Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14](=[O:46])[CH2:15][N:16]([S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N(S(=O)(=O)C(F)(F)F)CS(=O)C12
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (1.172 g.) in methylene chloride (10 ml.) was added dropwise a solution of m-chloroperbenzoic acid (430 mg.) in methylene chloride (6 ml.) at 0° C. with stirring over a period of 20 minutes, and the mixture was stirred for an additional 15 minutes. The mixture was diluted with methylene chloride and washed with a chilled dilute aqueous solution of sodium bicarbonate and a mixture of a dilute aqueous solution of sodium chloride and an aqueous solution of sodium bicarbonate. Drying over magnesium sulfate and removal of the solent left an amorphous solid (1.2 g.), which was chromatographed on silica gel (17 g.) with methylene chloride and then a mixed solvent of methylene chloride and ethyl acetate as an eluent to give an amorphous solid (1.10 g.) of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate-5-oxide.
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:37])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:29])(=[O:27])=[O:26])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:37])(=[O:27])=[O:26])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To 0.075 g (0.146 mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanol was added 0.10 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 2 h at room temperature, the catalyst was removed via filtration and the filtrate concentrated to give 0.056 g (91%) of the title compound as a white solid. MS Calcd.: 423. Found: 424 (M+H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:4]([O:3][C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(C#N)ccc21
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2cccnc2)cc2cc(C#N)ccc21
Temperature: 130 °C

Procedure:
A mixture of 1-Boc-5-cyanoindole-2-boronic acid (339 mg, 1.19 mmol), 3-bromo-pyridine (150 mg, 93 uL, 0.95 mmol), aqueous sodium carbonate (2M, 0.95 mL, 1.9 mmol) and DME (4 mL) is degassed with nitrogen and PS—Pd(PPh3) (285 mg, 0.11 mmol/g, 0.028 mmol) is added. The resulting mixture is then heated in the microwave at 120° C. for 20 min and at 130° C. for 25 min (three times). The reaction mixture is filtered through a sintered funnel and washed with dichloromethane (50 mL). The filtrate is dried over Na2SO4, filtered, and concentrated. The residue is purified by reverse phase HPLC (5 to 80% acetonitrile-0.1% aqueous ammonia) to give 5-cyano-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (400.3 MHz, CDCl3) δ ppm 1.34 (s, 9H), 6.67 (s, 1H), 7.39 (dd, J=4.9, 7.8 Hz, 1H), 7.61 (dd, J=1.6, 8.7 Hz, 1H), 7.74 (m, 1H), 7.92 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.65 (dd, J=1.6 Hz, 4.9 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H). MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:14]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(N)cc2)s1
Solvent: O=CO
Product: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NC=O)cc2)s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of acetic anhydride (1.1 g) and formic acid (0.8 g) was heated at 50° C. for 30 minutes. To the mixture was added ethyl 5-(4-aminophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.5 g). The mixture was stirred at ambient temperature for 4 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4-(formylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.38 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:6]=[S:5]1(=[O:7])[NH:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCNS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), is added potassium carbonate (71.0 mg, 0.514 mmol). The mixture is stirred at room temperature for 17 h, then diluted with water (7.5 mL). The reaction mixture is extracted with ethyl acetate (3×2 mL) and the extract is washed with water (2×2 mL), dried over MgSO4 and concentrated to give 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>CC1CCCO1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc(OCc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To 6-(benzyloxy)pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL) was added potassium t-butoxide (5.47 mL, 1.0M in tetrahydrofuran). After stirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2 mL) was added and the reaction heated to 75° C. for 1 hour. The reaction was cooled, diluted with ethyl acetate (150 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (SF40-80 g) eluting with a gradient of 5% to 20% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28](Cl)=[O:29])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1.Cl>O1CCCC1.O>[OH:3][NH:2][C:28](=[O:29])[CH:27]=[CH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:21]=1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.31 g, 4.40 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (6-8 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16b) (0.29 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl to pH˜5 of the reaction medium and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with hot ethyl acetate and methanol affording the title compound (0.12 g, 37%). M.p. 191° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.05 (2H, d, J=6.4 Hz); 6.56 (1H, d, J=16.0 Hz); 7.16-8.05 (7H, m); 8.16-8.49 (3H, m); 9.12 (1H, br s); 10.80 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 8% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 10:90; sample concentration 0.4 mg/ml; flow rate 1.3 ml/min; detector UV 270 nm). Anal. Calcd for C15H15N3O4S containing 0.5% of inorganic impurities, %: C 53.77, H 4.51, N 12.54. Found, %: C 53.72, H 4.33, N 12.41.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([O:24]C(C)(C)C)=[O:23]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([OH:24])=[O:23]
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Trifluoroacetic acid (2.0 mL) is added to a solution of tert-butyl α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (282 mg, 0.507 mmol) in CH2Cl2 (4.0 mL) at 0° C. The solution is stirred for 1 hour at 0° C. A second portion of trifluoroacetic acid (2.0 mL) is added, and the solution is stirred for 30 minutes at 0° C. and for 30 minutes at room temperature. Concentration and aqueous workup (CH2Cl2, MgSO4) to give 217 mg (90%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[C:42]1([C:48]2[N:52]=[C:51]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:50][N:49]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:56]1[CH2:55][CH2:54][CH:53]([C:51]2[O:50][N:49]=[C:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:52]=2)[CH2:58][CH2:57]1)=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: c1ccc(-c2noc(C3CCNCC3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (8c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 79%; 1H NMR (CDCl3) δ 8.06-8.09 (m, 2H), 7.48-7.51 (m, 3H), 4.49-4.54 (m, 1H), 3.90-3.94 (m, 1H), 3.24-3.33 (m, 2H), 2.97-3.06 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.17-2.24 (m, 4H), 1.93-1.98 (m, 4H). tR LCMS 6.0 min. Purity >99%; MS [M+H]+ m/z 368.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[CH:25]=2)[C:20]=1OB(O)O>>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[CH:25]=2)[C:20]=1[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1nccs1)c1cccc(Br)c1
Reactant: COc1cccc(-c2ccc3c(OB(O)O)c(OC)ccc3c2)c1
Product: COc1cccc(-c2ccc3c(-c4cccc(S(=O)(=O)Nc5nccs5)c4)c(OC)ccc3c2)c1
Yield: 14 %

