Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[S:10](Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:9][C:3]1[C:2]2=[N:1][S:10][N:8]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(N)c1N
Solvent: c1ccncc1
Solvent: O
Product: Cc1cccc2nsnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2,3-diaminotoluene (5.0g, 40.9 mmol) in pyridine (40 mL) at 0° C. was added thionyl chloride (7.0 mL, 98.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 mins, then water (200 mL) was added. The solution was extracted with dicholomethane (2×250 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give compound 839A (5.57g) as a dark brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CC(N(C)C)=O>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(NCCNC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(C(=O)NCCNC(=O)c2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
In a 2 litre volume autoclave for high pressure, N,N'-bis(p-nitrobenzoyl)ethylenediamine (140 g; 0.39 mol), Raney nickel (5 g) and dimethylacetamide (700 ml) are charged, and the atmosphere in the reaction vessel is well replaced by hydrogen. Then, the contents are stirred at 70 to 100° C for about 3 hours while introducing hydrogen (90 kg/cm2) to effect hydrogenation of the nitro group. The reaction mixture is heated to dissolve the produced diamine, Raney nickel is removed off by filtration, and the filtrate is poured into water (5 liters). The resultant precipitate of the diamine is separated and dried to obtain crude crystals (108 g; yield, 93%). Recrystallization from dimethylacetamide (1.5 liters) affords white crystals melting at 293.5° to 295° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[C:10]=12)=[O:5])[CH3:2].[Na].[CH3:21][SH:22].O>CN(C)C=O>[CH3:21][S:22][C:11]1[C:10]2[N:9]([N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CS
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c1c(SC)nc1ccccc12

Procedure:
2.76 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid ethyl ester are heated with 0.71 g. of the sodium salt of methyl mercaptan in dimethylformamide. After cooling, the reaction mixture is poured into water. The product 4-(methylthio)pyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester is filtered under suction and crystallized from ethanol as white needles, m.p. 97°-98°.
Reaction SMILES: [OH:1][CH:2]([CH:9]([NH:14][C:15](=[O:58])[CH:16]([NH:32][C:33](=[O:57])[CH:34]([CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OCC1C=CC=CC=1)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C.[H][H]>C(O)C>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([NH:32][C:33](=[O:57])[CH:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)[C:15]([NH:14][CH:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:2]([OH:1])[C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])=[O:58]
Reactant: [H][H]
Reactant: CC(C)CC(NC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Solvent: CCO
Product: CC(C)CC(NC(=O)C(CCCCN)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C

Procedure:
[2R-[2R*,3S*(S*)]-2-hydroxy-5-methyl-3-[[2-[[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]amino]-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]amino]hexanoic acid, 1-methylethyl ester, 3.97 g (5.0 mmol), is dissolved in 250 ml of absolute ethanol, 0.5 g of 20% palladiun charcoal is added, and the mixture exposed to hydrogen gas for 18 hours. After complete uptake of hydrogen the mixture is filtered and concentrated to afford 3.44 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([N:21]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:41][CH3:42])=O.[BH4-].[Na+].CO>O1CCCC1>[CH2:18]([O:17][C:15]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([O:41][CH3:42])=[C:5]([CH2:3][OH:2])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C@@H:11]1[CH3:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 108 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (Example 13) (100 mg; 0.16 mmol) in 20 mL tetrahydrofuran was added sodium borohydride (62 mg; 1.6 mmol). The reaction was heated to reflux and methanol (40 mL) was added slowly. After an additional 30 min at reflux the reaction was concentrated and the residue was diluted with 20 ml H2O and extracted 3×50 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, concentrated, and the residue was purified by chromatography (30-40% ethyl acetate:hexane) to afford 100 mg of the title product. 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 3.75 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1C=CC=CC=1>[CH2:21]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[C:2]([F:12])([F:1])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: NCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CNCc1ccccc1

