Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccc3)CN2C1=O
Yield: 47.4 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and benzoyl chloride (61 μL, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 56 mg (48%) of 18-benzoyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 673 (M−H)−, HRMS: calcd. 675.2700 and found 675.2709 (M+H)+, mp 135-137° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:44]([O-:46])=[O:45])=[C:33]([CH:35](C(OC)=O)[C:36]([O:38]C)=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:44]([O-:46])=[O:45])=[C:33]([CH2:35][C:36]([OH:38])=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(CC(=O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 55 °C
Yield: 75 %

Procedure:
To a stirred solution of dimethyl 2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)malonate (10.0 g, 15.3 mmol) in 1:1:1 THF/MeOH/water, was added 3N aqueous NaOH (20 mL). The resulting mixture was heated at 55° C. for 15 h. The reaction mixture was cooled to room temperature and treated with 5N aqueous HCl to pH 5. The aqueous layer was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with methanol and ether and the solid collected by filtration to give the title compound in 75% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (br. s., 1H) 8.49 (q, J=4.23 Hz, 1H) 8.09-8.15 (m, 1H) 8.02 (s, 1H) 7.96 (d, J=3.32 Hz, 4H) 7.31-7.44 (m, 4H) 7.25 (s, 1H) 3.98 (s, 2H) 3.56 (s, 3H) 2.84 (d, J=4.69 Hz, 3H) 1.94-2.03 (m, 1H) 0.85 (d, J=3.13 Hz, 3H) 0.48 (br. s., 1H). LCMS (m/z, ES+)=583 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:27])[CH:16]([CH2:21][CH:22]4[CH2:26][CH2:25][O:24][CH2:23]4)[CH2:17][C:18]=3[O:19]C)[CH:9]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:15](=[O:27])[CH:16]([CH2:21][CH:22]4[CH2:26][CH2:25][O:24][CH2:23]4)[CH2:17][C:18]3=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(CC2CCOC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2CCOC2)C1=O
Temperature: 120 °C
Yield: 10.4 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-5-(tetrahydro-furan-3-ylmethyl)-cyclopent-2-enone (150 mg, 0.37 mmol) in acetone (2 ml) was added 2N hydrochloric acid (2 ml) and the reaction heated to 120° C. for 60 minutes by microwave irradiation. The crude reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride solution (25 ml), brine (25 ml). The solvent was removed under reduce pressure and the residue purified by mass-directed preparative HPLC to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-4-(tetrahydro-furan-3-ylmethyl)-cyclopentane-1,3-dione (15 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: COc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 102 mg, 0.49 mmol) and 4-methoxy-benzyl bromide (73 μL, 0.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature overnight, then heated to 100° C. and left over the weekend. At this time it was found that the heating bath had failed and the reaction mixture was at room temperature. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-methoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (48 mg, 30%) as a white solid. APCI-MS (M+H) 327.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37][N:36]=2)[CH:30]=1)=O)(C)(C)C>>[CH3:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (44 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH:12]1([NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[N:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:19]([CH3:23])([CH3:22])[CH2:20][S:11]1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)(CO)NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)CSC(=Nc2c(Cl)cccc2Cl)N1C1CCCCC1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
N-Cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. A solution of 2,6-dichlorophenyl isothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine (1.0 g, 6.0 mmol) in CH2Cl2 (10 mL) was stirred for 20 h at room temp. The resulting mixture was concentrated under reduced pressure, then treated with a 33% HCl solution (15 mL). The resulting mixture was heated at the reflux temp. for 1 h, cooled to room temp. and neutralized with a 45% NaOH solution. The resulting slurry was filtered, and the resulting solids were washed with water (20 mL), then recrystallized (EtOH) to yield 2-(2,6-dichlorophenylimino)-3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine (0.70 g, 33%/o): mp 134° C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et2O (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[ClH:21].CCO[CH2:25][CH3:26]>>[ClH:21].[C:8]([C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[C:9][CH2:10][CH2:5][CH2:25][CH3:26]
Reactant: CCOCC
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Agent: Cl
Product: CCCCC#Cc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 18 %

