Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][C:10]2[C:13]([NH:35][C:36](=[O:39])[O:37][CH3:38])=[N:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:9]=2[CH:8]=1.[C:40]([N:47]1[CH:51]=[CH:50]N=C1)(N1C=CN=C1)=[O:41].Cl.[Cl:53][C:54]1[CH:59]=[CH:58][C:57]([C@H](N)C)=[CH:56][C:55]=1[O:63][CH3:64].CCN(C(C)C)C(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:53][C:54]1[CH:59]=[CH:58][C:57]([C@H:51]([NH:47][C:40](=[O:41])[NH:6][C:7]2[N:12]=[CH:11][C:10]3[C:13]([NH:35][C:36](=[O:39])[O:37][CH3:38])=[N:14][NH:15][C:9]=3[CH:8]=2)[CH3:50])=[CH:56][C:55]=1[O:63][CH3:64]
Reactant: COc1cc([C@@H](C)N)ccc1Cl
Reactant: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccc(Cl)c(OC)c3)ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 8 mL vial charged with imidazole (18 mg, 0.26 mmol) and crude methyl (6-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (23.8 mg, 0.053 mmol) in DCM (2 ml) was added 1,1′-carbonyldiimidazole (26 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 5 h, leading to a clear yellow solution. (R)-1-(4-chloro-3-methoxyphenyl)ethanamine HCl (23.41 mg, 0.105 mmol) and DIEA (0.046 ml, 0.264 mmol) was added. The vial was capped and the contents stirred at room temperature for 16 h. The reaction mixture was concentrated and the resulting residue was re-dissolved in TFA (1 ml) and stirred at room temperature for 20 minutes. Triethylsilane (0.013 ml, 0.079 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-methyl (6-(3-(1-(4-chloro-3-methoxyphenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (4.4 mg, 8.26 μmol, 15.67% yield) and 1,1′-(1H-pyrazolo[4,3-c]pyridine-3,6-diyl)bis(3-((R)-1-(4-chloro-3-methoxyphenyl)ethyl)urea), TFA (5 mg, 7.28 μmol, 13.82% yield) as white solids. (Example 322) MS ESI calc'd. For C18H20ClN6O4 [M+H]+ 419. found 419. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.40 (s, 1H); 8.95 (s, 1H); 7.81 (br s, 1H); 7.43 (s, 1H); 7.35 (d, J=8.1 Hz, 1H); 7.09 (d, J=1.9 Hz, 1H); 6.90 (dd, J=8.2, 1.9 Hz, 1H); 4.84 (t, J=7.2 Hz, 1H); 3.83 (s, 3H); 3.68 (s, 3H); 1.39 (d, J=6.9 Hz, 3H). (Example 314) MS ESI calc'd. For C26H28Cl2N7O4 [M+H]+ 572. found 572. 1H NMR (600 MHz, DMSO-d6): 9.70 (s, 1H); 9.06 (s, 1H); 7.84 (br s, 2H); 7.34-7.36 (m, 3H); 7.09-7.10 (m, 2H); 6.89-6.91 (m, 2H); 4.89 (t, J=7.2 Hz, 1H); 4.82-4.86 (m, 1H); 3.82 (s, 6H); 1.40 (dd, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:4](=[O:8])[O:5][CH2:6]Cl)[CH3:2].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:6][O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CCN(CCC(C)C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCN(CCC(C)C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 47.4 %

Procedure:
In the same manner as in step b) in Example 125, 213 mg of the title compound was prepared from 202 mg of chloromethyl N-ethyl-N-isoamylcarbamate and 328 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C([N:29](C(C)C)CC)(C)C.N>C(#N)C>[C:8]([C:7]1[N:6]=[N:5][C:4]([S:13][CH3:14])=[N:3][C:2]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)(=[O:10])[NH2:29]
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CC#N
Product: COC(=O)c1ccc(Nc2nc(SC)nnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (350 mg, 1.50 mmol) in acetonitrile (10 mL) was added methyl 4-aminobenzoate (340 mg, 2.25 mmol) and then diisopropylethylamine (DIEA, 0.39 mL, 2.25 mmol). The mixture was stirred at RT for 3 h. To the mixture was then added ammonia (7.0 N solution in methanol, 30 mL). The mixture was stirred overnight. The solid was isolated by filtration, washed with a minimum amount of cold acetonitrile and then washed with hexane. The solid was dried in a vacuum oven to afford methyl 4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)benzoate (2) (348 mg, 73% yield) in high purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:35]1[C:36]2[C:37]3[CH:50]=[CH:49][S:48][C:38]=3[C:39](=[O:47])[NH:40][C:41]=2[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[F:15][C:4]1[CH:3]=[C:2]([C:35]2[C:36]3[C:37]4[CH:50]=[CH:49][S:48][C:38]=4[C:39](=[O:47])[NH:40][C:41]=3[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1F
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)c(F)c1
Yield: 15.2 %