Procedure:
A mixture of 3.9 g. (0.0138 mole) of 2-(α,α,β,β -tetrafluorophenethyl)benzylamine, 1.77 g. (0.014 mole) of benzyl chloride, 2.5 g. of anhydrous potassium carbonate, and 25 ml. of benzene is stirred and heated to refluxing for about 40 hours. After filtration, the solvent is evaporated under reduced pressure, leaving the product as the residual oil. Purification is effected by column chromatography on 250 g. of silica, the product being eluted with 1% methanol in chloroform. The fractions that show one spot of rf 0.7 on a fluorescent silica thin layer plate developed with 5% methanol in chloroform are combined. Evaporation of the solvent under reduced pressure leaves the product as the residual oil. The base is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of 8N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 188°-189.5°C. Recrystallization from acetone yields a purified sample, m.p. 188.5°-190°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:25])([F:26])[F:24])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester (0.058 g, 0.14 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.04 mL, 0.28 mmol), followed by pivaloyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred at room temperature for 10 minutes. After work-up with CH2Cl2 and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C1(SC[Cl:9])C=CC=CC=1.C1(S[CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:19]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Cl:9][CH2:17][N:18]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:19]1(=[O:21])=[O:20]
Reactant: ClCSc1ccccc1
Reactant: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CCl
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 1, the latter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) of chloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08 g (0.0025 mol) of TBAB and the product, 2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated with sulfuryl chloride in MDC to give 0.36 g (95%) of 2-chloromethyl-4-phenylsaccharin.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 105.4 %

Procedure:
An N,N-dimethylformamide (5 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (500 mg, 1.84 mmol), 1,4-dibromobutane (2.19 mL, 18.36 mmol), and potassium carbonate (375 mg, 2.76 mmol) was stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (hexane:ethyl acetate=10:1), and the title compound (0.79 g) was obtained as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:28]([NH:38][C:15]([C@H:12]2[CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]2)=[O:17])[CH2:27][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid (23) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.50 g; 4.93 mmol), N,N-diisopropylethylamine (1.70 g; 13.15 mmol) and PyBOP (2.57 g; 4.93 mmol) are added sequentially. The reaction is stirred 4 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (20%→40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH+ 493
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:15]([C:17]([CH3:19])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:28]3[NH:32][C:31](=[O:33])[O:30][N:29]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:34][S-:35].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([CH3:27])[CH2:25][CH2:26]4)[C:15]([CH:17]([CH3:19])[CH2:18][S:35][CH3:34])=[N:16][C:12]=3[CH:11]=[C:10]([C:28]3[NH:32][C:31](=[O:33])[O:30][N:29]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C=C(C)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(C)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 65 °C

Procedure:
3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-methylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 100 mg, 0.22 mmol) was taken up in MeOH (1.5 mL) at room temperature, and sodium thiomethoxide (376 mg, 5.4 mmol) was added. The reaction was sealed and heated at 65° C. for 2 hours. The reaction was then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to afford 3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemate). 1H NMR (300 MHz, CDCl3) δ 8.69-8.74 (m, 1H), 8.57-8.62 (m, 1H), 8.43 (s, 1H), 7.89-7.94 (m, 1H), 3.71-3.93 (m, 2H), 3.22-3.38 (m, 1H), 3.06-3.19 (m, 1H), 2.88-2.99 (m, 1H), 2.07 (s, 3H), 1.48-1.59 (m, 1H), 1.53 (d, J=6.7 Hz, 3H), 1.22-1.38 (m, 2H), 1.08-1.21 (m, 1H), 0.85-1.07 (m, 3H), 0.78 (d, J=6.4 Hz, 3H), 0.66-0.75 (m, 1H), 0.47-0.66 (m, 2H); MS ES calc'd. for C25H29ClN6O2S [M+H]+ 513. found 513.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[CH3:39][O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)CC)C>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:50]3[CH2:49][CH2:48][CH:47]([N:44]4[CH2:45][CH2:46][CH:41]([O:40][CH3:39])[CH2:42][CH2:43]4)[CH2:52][CH2:51]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COC1CCN(C2CCNCC2)CC1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCC(OC)CC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 7i from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 55 mg (0.20 mmol) 4-methoxy-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt), using 100 μL (0.72 mmol) triethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:32]([O:34]C)=O)=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:36].CO>C1COCC1>[C:32]([C:16]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:17]=1)(=[O:34])[NH2:36]
Reactant: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (1015 mg, 2.0 mmol) in THF (15 mL) at room temperature under argon was added 7M ammonia in methanol (4.3 mL, 30 mmol). The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo. The crude product 1.0 g (100%) was used directly to next step. MS (ESI) 437 (M+H-tBu).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([CH2:9][OH:10])[CH3:8].[C:11]([C:15]([C:18](F)=[O:19])([F:17])[F:16])([F:14])([F:13])[F:12]>C([O-])(O)=O.[Na+]>[C:11]([C:15]([C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([CH2:9][O:10][C:18]([C:15]([C:11]([F:12])([F:13])[F:14])([F:16])[F:17])=[O:19])[CH3:8])=[O:19])([F:17])[F:16])([F:14])([F:13])[F:12]
Reactant: CC(CO)OCCCCO
Reactant: O=C(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(COC(=O)C(F)(F)C(F)(F)F)OCCCCOC(=O)C(F)(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
HO(CH2)4OCH(CH3)CH2OH (18.8 g) obtained in Example 2-3 was put into a round bottom flask and stirred while maintaining the internal temperature at 30° C. Together with nitrogen, CF3CF2COF (276 g) was supplied over 6 hours while maintaining the internal temperature at 30° C. After completion of the reaction, stirring was continued for 2 hours at an internal temperature of 30° C. while supplying nitrogen gas, whereupon a 5% NaHCO3 aqueous solution (300 ml) was added at an internal temperature of at most 15° C.
Reaction SMILES: [I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[NH:7]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.C(=O)(OC(C)(C)C)[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[N:7]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC12CCC(I)C(C1)NC2=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C2(C)CCC(I)C1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-1-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c, (9.5 g, 35.8 mmol) in CH2Cl2 (100 mL) was added DMAP (0.2 g, 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at room temperature. The product was extracted into CH2Cl2 and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:13]C(CC)CCBr.P(Br)(Br)Br.CC(CC)CCO>CCOCC.N1C=CC=CC=1>[CH3:13][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][CH2:1][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCc1cccnc1
Reactant: CCC(C)CCBr
Agent: BrP(Br)Br
Agent: CCC(C)CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C)CCCc1cccnc1

