Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](O)=[O:14])[C:10]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([N:40]2[CH2:39][CH2:38][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:14])[C:10]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C1CN(Cc2ccccc2)CC12CCCc1ccccc12)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylic acid (0.1 g, 0.311 mmol) in CH2Cl2 (4 ml) was added oxalyl chloride (0.187 ml, 0.373 mmol) followed by 2 drops of DMF. Stirred at room temperature for 30 minutes and concentrated. Dissolve in THF (5 mL) and added 4-phenylpiperidine (0.050 g, 0.311 mmol) and triethylamine (0.173 ml, 1.245 mmol).
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:17]=[C:12]([C:13]([NH:15][OH:16])=[O:14])[C:11](O)=[CH:10][CH:9]=1.[OH-].[NH4+]>O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:5][CH:1]3[CH2:2][CH:3]([CH3:4])[O:16][N:15]3[C:13](=[O:14])[C:12]=2[CH:17]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC2Oc3ccc(Cl)cc3C(=O)N2O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
360 ml. of tetrahydrofuran is combined with 90 gm. of crotonaldehyde and placed in an ice bath. 100 gm. of hydrogen chloride are passed into the mixture at 20°-30° C. 158 gm. of 5-chlorosalicylhydroxamic acid is added in one portion and the mixture stirred at 25°-30° C. for about two hours until the solid dissolves. The mixture is cooled in a water bath and 400 ml. of concentrated ammonium hydroxide diluted with 400 ml. of water is added with stirring. The temperature of the mixture is allowed to rise to about 50° C. during the alkali addition and the mixture is then heated on a steam bath to about 90° C. and a vacuum applied to remove as much tetrahydrofuarn as possible. A solid precipitates while heating. 400 ml. of water are added and the entire mixture is cooled to about 10° C. in an ice bath. The solid is filtered and washed with water and pulled dry. The cake is recrystallized from 800 ml. boiling isopropanol refrigerated overnight. The crystals are filtered, washed with cold isopropanol and dried at about 100° C. 136 gm. 7-chloro-2-methyl-3,3a-dihydro-2H, 9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one (m.p. 144°-148° C.) for a yield of 67% is obtained.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[C:8]1([CH2:14][SH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:16][C:17]1[N:25]=[C:24](Cl)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cl-].[Na+].O>[NH2:16][C:17]1[N:25]=[C:24]([S:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: SCc1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (410 mg, 10 mmol, 60% in mineral oil) were added α-toluenethiol (1.7 ml, 14 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 100° C. for 4.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (97 mg, yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: Fc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
5-(4-Fluorophenyl)-4-(pyridin-4-yl)pyrazole (6.0 g (25 mmol), prepared as described in WO 00/31063) was dissolved in dimethylformamide (60 ml). To the solution was added N-bromosuccinimide (8.93 g, 50 mmol), and the resulting mixture was stirred at room temperature for 3 days. At the end of this time, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether, to give the title compound (5.73 g) as a white powder (yield 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCO.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>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccccn1
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: CCO
Product: CCOC(=O)c1cccc(-c2ccccn2)c1
Temperature: 100 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (208 mg, 0.180 mmol) was added to a solution of 3-ethoxycarbonylphenyl boronic acid (350 mg, 1.80 mmol), 2 -bromopyridine (189 μL, 1.99 mmol) and potassium carbonate (499 mg, 3.61 mmol) in EtOH:toluene (4.00 mL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 100° C. in a sealed microwave vial for a total of 15 min. After cooling to rt, the reaction mixture was filtered through a short column of Celite®, eluting with EtOAc. The filtrate was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (isocratic elution; 10% EtOAc/hexanes as eluent) to afford the title compound i-2a. m/z (ES) 228 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH3:18][C:13]1[N:12]([C:4]2[CH:3]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C)n1-c1cc(C(C)(C)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (4.98 g, 15.6 mmol) in THF (75 mL) at −78° C., was added a solution of 2.50M n-butyllithium in hexane dropwise. The reaction mixture was allowed to stir for 30 min and then acetone (1.49 mL, 20.4 mmol) was added dropwise. The reaction mixture was allowed to stir at −78° C. for 30 min, and then allowed to warm to rt. Saturated aq. NH4Cl was added and the mixture was extracted with EtOAc (3×). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]propan-2-ol (2.29 g, 49.2%). LCMS: (FA) ES+ 298.2.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-])=O>C(OCC)(=O)C.C(O)C.[C].[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1ccc(NCCN(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.7 %

