mL) was added from an addition flask to a mixture of 1-(4-methyl-2-nitro-1H-imidazol-1-yl)-3-methyl-2-butene (5.0 g, 25.64) and isoamyl nitrite (20 mL), keeping the temperature in the range of 0° C. to 5° C. After the addition the reaction mixture was stirred at ice-cold temperature for 30 minutes. The solid which formed was removed by filtration and washed with ice-cold ethanol. The solid was dispersed in acetonitrile, cooled to 0° C. and filtered to provide the title product as a light blue colored solid; yield: 4.97 g (62%); mp. 110-113° C. (decomp); 1H NMR (DMSO-d6) δ 1.81 [s, 6H, C(CH3)2], 2.16 (s, 3H, imi-CH3), 5.36 (s, 2H, NCH2), 7.12 (s, 1H, imi-CH) and 11.98 (s, 1H, NOH). MS m/e 261 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[C@H:35]2[CH2:36][C@H:31]([CH2:32][CH2:33][C@@H:34]2[C:37]([OH:39])=O)[O:30]1.[C:40]1([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:40]1([N:46]2[CH2:51][CH2:50][N:49]([C:37]([C@H:34]3[CH2:33][CH2:32][C@H:31]4[CH2:36][C@@H:35]3[C:29](=[O:28])[O:30]4)=[O:39])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.0 g, 0.016 mol) was added To a solution of (1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylic acid (14.4 mmol, 0.0144 mol) and 1-Phenylpiperazine (2.4 mL, 0.016 mol) in N,N-dimethylformamide (30 mL, 0.4 mol) at 0 Celsius. After 5 minutes, N,N-diisopropylethylamine (7.5 mL, 0.043 mol) was added at 0 Celsius. The mixture was stirred at RT for overnight. The product was purified by flash chromatography on silica gel column (ethyl acetate in hexanes: 60%).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C([O-])(=[O:13])C.[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2](=[O:13])[NH:7][CH:6]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1nc(F)cnc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.6 %

Procedure:
In 10 mL of N,N-dimethylformamide was dissolved 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. At an ice-cooled temperature, 0.64 g of sodium acetate was added and stirred for 6 hours. The reaction mixture was added to a mixture of 20 mL of ethyl acetate and 20 mL of water, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate-: 1:1] to obtain 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile as a yellow-colored solid product.