Procedure:
3-(4-Methylhexyl)pyridine was prepared in a similar manner to that described above with regard to 3-hexylpyridine but using 3-methyl-1-pentylbromide [prepared by adding over 1 h, at -30° C. and under N2, 22.5 g of PBr3 (0.083 mol; 7.8 ml) to a mixture of 21.6 g (0.212 mol) of 3-methyl-1-pentanol, 3.95 g of anhydrous pyridine and 88.4 ml of anhydrous sulfuric ether; the mixture was allowed to react for 1 h at -30° C. and then for 1 night at room temperature; the reaction product was extracted and washed in the usual manner and purified on a Vigreux column to provide 20.8 g of pure product].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 4-bromobenzoyl chloride (250 mg; 1.14 mmol) in THF (5 ml) was treated with a 2 M solution of morpholine in THF (219 μl; 2.51 mmol). The reaction mixture was allowed to warm to RT and stirred for 2 days, diluted with EtOAc and washed with a saturated NH4Cl solution in water. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording the title compound as a pink solid (307 mg, quantitative yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 72.5 °C
Yield: 101.3 %

Procedure:
This compound was prepared in the manner of Example 4, using 221.0 grams (0.92 mole--1.0 equiv.) of 92.0% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, 202.3 grams (2.17 moles--2.36 equiv.) of triethylamine, 276.0 grams (2.17 moles--1.68 equiv.) of potassium carbonate, and 250.0 grams (1.63 moles--1.77 equiv.) of methyl 2-bromopropanoate in about 2000 mL (%Wt/Vol. Phenol to Solvent--11.1 %) of acetonitrile. This preparation differs in that the mixture was heated to 70° C. rather than 78° C. before the methyl 2-bromopropanoate was added and that the methyl 2-bromopropanoate was added during a 15 minute period at a rate to maintain the reaction temperature between 70-75° C. rather than during a ten minute period. A yield of 311 grams of 85.3% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]-propanoate was obtained (93.9% yield).
Reaction SMILES: [F:1][C:2]([C:6]1[C:7]([C:17]([OH:19])=O)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>ClCCl>[F:1][C:2]([C:6]1[C:7]([C:17]([F:28])=[O:19])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCC(F)(F)c1c(C(=O)O)noc1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(F)(F)c1c(C(=O)F)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carboxylic acid (8.4 mg, 0.031 mmol) and pyridine (3.05 μL, 0.038 mmol) in dichloromethane (1 mL) was added cyanuric fluoride (3.18 μL, 0.038 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (2 mL) and washed with ice-water (2×1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carbonyl fluoride (7.2 mg).