Procedure:
10% of palladium-carbon (0.738 g) was added to a solution containing 4-{[2-(dimethylamino)ethyl]amino}-N-methyl-3-nitrobenzamide (3.679 g) in a mixture of ethyl acetate (40 ml) and ethanol (37 ml), and the mixture was stirred for 4.5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.862 g) as brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:30][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]=3[CH:8]=2)=[CH:22][CH:21]=1
Reactant: CNc1nc2cc(NCc3ccc(C(=O)O)cc3)ccc2s1
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc2cc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)ccc2s1
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine (376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) was dissolved in acetonitrile (15 mL), treated with triethylamine (3 mL) and stirred overnight. The reaction mixture was quenched with methanol, concentrated and purified by chromatographic column on silica gel (40% EtOAc in DCM) and the obtained material crystallized from DCM to give 358 mg (0.88 mmol; 35% yield) of pure compound 456. 1H-NMR (300 MHz; DMSO-d6) δ (ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H). LRMS: calc: 403.5008. found: 404.2 (M+NH) and 202.6 (M+2H)/2.
Reaction SMILES: Br[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:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 19.3 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (75 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (18 mg, 19% over 2 steps) as a yellow-orange solid. NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.25-8.19 (m, 2H), 8.10 (br s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.32 (s, 2H), 7.07 (d, J=9.1 Hz, 1H), 4.53 (br s, 1H), 4.01 (dt, J=13.7, 4.0 Hz, 1H), 3.39-3.23 (m, 1H), 2.86 (br s, 1H), 2.22-2.12 (m, 1H), 1.97-1.88 (m, 1H), 1.78-1.64 (m, 2H), 1.26-1.16 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.96 min.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([OH:35])[CH:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([OH:35])[CH:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 84 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.), conc.hydrochloric acid (1.1 g.), methanol (16 ml.) and tetrahydrofuran (10 ml.) was stirred at room temperature for 2 hours. After methanol was removed in vacuo, the residue was dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorous pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+]>C(Cl)Cl>[CH:1]([NH:4][C:6](=[O:7])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)NC(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
Using the same procedure as in Example 4, isopropylamine (2.36g, 0.04 mole) was reacted with phenyl chloroformate (6.0g, 0.038 mole) in methylene chloride (35 ml) and with aqueous sodium hydroxide. The reaction mixture was stirred for two hours, then allowed to separate. The organic layer was dried over anhydrous magnesium sulfate, then gravity filtered. The filtrate was stripped of solvent on the Rotovap, leaving pure white crystals weighing 6.66g, MP 81°-82° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=2)[CH:15]=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:19]3[CH:20]=[C:21]4[C:16]([CH:15]=[CH:14][NH:13]4)=[CH:17][CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2cc[nH]c2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and indole-6-carboxylic acid (Lancaster) according to methods A and C; yield 59 mg, 0.17 mmol (48%): 1H NMR (300 MHz, methanol-d4) δ 2.12-2.30 (m, 6H), 2.49 (s, 2H), 3.49 (d, J=12 Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.41 (d, J=3 Hz, 1H), 7.55 (dd, J=8, 2 Hz, 1H), 7.62 (d, J=12 Hz, 1H), 7.94-8.04 (m, 1H), 8.22 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C18H21N3O.HCl.0.75H2O: C, H, N.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)cc1
