Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN1Cc2nc(Cl)ccc2C1=O
Product: CN1Cc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2C1=O

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (75 mg, 0.240 mmol) and 2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (43.8 mg, 0.240 mmol) as the starting materials.
Reaction SMILES: [C:1]1([C:24]([NH:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][OH:29])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][OH:20])=[O:16].[OH-].[Na+]>CO>[C:1]([O:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:24](=[O:25])[NH:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][O:29][C:10]([CH3:15])([CH3:11])[CH3:9])[C:21]([OH:23])=[O:22])([CH3:24])([CH3:6])[CH3:2]
Reactant: O=C(N[C@@H](CO)C(=O)O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OCC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(COC(C)(C)C)C(=O)O)C(=O)O
Reaction time: 18 h

Procedure:
A solution of N,N'-[dithiobis(2,1-phenylene carbonyl)]bis L-serine bis[O(1,1-dimethylethyl) bis (1,1-dimethylethyl)ester (1.0 g, 1.4 mmol) from Example 39, in 30 mL methanol was treated with 8 mL of 1N NaOH and allowed to stir for 18 hours. The methanol was removed in vacuo and the residual was diluted with 5 water and extracted with ethyl acetate. A slow stream of oxygen was passed thru the aqueous layer while dilute HCl was added to maintain a pH=6-7. After the disulfide formation was complete (2-18 hours), dilute HCL was added to a pH=3. The product was collected by filtration, washed with water, dried and was recrystallized from ethyl acetate to afford 0.4 g of the title compound, mp 206°-207° C.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=O.Cl>CN(C)C=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.3 g, 33.5 mmol) in dimethylformamide (50 mL) was added dropwise ethyl 2-mercaptoacetate (2.95 mL, 27 mmol) at 0° C. under an atmosphere of argon. After stirring at room temperature for 15 minutes, 2-chloro-5-nitrobenzaldehyde was added. The mixture was then stirred at 100° C. for 6 h, cooled to room temperature and poured into hydrochloric acid (250 mL, 1M). The precipitate was filtered off, washed with water (3×50 mL), dried under reduced pressure and recrystallised from ethyl acetate to give the title compound (5.5 g, 82%) as a solid, mp 163° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(C(O)=O)(F)(F)F.C(I)I.[NH2:16][C:17]1[N:21]([CH3:22])[C:20](=[O:23])[C:19]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[CH:37][CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])[CH:25]=2)[N:18]=1>C(Cl)Cl>[NH2:16][C:17]1[N:21]([CH3:22])[C:20](=[O:23])[C:19]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH:42]([F:44])[F:43])=[CH:39][CH:40]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[CH2:1][CH:31]3[CH2:32][O:33][CH3:34])[CH:25]=2)[N:18]=1
Reactant: COC/C=C/c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Reactant: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Solvent: ClCCl
Product: COCC1CC1c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Reaction time: 0.33 h
Yield: 16 %