Procedure:
Prepared from the product of step A (example 16) according to general procedure 6. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (27 mg, 18%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=9.7 Hz, 1H), 7.60 (s, 1H), 6.83 (d, J=9.7 Hz, 1H), 3.95 (m, 4H), 3.54 (t, J=6.4 Hz, 2H), 3.34-3.24 (m, 6H), 2.56 (t, J=6.4 Hz, 2H), 2.21-2.15 (m, 2H), 1.67-1.54 (m, 4H), 0.99 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 156.1, 136.6, 132.2, 124.9, 116.5, 115.1, 100.7, 68.1, 65.1, 56.8, 53.4, 39.5, 31.8, 24.3, 23.0, 20.1, 14.0; HPLC tR=12.7 min (Luna), 97.5%; ES-MS: (M+H)=342 m/z.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccco1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and furan-2-boronic acid according to the general procedure B. Obtained as an orange solid (282 mg).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride (Example 2, pt. a) in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N. H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown, viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, mp 101°-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(N(CC)CC)C.CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][O:17][C:20](=[O:21])[NH:19][CH3:18])[N:3]=1
Reactant: COCCCNc1nc(Cl)nc(NCCO)n1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OCCNc1nc(Cl)nc(NCCCOC)n1

Procedure:
A solution of 5 g 2-chloro-4-(3-methoxypropylamino)-6-(2-hydroxyethylamino)-s-triazine, 1.2 g methyl isocyanate and 10 drops triethylamine in 20 ml dimethylformamide was heated at 100° C. for 2 hours. The dimethylformamide was removed by distillation and the resulting residue was slurried with ether and filtered to give the product as a white powder. The melting point and elemental analysis on the product are tabulated in Table I.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc(N)cn1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1

Procedure:
To a solution of N-(5-aminopyridin-2-yl)acetamide (1.00 g, 6.62 mmol) and pyridine (0.647 ml, 7.94 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.10 ml, 7.94 mmol), and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.47 g (68.1%) of the desired product as a solid was separated by filtration.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].Cl>>[CH3:21][C:18]1[CH2:19][CH:20]=[C:16]([CH3:15])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=CCC(C)=C1c1ccccc1N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 102.2 %

