Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NC[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])C>CN(C)C1C=CN=CC=1.ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)OCCN(C)C)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a mixture of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-carboxypent-1-yl]oxy-4-methylphenyl]benzamide (250 mg), 2-dimethylaminoethyl (99 mg) and 4-dimethylaminopyridine (36 mg) in dichloromethane (10 ml) was added N-ethyl-N'-(3-dimethylaminoprop-1-yl)carbodiimide hydrochloride (71 mg) at 0° C. and stirred at the same temperature for 7 hours. The mixture was diluted with chloroform (20 ml) and the solution was washed with water (20 ml×2) and brine. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. This residue was purified by silica gel column chromatography (SiO2 30 g, 1-10% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(2-dimethylaminoeth-1-yl)oxycarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (238 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:3][CH2:2]1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NCCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of 4-morpholinobutan-1-amine (0.63 g, 4.00 mmol), 1,2-difluoro-4-nitrobenzene (0.64 g, 4.00 mmol) and K2CO3 (1.10 g, 8.00 mmol) in acetonitrile (20 mL) was stirred at rt for 19 h under N2, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[N:6]([C:10]([CH:14]=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Br)=[O:19].Cl>O1CCCC1>[CH:14]([C:10]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][CH2:23][C:22]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:18]([O:17][CH3:16])=[O:19])[C:5]2=[N:12][C:11]=1[CH3:13])=[O:15]
Reactant: Cc1nc2c(N)cccn2c1C=O
Reactant: COC(=O)Nc1cccc(C)c1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A suspension of 400 mg of commercial 80% sodium hydride in 10 ml of dry tetrahydrofuran is added to a solution of 2 g of 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine in 40 ml of dry tetrahydrofuran at RT. Brief heating at 50° C. is followed by vigorous evolution of gas. After the evolution of gas is complete, the mixture is cooled to 0° C., and a solution of 3.9 g of 2-methoxycarbonylamino-6-methylbenzyl bromide in 40 ml of dry tetrahydrofuran is added dropwise. The mixture is again heated to 50° C. and kept at this temperature for 3 h. It is then poured into ice-water, neutralized with a little dilute hydrochloric acid and extracted four times with ethyl acetate. The collected organic phases are washed with water and dried over sodium sulfate. The solvent is stripped off in vacuo, and the dark brown viscous residue is chromatographed on silica gel (ethyl acetate:petroleum ether=1:1 as eluent). Recrystallization from isopropanol results in 2.5 g of the title compound of m.p. 188°-190° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41].C(N(CC)CC)C.O>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[S:6]([O-:9])(=[O:8])=[O:7].[CH2:38]([S:42]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
30 g of 4-hydroxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate was dissolved in 300 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 17.9 g of n-butanesulfonyl chloride and 10.5 g of triethylamine were added in this order. The mixture was stirred for 20 minutes at room temperature. After the addition of 100 g of ion-exchanged water, the mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the solution was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dichloromethane solution, the residual liquid was dried under reduced pressure to obtain 26.7 g of 4-n-butanesulfonyloxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate. This compound is indicated as “acid generator (A-1)”.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([C:13](=[O:15])[CH3:14])[CH3:12])=[CH:7][CH:6]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>O>[O:17]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:14][C:13](=[O:15])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)([CH3:16])[CH3:12])[CH:29]=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)(C)C(=O)C=Cc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To 50 ml of ethanol were added 5.3 g of 2-(4-methylphenyl)-2-methyl-3-butanone, 6.0 g of 3-phenoxybenzaldehyde and 6.0 g of KOH, and the mixture was stirred at room temperature for one hour and 20 minutes. Then, the reaction mixture was poured into 300 ml of water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure to give 10.4 g of crude 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one. Then, the crude product was purified by column chromatography on 250 g of silica gel (eluent:benzene) to give 6.8 g of pure 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46].Cl>C(Cl)Cl.N1C=CC=CC=1>[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45]([NH:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:37])([F:36])[F:38])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:46]