Procedure:
A 1M solution of diethyl zinc (4.92 ml, 4.92 mmol) in dry CH2Cl2 at 0° C. is treated very slowly with a solution of CF3CO2H (0.56 g, 4.92 mmol) in dry CH2Cl2, stirred for 20 min, treated dropwise with a solution of CH2I2 (0.66 g, 2.46 mmol) in dry CH2Cl2, stirred for 20 min, treated with a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one (197 mg, 0.492 mmol) in dry CH2Cl2, allowed to come to room temperature, stirred for 2 h at room temperature, quenched with aqueous NH4Cl and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by SCX cartridge and preparative HPLC to give the title compound as a white solid, 32 mg (16% yield), identified by NMR and mass spectral analyses. (1H-NMR 300 MHz, DMSO): 7.46(d, 2H); 7.24-7.13(m, 3H); 7.16(t, 1H); 7.10(d, 2H); 6.88(m, 1H); 6.64(s br, 2H); 3.44-3.34(m, 2H); 3.24(m, 1H); 3.23(s, 3H); 2.97(s, 3H); 1.76(m, 1H); 0.90-0.76(m, 2H). MS [M+H]+ 416.1
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([OH:15])[C:5]1[CH:16]=[C:17]([C:20]([CH2:23][CH3:24])([CH3:22])[CH3:21])[CH:18]=[CH:19][C:4]=1[O:3]2.[C:25]([OH:28])(=O)[CH3:26].N1C=CC=CC=1.C1C[O:38][CH2:37][CH2:36]1>>[C:37]([O:3][C:4]1[CH:19]=[CH:18][C:17]([C:20]([CH2:23][CH3:24])([CH3:22])[CH3:21])=[CH:16][C:5]=1[C:6]1([O:15][C:25](=[O:28])[CH3:26])[C:7](=[O:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1])(=[O:38])[CH3:36]
Reactant: CCC(C)(C)c1ccc2c(c1)C1(O)C(=O)c3ccccc3C1(O)O2
Reactant: CC(=O)O
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OC(C)=O)c(C2(OC(C)=O)C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
4b,9b-Dihydroxy-8-tert-pentyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.46 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.50 g, 4.93 mmol), pyridine (0.19 ml, 2.46 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.71 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]([NH:21][C@H:22]([C:24](O)=[O:25])[CH3:23])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:14]([NH:21][C@H:22]([C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:25])[CH3:23])([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)glyoxylate (4.0 g) and Boc-L-alanine (5.67 g) were dissolved in 40 ml of N,N-dimethylformamide (hereafter abbreviated as DMF), and thereto was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (5.74 g) under ice-cooling followed by addition of 4-dimethylaminopyridine (0.4 g). The mixture was stirred at room temperature for 5 hours. Water (400 ml) was added thereto, and the mixture was extracted twice with ethyl acetate (300 ml). The ethyl acetate layer was washed with 10% aqueous solution of citric acid (200 ml), saturated aqueous solution of sodium bicarbonate (200 ml) and saturated brine (200 ml) in this order, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography eluted with benzene-ethyl acetate. The object fraction was concentrated to give 5.30 g of ethyl 2-[2-(Boc-L-alanyl)aminothiazol-4-yl]glyoxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].COB([C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)O.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:2]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: COB(O)c1ccc(C(=O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2cc(C(=O)O)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Dimethyl 5-bromoisophthalate (8.15 g, 29.9 mmol), methyl 4-carboxyphenylboronic acid (5.91 g, 32.8 mmol), K2CO3 (8.29 g, 60.0 mmol), toluene (60 mL), ethanol (30 mL) and water (30 mL) are added into a 200 mL round-bottomed flask equipped with a magnetic stir bar and water jacketed condenser. The resulting suspension is degassed for 15 min by sparging with nitrogen gas. Pd(PPh3)4 (0.862 g, 0.746 mmol) is added, and the mixture is heated to reflux overnight under a nitrogen atmosphere. After cooling to room temperature both layers are separated, the organic layer is dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure. The residue is filtered on a short silica plug using acetone as eluent and the solvent is removed by evaporation. The crude product is dissolved in dioxane (50 mL) and an aqueous KOH solution (9 M, 50 mL) is added. This mixture is heated to reflux for 12 h. The solvent is evaporated then the residue is dissolved in H2O (100 mL). The residual solids are filtered off and the filtrate is acidified with concentrated HCl (20 mL). The target compound is collected by filtration, washed with H2O and acetone and dried under vacuum to yield 5.15 g of biphenyl-3,4′,5-tricarboxylic acid (18.0 mmol as a white powder, 60%): mp>300° C.; 1H NMR (400 MHz, DMSO-d6): δ 13.23 (br s, 3H), 8.41 (d, J=1.0 Hz, 1H), 8.33 (t, J=1.0 Hz, 2H), 7.99 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 166.8, 142.8, 140.3, 132.6, 131.8, 130.8, 130.6, 129.9, 127.4; HRMS (EI) calcd. for C15H10O6 (m/e): 286.0477. found: 286.0485; Anal. Calcd for C15H10O6: C, 62.94; H, 3.52. Found: C, 62.54; H, 3.57.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([CH2:10][Br:1])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccccc2)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1ccccc1

Procedure:
In this instance one equivalent of Br2 was added dropwise to a refluxing solution of 2-fluoro-4-methylbiphenyl and CCl4 while being irradiated with a sunlamp. NMR analysis showed the ratio of starting material:monobromide-dibromide to be 21:67:12.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([F:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1cc(F)c(N)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1cc(F)c(CC(=O)O)cc1F
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a stirred solution of ethyl 4-amino-2,5-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF—MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,5-difluorophenylacetic acid (214 mg, 46%) as a white solid. 1H-NMR (CDCl3) δ2.30 (s, 3H), 3.35 (m, 2H), 7.02 (m, 2H), 7.18 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 8.03 (m, 1H); MS (FAB) m/z 321 (M++1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:6]=1)=[NH:4].[C:22](OCC)(=O)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Cl-]>C1COCC1.C(OCC)(OCC)OCC>[O:1]1[CH:22]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[N:6]=2)=[N:2]1
Reactant: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: C1CCOC1
Product: c1cncc(-n2cc(-c3cccc(-c4ncon4)n3)cn2)c1
Reaction time: 2 h

Procedure:
0.24 g of N-hydroxy-6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carboxamidine (crude product from the previous step) was dissolved in THF/triethyl orthoformate, and 0.2 g of BF3-ET2O was added. After 2 h, ethyl acetate, aq. citrate buffer pH=6 and aq. NaCl were added and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried with MgSO4 and concentrated by evaporation, and the residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][CH:9]=[C:8]([C:11]3[S:15][CH:14]=[N:13][CH:12]=3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[CH:38]=[CH:37][NH:36][C:33]3=[N:34][CH:35]=2)O1>>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][CH:9]=[C:8]([C:11]4[S:15][CH:14]=[N:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]4[CH:38]=[CH:37][NH:36][C:33]4=[N:34][CH:35]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: Clc1nc(N2CCOCC2)c2scc(-c3cncs3)c2n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: c1cc2cc(-c3nc(N4CCOCC4)c4scc(-c5cncs5)c4n3)cnc2[nH]1