Procedure:
Following General Procedure E, 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (3.30 mg, 1.1 mmol) was reacted with bis(pinacolato)diborane (300 mg, 1.2 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (310 mg, 1.0 mmol) to afford the desired product (68 mg, 13%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.04 (t, J=5.8 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.93 (d, J=5.4 Hz, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.49-7.43 (m, 2H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 5.89 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 3.72 (s, 3H), 3.46 (q, J=6.2 Hz, 2H), 3.05 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][O-:17].[Na+].CO.O.Cl>CO>[CH3:16][O:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of methyl 4-chloromethyl-2-nitrobenzoate (1.6 g), 28% sodium methoxide-methanol solution (2.5 ml) in methanol [16 ml) was stirred under reflux for 24 hours. To this mixture, water (5 ml) was added and the mixture was stirred for 2 hours, acidified with 1N hydrochloric acid, extracted with ethyl acetate. The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give 4-methoxymethyl-2-nitrobenzoic acid (0.84 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([CH:31]2[CH2:32][CH2:33][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:35][CH2:36]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCC(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then treated with 1.6 g (0.01 mole) of 4-phenylpiperidine. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were combined, dried and concentrated in vacuo to yield 4.95 g of crude oil which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 1.5 g (37%) of coarse white crystals, m.p. 72°-74° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]([OH:13])=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:6][CH:5]=1.I[CH2:22]I.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[O:13]1[C:12]2[C:11]3[CH:10]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[O:3][CH2:22]1
Reactant: CCC(=O)NCCC1CCc2ccc(O)c(O)c21
Reactant: ICI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCC(=O)NCCC1CCc2ccc3c(c21)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Hexamethyl phosphoramide (5 mL) was cooled with ice, to which was gradually added sodium hydride (0.28 g, 7.5 mmol.), content 65%). To this mixture was added dropwise a solution of N-[2-(6,7-dihydroxyindan-1-yl)ethyl] propionamide (0.85 g, 3.41 mmol.) in hexamethyl phosphoramide (5 mL) at room temperature over 6 minutes. At the time when the bubbling of hydrogen gas ceased, diiodomethane (1.1 g, 4.1 mmol.) was added dropwise to the reaction mixture, followed by stirring for two hours at room temperature. The reaction mixture was poured into water, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 280 mg, 31%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: BrC1=CCCCC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2=CCCCC2)cc1

Procedure:
To a stirred solution of p-hydroxybenzoic acid (1.38 gm, 10 mmol) in THF (30 ml) is added sodium hydride (0.48 g, 20 mmol), followed by cyclohexenyl bromide (1.63 gm 10 mM). The mixture is heated to reflux for 12 hours. After cooling the reaction mixture is poured into ethyl acetate and extracted with 1N NaOH (3×). The combined aqueous extracts are combined, acidified to pH 2 with concentrated HCl, and extracted 3× with ethyl acetate. The combined organic extracts are dried over Na2SO4 and evaporated under reduced pressure to afford the product.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)C.Cl>O1CCCC1>[O:3]=[CH:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
10.07 g of 5-[4-(2,2-diethoxyethoxy)benzyl]-thiazolidine-2,4-dione (prepared as described in Preparation 19) were dissolved in 80 ml of tetrahydrofuran, and then 20 ml of 6N aqueous hydrochloric acid were added to the resulting solution. The mixture was then left to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 5.92 g of the title compound having an Rf value of 0.37 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:46]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:43]#[N:44])([CH3:42])[CH3:41])[CH:35]=4)[CH:28]=[CH:29][C:30]=3[CH3:31])=[CH:23][N:18]2[N:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:43]([C:40]([C:36]1[CH:35]=[C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[O:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([NH:15][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[O:8])[N:46]=3)[CH:23]=2)=[O:45])[CH:39]=[CH:38][CH:37]=1)([CH3:42])[CH3:41])#[N:44]
Reactant: O=C(O)c1cscn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cscn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 1,3-thiazole-4-carboxylic acid (121 mg, 938 μmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (102 μL, 1.17 mmol) and N,N-dimethylformamide (20 μL) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.469 mmol) were dissolved in pyridine (5 mL), and the mixture was stirred at room temperature for 16 hr. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→99/1), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration, and dried to give the title compound (206 mg, 82%) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH2:9]>C(C1C=CC=CC=1C)C>[CH2:8]([C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1)[CH3:9]
Reactant: C=C
Reactant: Cc1ccccc1
Agent: CCc1ccccc1C
Product: CCc1ccc(C)cc1