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a suspension of p-toluenesulfonic acid salt of benzyl 7-amino-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (800 mg.) in methylene chloride (8 ml.) was added pyridine (146 μl). After stirring at -55° C. for 5 minutes, 2-(2-thienyl)acetyl chloride (290 mg.) was added thereto, and then the mixture was gradually allowed to warm to 0° C. over a period of 1.5 hours. The mixture was poured into chilled dilute hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with water (×2), a dilute aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent left an amorphous solid (800 mg.), which was chromatographed on silica gel (10 g.) with a mixed solvent of methylene chloride and ethyl acetate (95:5 to 90:10 by volume) to give benzyl 7-[2-(2-thienyl)acetamido] -8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (667 mg.).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:17]=[CH:16][C:10]([C:11](OCC)=[O:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[N:3]([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(-n2ccnc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: Cc1nccn1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 4-(2-methylimidazol-1-yl)benzoate (46 g, 0.2 mol) in dry CH2Cl2 (1 l ) cooled to -75° C. under a nitrogen atmosphere was added diisobutyl-aluminum hydride (540 ml, 0.93M in hexane) carefully over 30 minutes and then the mixture was allowed to warm slowly to ambient temperature. After stirring for 5 hours the reaction mixture was cooled in an ice-bath and methanol (30 ml) carefully added. A 30% aqueous solution of Rochelle's salt (500 ml) was then added and the mixture stirred at ambient temperature for 16 hours. Insolubles (essentially product) were removed by filtration and the organic phase separated and washed with water (500 ml), dried (MgSO4) and evaporated. The combined resultant solids were recrystallized from ethanol (ca 300 ml) to afford the titled compound (35.6 g, 95%) as white needles.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.CN(C=O)C>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
(3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol), tert-butyldimethylsilyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol) are combined with 60 mL of DMF. The reaction is stirred at room temperature overnight. The mixture is diluted with 1 L of water. The resulting mixture is extracted with a 1:1 ( 2×200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine solution, dried with NaSO4, and concentrated. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one as a white solid; 1H NMR (CDCl3) δ5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:15][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc(Cl)cc2c1CCC2
Product: CC(=O)OC1CCc2cc(Cl)cnc21

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide (2.07 g, 12.2 mmol) in acetic acid anhydride (62.2 ml, 659 mmol) was stirred at 110° C. for 20 hours. For the workup, the solvent was removed at reduced pressure and the residue quenched with saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane, the resulting organic layers combined and dried over sodium sulphate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The acetic acid 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl ester was obtained as a red liquid (1.57 g, 61%); (calculated) C10H10ClNO2 [211.65]; (found) [M+H]+=212.
Reaction SMILES: ClC1[CH:3]=[C:4](C=CC=1)[C:5]([OH:7])=O.C(O[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C=C>C(Cl)Cl>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:3][CH:4]3[O:7][CH2:5]3)=[CH:20][CH:19]=2)=[CH:26][CH:25]=1)#[N:28]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(CC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
20 g of m-chlorobenzoic acid was added to a reaction mixture obtained by dissolving 19 g of 4-allyloxy-4′-cyanobiphenyl in 150 mL of methylene chloride as divided into several times, and the mixture was stirred at room temperature for 24 hours. Insoluble matters thus deposited were removed by filtration, and water was added thereto. After separating the mixture, the organic layer was washed with a saturated aqueous solution of sodium hydrosulfite and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a residue, which was purified by silica gel column chromatography and then subjected to recrystallization from ethanol to obtain 13 g of 4-cyano-4′-glycidylbiphenyl.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br>>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[C:33]([F:32])([F:42])[F:43])[CH2:29][CH2:30]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:8][CH:9]=1
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cl
Product: O=C(CCC1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, and 2-(trifluoromethyl)benzyl bromide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[NH2:3][C:4]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Sodium hydride (60% in oil, 1.26 g) was added to a 0° C. solution of 2-aminopyridine (2.00 g) in THF (10 ml) and the resultant mixture stirred at 0° C. for 1 h. A solution of 2-fluoronitrobenzene (2.21 ml) in THF (8 ml) was added dropwise and the resultant mixture allowed to attain rt overnight. Saturated aqueous sodium carbonate (10 ml) was added and the separated aqueous phase extracted into dichloromethane (3×10 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. Flash column chromatography (cyclohexane: ethyl acetate; 3:1 as eluant) gave the title compound (2.23 g) as an orange/red solid.
