Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cccnc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.14 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (14 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture, 10% palladium-carbon (14 mg) was added. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Acetic acid (2 mL) and 10% palladium-carbon (0.11 g) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 mL) was added to the obtained residue, followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue. After adjusting the pH to 5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.070 g of 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.51) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.022 g, 11%). MS (ISP) 412.4 [(M+H)+]; mp 248° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH:30]2[CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:28][CH2:29]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Methyl 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate was prepared from methyl 4-benzyloxy-2-hydroxybenzoate and 1-Boc-4-hydroxypiperidine using a procedure similar to that described in Example 21-C. The crude material, in dichloromethane, was filtered and purified by chromatography over silica gel using a preparative high pressure chromatography apparatus, eluting with a gradient of 9:1 to 4:1 to 3:1 hexane:ethyl acetate to give 12.8 g of a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21]([NH:20][CH2:19][C@H:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]([O:17][CH3:18])=[O:16])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1

Procedure:
2 g (25% by weight) of palladium-on-carbon at 10% are added to a solution of 8 g (21 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate (prepared as described in example 17.4) in 120 ml of ethanol, degassed beforehand under a nitrogen stream. The reaction medium is then placed under a hydrogen atmospheric pressure for 24 h and then filtered through celite and thoroughly rinsed with dichloromethane. After concentration under vacuum, 6.1 g (100%) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[F:39][C:40]1([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:43][NH:42][CH2:41]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:42]1[CH2:41][C:40]([C:44]2[CH:45]=[CH:46][C:47]([C:48]#[N:49])=[CH:50][CH:51]=2)([F:39])[CH2:43]1)=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1Cl
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(F)(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CO)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 28.1) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(3-Fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 425 (M+H)+.
Reaction SMILES: NC1C=C(OC)C(OC)=CC=1C1CCC2C=C(O)C=CC=2C1.[CH2:23]([NH:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[CH:36]1[CH2:45][CH2:44][C:43]2[CH:42]=[C:41]([OH:46])[CH:40]=[CH:39][C:38]=2[CH2:37]1)[CH3:24].[N:47]1([CH2:54][CH2:55][O:56][C:57]2[CH:64]=[CH:63][C:60]([CH:61]=O)=[CH:59][CH:58]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:54][CH2:55][O:56][C:57]2[CH:64]=[CH:63][C:60]([CH2:61][CH2:24][CH2:23][NH:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=3[CH:36]3[CH2:45][CH2:44][C:43]4[CH:42]=[C:41]([OH:46])[CH:40]=[CH:39][C:38]=4[CH2:37]3)=[CH:59][CH:58]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Reactant: O=Cc1ccc(OCCN2CCCCCC2)cc1
Agent: COc1cc(N)c(C2CCc3cc(O)ccc3C2)cc1OC
Product: COc1cc(NCCCc2ccc(OCCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 67.1 %

Procedure:
Synthesized from 6-(2-amino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol according to an analogous synthetic method to Example 36, 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (55 mg) and 4-(2-azepan-1-ylethoxy)benzaldehyde (192 mg) were used according to an analogous synthetic method to Example 38 to provide the title compound (63 mg).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:44]1[O:46][CH:45]1[CH2:47][OH:48]>C(O)CC>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH:45]([OH:46])[CH2:47][OH:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: OCC1CO1
Solvent: CCCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CC(O)CO)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Yield: 27 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in 1-propanol (1 mL), and irradiated with microwave (300 W, 100° C., 2 hours) after adding glycidol (0.111 mL, 1.67 mmol). The reaction solution was concentrated under reduced pressure after adding water. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 87/13) to give compound 24 (30.4 mg, 27.1%).
Reaction SMILES: [Cl:1][C:2]([Cl:38])([Cl:37])[CH2:3][O:4][C:5](=[O:36])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[CH:22]([CH3:24])[CH3:23])=[CH:16][C:15]=2[N+:33]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:37][C:2]([Cl:1])([Cl:38])[CH2:3][O:4][C:5](=[O:36])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[N:21]([C:25]3[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=3)[CH:22]([CH3:24])[CH3:23])=[CH:16][C:15]=2[NH2:33])=[CH:9][CH:8]=1
Reactant: CC(C)N(C(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)N(C(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c(N)c1)c1ccc(Br)cc1
Yield: 53.7 %