Procedure:
0.130 g (1.29 mmol) of triethylamine and 0.155 g (1.29 mmol) of pivaloyl chloride were added to 0.263 g (1.42 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine dissolved in 10 mL of an MC solvent and then reacted at room temperature for one hour. 5 mL of 2N HCl was added to the reaction solution and then strongly stirred for a few minutes. The organic layer was collected and then neutralized by 5 mL of NaHCO3 saturated aqueous solution. The resultant product was purified through a column chromatography using a solvent of hexane/ethyl acetate (v/v, 10:1), and then dried in vacuum to remove the solvent therein, thereby obtaining white solid (0.355 g, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:13][O:14][CH2:15][C:16]2[N:21]=[C:20]([N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:13][O:14][CH2:15][C:16]2[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccsc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(=NOCc1cccc(N)n1)c1ccsc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)-methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (6.80 g, 15.3 mmol) in tetrahydrofuran (30 mL) was added dropwise hydrazine hydrate (3.72 mL, 76.7 mmol). After stirring at room temperature for 30 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]pyridin-2-amine [3.02 g, yield 60%; HPLC/MS: m/z=314 (M+H); log P(HCOOH)=0.39].
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].O.[NH2:23][NH2:24]>CO>[CH3:19][N:17]1[CH:18]=[C:14]([C:11]2[CH:12]=[C:13]3[C:5]([C:3]([NH:23][NH2:24])=[O:4])=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:15]=[N:16]1
Reactant: NN
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c3c2)cn1
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)NN)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of the trichloroethanone 3 prepared above are suspended in 150 ml of methanol, and 34 ml of hydrazine hydrate are slowly added dropwise at 5-10° C. When the addition is complete, the mixture is stirred at RT for a further 1 h. Half of the liquid components are subsequently removed in vacuo, and the residue is cooled to 0° C. The precipitating crystals are filtered off with suction and washed with methanol. The residue is subsequently dried at 80° C. in vacuo, giving 5.4 g of the hydrazide 4. HPLC-MS: Rt=1.263 min; [M+H+]: 257.1
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC#N>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:5][CH:4]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)NCc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
To 1-(4-bromophenyl)methanamine hydrochloride (8.56 g, 38.5 mmol), MeCN (50 mL) and NEt3 (5.36 mL, 38.5 mmol) was added methyl 3-chloro-3-oxopropanoate (3.17 mL, 29.6 mmol). The reaction was aged about an hour before NEt3 (10.7 mL, 77 mmol) was added. The reaction was aged about 20 min and was concentrated. The reaction was diluted with EtOAc and washed with brine and aq. 2M Na2CO3 solution followed by aq. 2 M HCl and water. The organic portion was concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-90% EtOAc/hexane to afford the product.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[OH:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(C)(O)CN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Then similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-2-methyl-propylamine and DIEA to give 2-(2-hydroxy-2-methyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 328 (MH+).
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])C.Cl.[O:32]1CCOCC1>>[Cl:28][C:24]1[CH:23]=[C:22]([C@@H:20]([OH:21])[CH2:19][NH:18][C@H:16]([CH3:17])[CH2:15][C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:32])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c2c1
Reactant: C1COCCO1
Agent: Cl
Product: C[C@H](Cc1c[nH]c2cc(C(=O)O)ccc12)NC[C@H](O)c1cccc(Cl)c1
Yield: 44 %

Procedure:
To a solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxy-ethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (800 mg, 1.87 mmol) in 1,4-dioxane (10 ml) is added 6N—HCl (10 ml), and the mixture is refluxed for 24 hours. After allowed to cool, the reaction solution is concentrated under reduced pressure, and the residue is purified by octadecylsilyl column chromatography (trifluoroacetic acid/methanol/water), and further crystallized from aqueous methanol (pH 7) to give 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]-propyl}-1H-indole-6-carboxylic acid (304 mg, 0.815 mmol, 44%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)[NH:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[NH:1]1[CH:5]=[CH:4][N:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)[NH:2]1
Reactant: CCOC(=O)c1cn2cc(N3C=CNN3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(N3C=CNN3)ccc2n1
Yield: 64.6 %

Procedure:
125 mg of ethyl 6-(1H-1,2,3-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3), to give 72 mg of 6-(1H-1,2,3-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:11][C:6]1[CH:5]=[C:4]([C:2]2[O:3][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:1]=2)[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cc(Cl)cc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3,5-dichloroacetophenone (2 g, 10.58 mmol), trimethylsilyl triflate (2.35 g, 10.58 mmol), triethylamine (2.14 g, 21.16 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.64 g, 5.29 mmol). Isolated yield: 70% m.p. 168°-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 7.01 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.83 (m, 1H), 7.88 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[N:4]1)[CH3:2].[H][H]>CO>[NH2:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[CH:6]=1
Reactant: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1N
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Pt/Vd (3%/0.6% wt/wt on carbon, 50 mg, 0.008 mmol, 0.005 equiv) was added to a stirring solution of 3-[1-ethyl-5-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-3-yl]benzonitrile (0.54 g, 1.53 mmol, 1 equiv) in methanol (15.3 mL). A 3-way stop cock with a hydrogen balloon was installed and the reaction vessel was subjected to alternating vacuum and H2 gas (4×). The resulting mixture was stirred at 22° C. for 2 hours. The mixture was then subjected to alternating vacuum and nitrogen gas (4×) before the mixture was filtered through a nylon syringe filter and concentrated in vacuo to afford 3-[5-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-3-yl]benzonitrile. The crude reaction product was carried forward without further purification. Calcd (M+1)+: 323.1. Found: 323.0.