Reaction SMILES: [C:1]12([C:7]3[O:11][N:10]=[C:9]([CH3:12])[N:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(=O)(O)[O-].[Na+].[Cl-].[Na+].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>O.CO>[C@@:1]12([C:7]3[O:11][N:10]=[C:9]([CH3:12])[N:8]=3)[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2
Reactant: Cc1noc(C23CNCC2C3)n1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1noc([C@]23CNC[C@H]2C3)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
5-(3-Azabicyclo[3.1.0]hexan-1-yl)-3-methyl-1,2,4-oxadiazole (105) (923 mg, 4.58 mmol) was dissolved in water (20 mL) and treated with saturated sodium bicarbonate (40 mL), and 5 g of sodium chloride (pH=8). The aqueous layer was extracted with dichloromethane (6×100 mL), the organic layers combined, dried over magnesium sulfate and filtered through a fritted glass filter. The filtrate was treated with D-tartaric acid (655 g, 4.36 mmol) in 60 mL of methanol and evaporated to dryness. The solid residue was dissolved in 6 mL of methanol and then 23 mL of acetonitrile were added. An oily residue that formed was decanted away from and dried under vacuum. The crude solid was dissolved into a minimal amount of boiling methanol (40 mL) and then acetonitrile (100 mL, 2.5:1, acetonitrile to methanol ratio) was added. The mixture was allowed to stir at room temperature for 20 minutes prior to isolation. The process was repeated until the crystalline substance exceeded an enantiomeric purity of 99.5%; obtained 440 mg of 5-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-3-methyl-1,2,4-oxadiazole (106b). The optical purity was determined by HPLC analysis (Chiral Technologies Chiral-AGP, 4.0 mm×150 mm, 0.5% methanol, 20 mM sodium phosphate pH=7). (106b) MS (ESI) m/z 165.8 [M+H]+. 1H NMR (DMSO-d6) δ: 1.44 (m, 2H), 2.23 (m, 1H), 2.28 (s, 3H)m, 3.06 (s, 2H), 3.35 (m, 2H), 4.13 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(F)c(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (1.0 g, 7.2 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.32 g, 7.91 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.0 g, 7.2 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered and dried to afford 1.58 g of 2-fluoro-5-(4-methoxybenzyloxy)benzonitrile.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[N:11][CH:12]=1.CN(C)[CH:25]=[O:26]>O1CCCC1.C(OCC)(=O)C>[CH:25]([C:7]1[CH:8]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[N:11][CH:12]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(C#Cc2cncc(Br)c2)c1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc(C#Cc2cncc(C=O)c2)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (220 mg, 2.12 mmol) to a −20° C. solution of 3-(5-bromopyridin-3-ylethynyl)-benzonitrile, (prepared essentially as described in PREPARATION 19), (300 mg, 1.06 mmol) in tetrahydrofuran (2 mL) and stir for 1 h. Add N,N-dimethylformamide (150 mg, 2.12 mmol) in one portion, warm to room temperature, dilute with ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0:100 to 60:40 tetrahydrofuran:hexanes to give the title compound (92 mg, 37%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:16]=1[C:17](OCC1C=CC=CC=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][C:15]1[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:16]=1[CH2:17][OH:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)c1cccc(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(CO)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
A solution of LiAlH4 (1M in THF, 8.13 ml) was added to freshly distilled THF (10 ml) 10 ml. A solution of benzyl 2-benzyloxy-3-isopropylbenzoate (2.27 g, 6.31 mmole) in THF (10 ml) was added via a syringe to the LiAlH4 solution. The temperature was maintain below 40° C. using a water bath and the reaction mixture stirred at ambient temperature overnight. The reaction was quenched with water and the pH adjusted to ~7 with dilute HCl. The resultant precipitate was filtered off and the filtrate partitioned between ethyl acetate/H2O. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography (eluant: ethyl acetate/hexane) to give 2-benzyloxy-3-isopropylbenzylalcohol (1.38 g, 83%).