Procedure:
Toluene and ethylene were reacted over the Ba-modified ZSM-11 at 400° C. The feed WHSV for toluene was 7.0 and for ethylene was 0.5. Conversion of toluene was 5.3% and the yield of para-ethyltoluene in the ethyltoluene produced was 89.0%.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=[O:13].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>>[C:19]([O:18][C:16]([CH2:15][N:4]1[C:3](=[O:13])[CH:2]([CH3:1])[S:6][CH:5]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1SC(c2cccnc2)NC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC1SC(c2cccnc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
According to the procedure of Example 24 the trans-isomer and the cis-isomer of the title compound were prepared by using 5-methyl-2-(3-pyridyl)thiazolidin-4-one, t-butyl bromoacetate, and sodium hydride.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][C:30]([N:32]([CH2:34][C:35](O)=[O:36])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N>C(Cl)Cl.C(N(CC)CC)C>[CH2:22]([O:29][C:30](=[O:31])[N:32]([CH2:34][C:35](=[O:36])[NH:21][CH2:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of C-(6-benzenesulfonyl-naphthalen-1-yl)-methylamine, (Benzyloxycarbonyl-methyl-amino)-acetic acid, 1-hydroxybenzotriazole, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide and triethylamine in methylene chloride is stirred at room temperature. The reaction is quenched by addition of water, and the mixture is eluted through silica gel to give {[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([O:23][CH3:24])=[N:4][C:5]([N:9]2[CH2:16][CH:15]3[C:11]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)([NH:12][O:13][CH2:14]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].CO>C(O)C.[Ni].O>[NH2:12][C:11]1([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:10][N:9]([C:5]2[N:4]=[C:3]([O:23][CH3:24])[C:2]([F:1])=[C:7]([CH3:8])[N:6]=2)[CH2:16][CH:15]1[CH2:14][OH:13]
Reactant: COc1nc(N2CC3CONC3(c3cnccn3)C2)nc(C)c1F
Agent: [Ni]
Solvent: CO
Solvent: O
Solvent: CCO
Product: COc1nc(N2CC(CO)C(N)(c3cnccn3)C2)nc(C)c1F
Yield: 99.3 %

Procedure:
A solution of 5-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-6a-pyrazin-2-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (0.92 g, 2.77 mmol) in ethanol (40 mL) is hydrogenated at 50 psi in the presence of Raney nickel (as a slurry in water) (2.7 g, 45.54 mmol) for 5 hours using a PARR hydrogenator. Methanol is added and the catalyst removed by filtration through a pad of diatomaceous earth. The diatomaceous earth pad is washed with methanol. The combined filtrates are concentrated under reduced pressure to give the title compound (0.92 g, 99%). ES/MS (m/e): 335 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:73])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27][Cl:73])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CO)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CCl)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of Intermediate 61e (124 mg, 0.15 mmol) in DCM (1.5 mL) at 0° C. was treated with DIPEA (79 μL, 0.45 mmol) then methanesulfonyl chloride (23 μL, 0.30 mmol) and the mixture was stirred at RT for 1 h. The mixture was cooled to 0° C. and treated with another portion of DIPEA (40 μL, 0.23 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol) and stirred at RT for 30 min. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (34 mg, 27%). LCMS (Method 3): Rt 5.56 min, m/z 839 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure BF above, and using 3,5-dichlorophenylacetic acid (from Example BC above) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 115°-116° C. The reaction was monitored by tlc on silica gel (Rf=0.40 in 3% methanol/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](Cl)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([OH:23])[CH2:16]2>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([O:23][CH:17]3[CH:18]4[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]4)[CH2:16]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCC1
Reactant: OC1CN2CCC1CC2
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2ccc(Cl)cc2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-(4-chlorophenyl)-cyclobutanecarbonyl chloride with 3-quinuclidinol at 80° C. for 25 h. The yield was 0.7 g (43%); mp 205-208° C.; 1H NMR (D2O) δ 1.73-1.85 (m, 2H), 1.86-1.97 (m, 2H), 2.04-2.15 (m, 2H), 2.32 (m, 1H), 2.48-2.63 (m, 2H), 2.87 (m, 2H), 3.12 (m, 1H), 3.22 (d, 1H), 3.27-3.42 (m, 3H), 3.73 (m, 1H), 5.17 (m, 1H), 7.37 (d, 2H), 7.43 (d, 2H). Anal. (C18H22ClNO2.HCl) C, H, N.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 95.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (750 mg, 4.38 mmol) in MeCN (10 mL) was added morpholine (3.83 mL, 43.8 mmol) and potassium carbonate (606 mg, 4.38 mmol). The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (1.0 g, 96%).