Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:23]1(C)C=CC=C[C:24]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:17]1([S:14]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:23]=[CH2:24])[CH:3]=3)[NH:7][C:6]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 100 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), palladium(II)acetate (12 mg, 0.012 mmol, 0.1 equiv), tri-o-tolylphosphine (31 mg, 0.10 mmol, 0.2 equiv) and triethylamine (150 μL, 1.03 mmol, 2.0 equiv) were dissolved in 5 mL of DMF, the vessel was charged with 1 atm of ethylene and heated to 100° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C15H18N3O4S (M+H+): 336.1013. Found 336.1016.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]([NH2:18])=O)=[CH:12]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16](=[S:36])[NH2:18])=[CH:12]2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOCCN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CCOCCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of 7-[(2-ethoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.70 g), Lawesson's reagent (3.06 g) and tetrahydrofuran (30 ml) was stirred at 70° C. for 3 hr. The reaction mixture was concentrated, and toluene was added to the residue. The obtained solid was washed with toluene to give the title compound (2.99 g, yield 58%) as crystals. melting point 182° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C([Li])CCC.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CCOCC>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Ic1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
A solution of 1,4-diiodobenzene (46.8 g, 142 mmol) in dry ether (450 mL) under argon was cooled in a salt-ice bath. n-Butyllithium (2.0 M in pentane, 72 mL, 142 mmol) was added, and the solution was stirred for 10 minutes. 2-Fluoropyridine (13 mL, 150 mmol) was added and the reaction was allowed to warm to room temperature over 2 hours. Water (500 mL) was added and the organic layer was separated. The aqueous layer was extracted with ether (3×200 mL) and the combined organic layers were washed with brine (1000 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent completely removed. The residue was purified in two steps; first by column chromatography over silica using a dichloromethane/light petroleum mixture (1:1) followed by recrystallisation of the main fraction from a dichloromethane/light petroleum mixture to give (1) (17.0 g, 40%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: CC(=O)OCCBr
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
5-(4-Chloro-phenyl)-N-piperazin-1-yl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxamide trifluoroacetate (1:1) (200 mg, 378 μmol, example 13b) was combined with acetonitrile (10 mL) to give a yellow solution. To this solution 2-bromoethyl acetate (760 mg, 500 μl, 4.55 mmol) and K2CO3 (157 mg, 1.13 mmol) were added successively. The reaction mixture was heated to 60° C., stirred for 20 h, filtered through a Celite® pad after cooling to ambient temperature and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 50% methanol in ethyl acetate) to give the title compound (107 mg, 57%) as white solid; LC-MS (UV peak area/ESI) 97.8%, 501.1510 (M+H)+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3]C1.[Mg].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1>C1COCC1>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:7]3([OH:10])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc3c(c2)OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole) in 50 ml dry THF was added to a of the Grignard reagent prepared from magnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75 g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturated NH4Cl and extracted with ether. The ether extracts were dried with Na2SO4 and the solvent removed in vacuo. Acetone (75 ml) and 1N HCl (75 ml) were added and the solution was stirred 18 hr to give a tan precipitate which was filtered and air dried (6.38 g, 59.1%). This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cccc(N)c1C(=O)O
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc2nc(-c3c(F)cccc3F)oc(=O)c12

Procedure:
2-Amino-6-methylbenzoic acid (0.498 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (20 mL) were reacted as described under (10).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:45][NH2:46].CCOC(C)=O>C1COCC1>[CH3:45][NH:46][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
The above mentioned tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate was dissolved in 20 mL 2M THF solution of methanamine (20 mL, 40 mmol) in a microwave heating tube. The tube was heated at 120° C. for 10 minutes. The THF solution was mixed with 200 mL EtOAc. The organic phase was washed with water, twice with saturated aqueous ammonium sulfate twice, and dried over sodium sulfate. After removing the solvent, the product was used directly in the next step.
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20]>>[CH:15]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([CH2:18][C:19]([OH:21])=[O:20])[C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: O=C(O)CC(=O)O
Product: O=C(O)CC1c2ccccc2C=Cc2ccccc21
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A round bottom flask, equipped with a distillation apparatus, is charged with dibenzosuberenol (10.0 g, 48.01 mmol) and malonic acid (25.0 g, 240.08 mmol). The mixture is heated in a 160° C. oil bath. The solids melt. Gas bubbles form and water and acetic acid are distilled through the condenser. After 1.5 hours, the mixture is cooled to room temperature and dissolved in ethyl acetate. The organic solution is washed with brine and dried over MgSO4. The solvent is removed in vacuo to give an off white solid, which is recrystallized from hexane-ethyl acetate-(AcOEt)/1:1 to yield the title compound as white crystals, 10.2 g; mp167 °-168° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: C1COCCN1
Product: COc1ccc(N(C)c2nc(N3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and morpholine (30 μL) by a procedure similar to example 5 and was isolated as white powder (10 mg, 66%). 1H NMR (CDCl3): 7.46 (d, J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.67 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)(C)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CCN1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.0986 g, 0.376 mmol) in isopropanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0550 g, 0.376 mmol) and piperidine (0.00320 g, 0.0376 mmol), and the mixture was refluxed by heating for 2 hours. The reaction mixture was cooled to room temperature, and then added with isopropanol (2 mL), and the precipitated solid was suspended in isopropanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.106 g, 72%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][OH:11])=[CH:4][C:3]=1[O:12][CH3:13].[H-].[Na+].I[CH3:17]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:17])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CI
Reactant: COc1cc(CO)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OC)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under cooling in an ice water bath, to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide (960 mL) was added sodium hydride (60% oily; 24.7 g), and the mixture was stirred for 10 minutes. To this iodomethane (41.7 mL) was dropped. Thereafter, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (2.5 L), and extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate (4:1), 121.3 g of a title compound was obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(Br)cccc23)CC1
Yield: 28.5 %