Procedure:
2-Chloro-4-morpholin-4-yl-7-thiazol-5-yl-thieno[3,2-d]pyrimidine and 5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine were reacted according to General Procedure A to give 318. NMR (DMSO, 400 MHz), 3.86 (4 H, t, J=4.4), 4.09 (4 H, t, J=5.2), 6.61-6.63 (1 H, m), 7.54-7.57 (1 H, m), 8.78 (2 H, s), 9.03 (1 H, s), 9.20 (1 H, s), 9.44-9.46 (1 H, m), 11.88 (1 H, s). MS: (ESI+): MH+=421
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.ClCCl.[CH2:20]([O:27][C:28](ON1C(=O)CCC1=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:5][CH2:4]1
Reactant: NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368 mmol) in toluene (600 mL) were heated to reflux under dean stark conditions for 2 h. The resulting reaction mixture was cooled to room temperature and 500 mL dichloromethane was added. The resulting solution was cooled to 5° C. and treated with N-(benzyloxycarbonyloxy)succinimide (91.7 g, 368 mmol). After 10 min, the cooling bath was removed and the reaction mixture stirred for 1 h. The solvents were evaporated and the resulting residue was stirred with 400 mL THF and 400 mL 2 M HCl for 1 h. The mixture was concentrated to remove organics and was then extracted with ether (3×300 mL). The aqueous phase was adjusted to pH14 with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give benzyl 4-(aminomethyl)piperidine-1-carboxylate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1cccc(F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([S:32][CH3:33])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:33][S:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: CSc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 79 %

Procedure:
Following procedures as described in Example 219, mix 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1 equivalent), 4,4,5,5-tetramethyl-2-(3-methylsulfanyl-phenyl)-[1,3,2]dioxaborolane (1.25 equivalents), 2N Na2CO3 (2 equivalents) and tetrakistriphenylphosphine palladium (0.05 equivalents)in a suitable solvent. Purify the product by silica gel chromatography to obtain a 79% yield of the title compound. MS(ES)=329(+)
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.ClC1C=CC=CC=1CN1C(/C=C(\CC2SC=CC=2)/C(O)=O)=CN=C1SCCC.[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[C:59](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53].[CH2:79]([CH:86]([C:92]1[S:93][CH:94]=[CH:95][CH:96]=1)[CH2:87][C:88]([O:90]C)=[O:89])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[CH:59]=[C:87](\[CH:86]([C:92]2[S:93][CH:94]=[CH:95][CH:96]=2)[CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)/[C:88]([OH:90])=[O:89])=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53]
Reactant: COC(=O)CC(Cc1ccccc1)c1cccs1
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(Cc2ccccc2)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl 3-benzyl-3-(2-thienyl)propanoate [prepared following the procedure described in Tetra. 44 (7) 2055 (1988)]; mp 200°-202° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:36])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (500 mg, 2.7 mmol) and triphenylphosphine (840 mg, 3.2 mmol) are dissolved in 12 mL of DCM and NBS (570 mg, 3.2 mmol) is added. The mixture is stirred for 4 hrs and then the reaction mixture is directly purified by flash column chromatography give 455 mg of 3-bromo-5-bromomethyl-pyridine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>C(Cl)Cl>[Si:41]([O:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78.2 %

Procedure:
tert-Butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (1.94 g, 5.4 mmol) (prepared as shown in Scheme 19) was taken up in 50 mL of DCM and chilled to 0° C. DIEA (2.4 mL, 13 mmol) was added, followed by slow addition of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (1.5 mL, 6.5 mmol). After 45 minutes, an additional 0.20 mL of TBSOTf was added. After an additional 20 minutes, the reaction was quenched with 50 mL of aq NaHCO3. The mixture was partitioned, and the aqueous portion was extracted twice with 50 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (1% to 7.5% EtOAc/hexanes), afforded tert-butyl (2S,3S,E)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (2.0 g, 78% yield) as a clear oil. The oil crystallized over 12 hours. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J=8.02 Hz, 2 H) 7.35 (d, J=8.02 Hz, 2 H) 5.61 (s, 1 H) 5.59 (d, J=5.87 Hz, 1 H) 4.62-4.60 (m, 1H) 3.97-3.92 (m, 1H) 3.79-3.76 (m, 1H) 3.66-3.59 (m, 2H) 1.69 (d, J=5.28 Hz, 3 H) 1.26 (s, 9 H) 0.92-0.97 (m, 9 H) 0.06 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:34])[F:33])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:33])[F:34])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (43, 107 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to provide (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (44) as a white solid (66 mg, 71%): 1H NMR (500 MHz, DMSO-d6) δ 13.52-13.13 (m, 1H), 9.41 (br s, 2H), 7.77 (dd, J=9.0, 5.7 Hz, 1H), 7.62-7.50 (m, 1H), 7.32-7.21 (m, 1H), 5.00-4.83 (m, 1H), 4.75-4.58 (m, 1H), 4.37-4.19 (m, 2H), 3.41-3.24 (m, 2H, overlaps with H2O), 3.22-3.04 (m, 2H), 2.94-2.73 (m, 3H), 1.86-1.64 (m, 4H); ESI MS m/z 397 [M+H]+.