Procedure:
The product from Example 208A (0.6428 mmol) was reduced with Fe and NH4Cl following the procedure from Example 9E to yield the title compound (218 mg, 53% yield) as an off white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33].C(NC1CCCCC1)(NC1CCCCC1)=O>C(OCC)(=O)C.C(O)(=O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([O:22][N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33])=[O:21]
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(ON1C(=O)CCC1=O)c1cccc(O)c1
Reaction time: 0.02 h

Procedure:
As illustrated in Scheme 1 below, 1,3-dicyclohexylcarbodiimide (82 mg, 0.40 mmol) was added to a solution of 3-hydroxybenzoic acid (50 mg, 0.36 mmol) and N-hydroxysuccinimide (46 mg, 0.40 mmol) in ethyl acetate (1 mL). After 1 minute, crystals of dicyclohexylurea appeared. The next day, acetic acid (20 μL) was added. The mixture was filtered through glass wool, washed with dilute HCl (1N) and dried over Na2SO4. The solution was concentrated to a white solid. Thin layer chromatography on silica gel with 1:1 ethyl acetate:hexane showed complete conversion of the starting acid to a fluorescent, lower rf product. ##STR2##
Reaction SMILES: [I-].[CH:2](=[N:9][CH:10]1[C:53](=[O:54])[N:12]2[C:13]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[C:14]([CH2:17][P+:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][S:16][C@H:11]12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(Cl)Cl>[CH:2](=[N:9][CH:10]1[C:53](=[O:54])[N:12]2[C:13]([C:37]([O:39][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:38])=[C:14]([CH:17]=[P:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][S:16][C@H:11]12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=P(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Temperature: 5 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of diphenylmethyl 7-benzylideneamino-3-[(triphenylphosphonio)methyl]-3-cephem-4-carboxylate iodide (XV) [prepared according to the procedure of Japan published patent application (Kokai) No. 56-86187 (7/31/81)] (60 g, 70 mmole) in CH2Cl2 (350 ml) were added N NaOH (140 ml) and Amberlite IRA-410 (OH- form, 35 g) at 5° C. The mixture was stirred for 1 hour at 5° C. and filtered. The organic layer was separated, dried over MgSO4, concentrated to ca. 100 ml of volume and precipitated with ethyl acetate (500 ml). The resulting yellow solid was collected by filtration and dried in vacuo to afford 48 g (94%) of the title compound XVI, melting at 195°-8° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.[Cl-].[Na+].O>[C:1]1([C:7]2[N:11]([S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (140 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 66 mg) at room temperature, and the mixture was stirred for 30 min. 15-Crown-5 (361 mg) was added dropwise, and the mixture was stirred for 30 min. Benzenesulfonyl chloride (217 mg) was added, and the mixture was further stirred for 1 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give 5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde as a colorless oil. The obtained oil was dissolved in methanol (20 mL), a 2 mol/L tetrahydrofuran solution (4.1 mL) of dimethylamine was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (93 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=4:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 200 mg, 65%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.[Cl-].[Cl-].[NH3+:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][NH+:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([C:4]2[C:5]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:34])[F:35])=[CH:27][N:26]=4)[CH3:24])=[O:19])=[CH:14][CH:15]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: O=C(O)Cc1ccc(-c2nccnc2C2CC2)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Cc1ccc(-c2nccnc2C2CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 0.080 g (0.32 mmol) of ([4-(3-cyclopropylpyrazin-2-yl)phenyl]acetic acid in 1.00 ml DMF was added 0.11 g (0.38 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.056 g (0.41 mmol) of HOAt, 0.078 g (0.41 mmol) of EDC, and 0.17 mL (0.94 mmol) of DIEA. After 12 h at room temperature, the reaction mixture was purified by reverse-phase preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.13 g (73.8%) of 2-[4-(3-cyclopropylpyrazin-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 2H); 8.27 (d, J=2.74 Hz, 1H); 7.68 (d, J=8.15 Hz, 2H); 7.40 (d, J=8.06 Hz, 2H); 7.34 (m, 2H); 7.20 (d, J=5.95 Hz, 1H); 5.15 (m, 1H); 4.41 (dd, J=7.88, 15.84 Hz, 2H); 3.65 (s, 2H); 2.22 (m, 1H); 1.46 (d, J=6.95, 3H); 1.19 (m, 2H); 0.99 (m, 2H). HRMS (ES) [M+1]+calcd for C24H24F3N4O2: 457.1851, Found: 457.1831. FLIPR alpha1I IP=47 nM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 80 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (225 mg, 0.724 mmol) was reacted with tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (300 mg, 1.09 mmol) to afford the desired product (320 mg, 80%) as an orange solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[NH2:19][NH2:20]>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[NH:20][N:19]=1)([O-:13])=[O:12]
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Product: N#Cc1c(Cc2cccc([N+](=O)[O-])c2)n[nH]c1N