Procedure:
A stirred solution of 7-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (215 mg, 29%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][NH2:70])=[CH:67][CH:66]=1.O>ClCCl>[CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([NH:70][CH2:69][C:68]2[CH:71]=[CH:72][C:65]([F:64])=[CH:66][CH:67]=2)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCc1ccc(F)cc1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCc1ccc(F)cc1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min. 4-fluoro benzyl amine (1.5 mg) was added, The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[N:23]=C(Cl)C=[CH:20][N:19]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:1]([N:3]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]2)[CH:2]=[CH:20][N:19]=1
Reactant: CCn1cc(C=O)c(C)n1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(Cl)n2)cc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.47 g, 42%); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)c(C)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4′-chloro-3′-methylacetophenone (10.0 g), sodium hydride (60%, oil, 2.38 g) and diethyl carbonate (80 ml) was stirred for 90 min at 80° C. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(4-chloro-3-methylphenyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (10.6 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (8.24 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of ethyl 5-(4-chloro-3-methylphenyl)isoxazole-4-carboxylate (9.26 g, yield 59%) were obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) and recrystallized from hexane to give a colorless prism. melting point: 50–51° C.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH2:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:38][CH2:37][CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: CS(=O)(=O)OCCCCc1ccccc1
Agent: Cl
Product: O=C1N(CCCCc2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 115° C. and MS: m/e=502.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and methanesulfonic acid 4-phenyl-but-1-yl ester.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC>>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:6]1[CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[O:8][N:7]=1)=[O:11]
Reactant: O=C(O)c1cc(C2CC2)on1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CON(C)C(=O)c1cc(C2CC2)on1
Yield: 96 %

Procedure:
In a manner analogous to that described in Example 1 d), the condensation of 5-cyclopropyl-isoxazole-3-carboxylic acid and N,O-dimethylhydroxylamine hydrochloride by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride yielded the title compound (96% yield) as a pale yellow oil. MS (ISP): m/z=197.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1ccc(Cl)s1

Procedure:
N-[(tert-Butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate (74) is synthesised from 5-chlorothiophene sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (1.89 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 1.48 (9H, s), 1.35 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5-Hydroxyindole (2 g, 15 mmol) was dissolved in methanol (60 ml) under argon. Sodium cyanoborohydride (1.89 g, 30 mmol) and trifluoroboron etherate (4.2 ml, 33 mmol) were added and the mixture was heated at reflux for 3 hours then left to cool to ambient temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Ammonia was added to adjust the pH to 10 and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with water, brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by flash chromatography using dichloromethane/methanol (95/5) as solvent. Evaporation of the solvent gave 5-hydroxy-2,3-dihydro-1H-indole (1.45 g, 73%) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:19]=O)=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[CH3:21][C:22]([S@@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[C:3](/[CH:19]=[N:27]\[S@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[N:4][CH:5]=[C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C\c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Copper(II) sulfate (anhydrous, 5.8 g, 36.2 mmol) was added to a solution of 3-bromo-5-(1,3-dioxoisoindolin-2-yl)picolinaldehyde (30B, 6 g, 18 mmol) and (S)-2-methylpropane-2-sulfinamide (2.2 g, 18 mmol) in CH2Cl2 (60 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then filtered and washed with CH2Cl2. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc and methylene chloride to yield the title compound. MS (m/z) 433.87 [M+H]+.