Procedure:
The compound is prepared by the reaction of 3-bromo-N-(thiazol-2-yl)benzenesulfonamide (88.8 mg, 0.28 mmol, 1 eq) with 2-methoxy-6-(3-methoxyphenyl)-naphthalene-1-ylboric acid (100 mg, 0.36 mmol, 1.3 eq) according to method C. Purification by column chromatography with dichloromethane/methanol 95/5 yields the desired compound in a yield of 14%, 19 mg.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[NH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.CCN(C(C)C)C(C)C>O>[Cl:4][CH2:3][CH2:2][N:17]1[CH2:18][CH2:19][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH:7]=[CH:6][NH:5]3)[CH2:15][CH2:16]1
Reactant: ClCCBr
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: ClCCN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 36 %

Procedure:
8.3 mL of 1-bromo-2-chloroethane, 1.2 g of 1-(4-indolyl)piperazine and 1.2 mL of DIPEA was stirred at 60° C. for 3 h under nitrogen atmosphere. To the solution, cooled at r.t., was added 30 mL of H2O. The mixture was then extracted with CH2Cl2-MeOH 7:3 (3×15 mL). The organic layer, dried on an. Na2SO4, was evaporated to dryness. The crude was purified by flash chromatography (CH2Cl2-MeOH 98:2) to give 0.57 g (36%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:15][NH2:16]>CN(C=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CN
Reactant: CC(C)c1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1nc(Cl)nc2c(C(C)C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 10 ml of a solution of 100 mg (0.41 mmol) of 2,4-dichloro-7-isopropylthieno[3,2-d]pyrimidine in DMF was added 40% methylamine solution in methanol under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 90 mg (yield: 92.0%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:33][C@@H:34]1[CH2:39][NH:38][CH2:37][C@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:38]4[CH2:39][C@@H:34]([CH3:33])[CH2:35][C@@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5C[C@@H](C)C[C@@H](NC(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 60.7 %