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (0.97 g; 4.0 mmol) was combined with hydrazine (0.3 mL; 6.0 mmol; Sigma-Aldrich) in 10 mL EtOH for 90 minutes at room temperature. Afterwards the reaction was concentrated in vacuo, suspended in brine and extracted with chloroform (3×50 mL). The organic layer was dried over MgSO4, then filtered, and concentrated in vacuo to afford 3-(3-nitrobenzyl)-5-amino-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M+H]+ found 244.5, calculated 244.1). The product was combined with formamide (1.5 mL) and heated to 160° C. overnight. H20 was added to the cooled reaction and the precipitate was filtered and dried to afford 3-(3-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 271.4, calculated 271.1). This recovered solid (50 mg, 0.19 mmol) was then added to a solution containing benzyl bromide (0.1 mL, 0.28 mmol), K2CO3 (0.125 g), DMF (1.0 mL). The reaction mixture was purged with Argon and stirred overnight at 80° C. The reaction was filtered to remove solid K2CO3, and the filtrate was combined with brine and the organic product was extracted in CH2Cl2 (3×50 mL) to afford 3-(3-nitrobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 361.4, calculated 361.1). This precipitated intermediate was then mixed with excess Zinc dust, 5 mL THF, 0.4 mL HOAc for 12 hours under Argon at room temperature. Afterwards the reaction was filtered through Celite®, extracted with EtOAc and concentrated in vacuo to afford 3-(3-aminobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 331.5, calculated 331.2). To this reduced precursor, molar equivalents of 3-(trifluoromethyl) benzoyl chloride (Sigma-Aldrich) were added drop wise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to yield final Cmpd BB5 N-(3-((4-amino-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(trifluoromethyl)benzamide (ESI-MS m/z [M+H]+ found 503.4, calculated 503.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Cl)c(Cl)c2)CC1

Procedure:
4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated to give the sub-title compound (14.58 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][CH2:5]/[CH:6]=[C:7](\[F:15])/[S:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCSC(F)=CCOC(=O)N(C)C
Solvent: ClCCl
Product: CCCCCCS(=O)/C(F)=C/COC(=O)N(C)C
Reaction time: 0.25 h

Procedure:
To the above carbamate is added a solution of m-chloroperbenzoic acid (431 mg, 2.5 mmol) in 10 ml of methylene chloride. After 15 min, the reaction mixture is extracted with KHCO3 and Na2SO3 and stripped. The product is purified by prep. TLC eluting with ethyl acetate (neat). The upper band is collected to give (E)-3-fluoro-3-hexylsulfinyl-2-propenyl dimethylcarbamate (cpd. 28, Table A).