Yield: 84.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0348 g, 0.059 mmol) and LiOH (0.014 g, 0.591 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0279 g, 0.050 mmol, 84% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 7.03-7.08 (m, 3H), 6.96 (d, J=7.9 Hz, 2H), 5.97 (br. s., 1H), 5.04-5.11 (m, 2H), 3.85 (s, 3H), 3.59 (br. s., 1H), 2.91 (br. s., 1H), 2.63 (br. s., 3H), 2.24-2.30 (m, 1H), 2.22 (s, 3H), 2.02-2.14 (m, 1H), 1.24 (s, 9H), 0.87 (br.s., 3H), 0.67 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=561.4.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1Cl.CCN(CC)CC>CS(C)=O.C(Cl)Cl.O>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[N:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1
Reactant: Cc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc2[nH]c(C3CN(c4c(Cl)cncc4Cl)C3)nc2c1
Temperature: 120 °C

Procedure:
The mixture of 2-azetidin-3-yl-5-methyl-1H-benzoimidazole (450 mg, 2.4 mmol), 3,4,5-trichloro-pyridine (438 mg, 2.4 mmol) and Et3N (969 mg, 9.6 mmol) in DMSO (20 ml) was heated at 120° C. under microwave for 1.5 h. Then it was diluted with DCM and H2O. The organic layers were concentrated to give the title compound which was purified by column chromatography and followed by preparative HPLC to afford the pure product 2-[1-(3,5-dichloro-pyridin-4-yl)-azetidin-3-yl]-5-methyl-1H-benzoimidazole (800 mg, yield 55%). [M+1] 333. IC50 (uM) 0.21.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[NH:28][C:29](=[O:34])[C:30]([O:32]C)=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37]O.[OH-].[Na+:40]>O1CCCC1>[Na+:40].[CH3:37][N:28]([C:12]1[CH:13]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]1[CH:35]=[CH:36][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[C:29](=[O:34])[C:30]([O-:32])=[O:31]
Reactant: CO
Reactant: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)C(=O)[O-])c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of methyl N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (436 mg, 0.869 mmol), methanol (2 ml), tetrahydrofuran (2 ml) and 2N aqueous sodium hydroxide (1.3 ml) was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with methanol to give the title compound (390 mg, 88.1%) as a white solid.
Reaction SMILES: C([C:3]([CH:10]=[CH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)=[C:4]([CH2:8][CH3:9])[C:5]([OH:7])=[O:6])C>CCOCC>[CH2:21]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:11]=[CH:10][CH:3]=[C:4]([CH2:8][CH3:9])[C:5]([OH:7])=[O:6])=[CH:13]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCC(C=Cc1cn(Cc2ccccc2)c2ccccc12)=C(CC)C(=O)O
Solvent: CCOCC
Product: CCC(=CC=Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)O

Procedure:
In a manner similar to Example 2, 1.8 g (5 mmol) of ethyl 5-(1-benzylindol-3-yl)-2-ethyl-2,4-pentadienoic acid was hydrolyzed to give the corresponding acid, m.p. (ether): 169-170. NMR (CDCl3 /DMSO-d6) spectrum shows broad triplet and quartet at δ1.10 and δ2.47 respectively; the benzyl methylene signal appears at δ5.30 as a broad singlet.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:23][CH:24]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)(=[O:31])=[O:30])[CH2:25]1)(C)(C)C>>[Cl:45][C:44]1[C:39]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:29]([N:26]2[CH2:27][CH2:28][CH:24]([OH:23])[CH2:25]2)(=[O:30])=[O:31])=[N:40][C:41]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:42][CH:43]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n1)CCN(CCO)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and {2-[3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as a white foam (25 mg, 22%). MS (ESI+): 589 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.25 (m, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.89 (s, 4H), 3.65 (t, J=9 Hz, 2H), 3.42 (m, 3H), 3.41 (d, 1H), 2.87 (m, 2H), 2.72-2.66 (m, 8H), 1.97 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:13]=3)=[CH:10][C:9]([NH2:29])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]=[C:31]1[NH:35][CH2:34][C@@H:33]([C:36](O)=[O:37])[CH2:32]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])[CH:13]=3)=[CH:10][C:9]([NH:29][C:36]([C@H:33]3[CH2:32][C:31](=[O:30])[NH:35][CH2:34]3)=[O:37])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: Nc1cc(-c2cccc(COC(C(F)(F)F)C(F)(F)F)c2)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COC(C(F)(F)F)C(F)(F)F)c3)n(-c3ccccc3)n2)CN1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (78 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (29 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (44 mg) at room temperature, and the mixture was stirred overnight. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (54 mg).