Procedure:
Example ER-896389 was prepared in two steps from compound 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (25 mg, 0.056 mmol) and commercially available tert-butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate (48 mg, 0.224 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl ((3R,5S)-1-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)-5-methylpiperidin-3-yl)carbamate (22 mg, 0.034 mmol, 61% yield). Then, this intermediate (20 mg, 0.031 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896389 (17.5 mg, 97% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:25]3[S:21][C:22](=[O:27])[NH:23][C:24]3=[O:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2c(c1)N(Cc1ccccc1)C(=O)CO2
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (intermediate 66) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: C([O:4][CH:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=2)[N:8]([CH3:24])[N:7]=1)(=O)C.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].O>C(O)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1[N:8]([CH3:24])[N:7]=[C:6]([CH:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[OH:4])[N:10]=1
Reactant: CC(=O)OC(c1ccccc1)c1nc(NCCCOc2cccc(C=O)c2)n(C)n1
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nc(C(O)c2ccccc2)nc1NCCCOc1cccc(CNCc2ccco2)c1
Reaction time: 16 h

Procedure:
A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol acetate (ester) (1.0 g) and furfurylamine (5 ml) in ethanol (30 ml) was stirred at 21° for 1.5 h before a suspension of sodium borohydride (1.3 g) in ethanol (10 ml) was added and stirring was continued for a further 16 h at 21°. Water (20 ml) was added, the mixture concentrated to remove ethanol and the aqueous residue extracted with 4-methylpentan-2-one. The extract was dried and evaporated to give an oil. Excess furfurylamine was removed in vacuo and the residue was dissolved in 2N hydrochloric acid, the acidic layer washed with ethyl acetate, basified (pH 9) with sodium carbonate, and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give a brown gum (0.65 g) which was chromatographed on silica (Merck No. 7729) using System B as eluent to give the title compound (0.5 g) as a pale orange gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:24])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)CC(C)(N)CO
Product: CC(C)CC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2,4-dimethyl-1-pentanol (CAN 13893-55-5) as starting materials and isolated (193 mg, quant.) as colorless oil; LC-MS (UV peak area, m/z) 100%, 341.1623 (MH+).
Reaction SMILES: Cl.NC[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7](O)[CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(N(CC)CC)C>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:4]=1
Reactant: NCc1ccc2cccc(O)c2n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc2ncccc2c1

Procedure:
A mixture of 2-aminomethyl-8-hydroxyquinoline hydrochloride (1.05 g, 5 mmol) N-succinimidyl S-tetrahydropyranylmercaptoacetate (1.37 g, 5 mmol), and triethylamine (0.51 g, 5 mmol) in acetonitrile (15 mL) was heated under reflux for 2 hours. The reaction mixture was poured onto water and extracted with methylene chloride (3×20 mL). The combined organic layers were washed with water and dried (MgSO4) to give the ligand of Formula 17 as an orange gum which was sufficiently pure for complexation purposes. 1H-NMR (CDCl3) δ8.42 (broad, 1H), 8.20 (d, 1H), 7.41 (d, 1H), 7.35 (m, 2H), 7.18 (d, 1H), 4.95 (dd, 1H), 4.82(dd, 1H), 4.73 (dd, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 3.57 (d, 1H), 3.35 (d, 1H), 2.10-1.55 (m, 6H); 13C-NMR (CDCl3) δ169.6, 154.1, 152.1, 137.0, 136.9, 127.5, 127.4, 120.2, 117.8, 110.9, 83.7, 65.5, 44.7, 35.2, 30.8, 25.0, 21.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21]C)=[O:20])=[N:11][C:12]([O:17][CH3:18])=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[N:11][C:12]([O:17][CH3:18])=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(OC)cc(OC)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(OCc2ccccc2)c(C(=O)O)n1
Reaction time: 4 h

Procedure:
Methyl 3-benzyloxy-4,6-dimethoxypicolinate (33 mg) was dissolved in 2 ml of methanol. A 1 N aqueous sodium hydroxide solution (0.54 ml) was added to the solution, and a reaction was allowed to proceed at room temperature for 4 hr. The reaction solution was neutralized with 1 N hydrochloric acid, and was then concentrated under the reduced pressure to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][C:13]=1[F:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:24]1CCOCC1>O>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[O:24])=[N:19]2)=[CH:14][C:13]=1[F:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cc(F)c(OCCO[Si](C)(C)C(C)(C)C)cc2n1
Reactant: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc2nc(C=O)ccc2cc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 7-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-fluoro-2-methylquinoline (2.74 g, 8.17 mmol) in dioxane (24 mL) and water (0.24 mL) was added SeO2 (0.997 g, 8.98 mmol). The reaction mixture was heated at reflux for 4 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-fluoroquinoline-2-carbaldehyde (2.69 g, 94%).