Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][C:17]([CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])=[C:18]2[C:22]([O:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:25]([O:24][C:22]([C:18]1[N:19]2[CH:14]([S:15][CH2:16][C:17]=1[CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH:13]([NH:12][C:5](=[O:6])[C:4](=[N:8][O:9][CH3:10])[C:3](=[O:11])[CH2:2][Br:1])[C:20]2=[O:21])=[O:23])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)cc1
Reactant: CON=C(C(=O)Cl)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride syn isomer (2 g) in acetone (10 cc) is added, in the course of 7 minutes, to a solution, cooled to -10° C., of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene, E-form (4.7 g) in acetone (50 cc), water (5 cc) and sodium bicarbonate (2.8 g). The mixture is stirred for 1 hour at -10° C. and is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). Crude 2-benzhydryloxycarbonyl-7-(4-bromo-2-methoxyimino-3-oxo-butyrylamino)-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (11 g) is obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[OH:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][NH2:63])=[CH:60][C:59]=1[O:66][CH3:67]>CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:63][CH2:62][C:61]2[CH:64]=[CH:65][C:58]([OH:57])=[C:59]([O:66][CH3:67])[CH:60]=2)=[O:16])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: COc1cc(CN)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1O
Reaction time: 0.08 h

Procedure:
To 139 mg (0.5 mmol) of 3-(phenylsulfonyl)aminobenzoic acid as prepared in Example 9 in 1 mL of N,N-dimethylformamide was added sequentially 1 mL of 0.5M (0.5 mmol) of Castro's reagent (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) in N,N-dimethylformamide and then 500 μL of N,N-diisopropylethylamine. After 5 min, 95 mg (0.5 mmol) of 4-hydroxy-3-methoxybenzylamine HCl was added. After 30 min, the reaction mixture was quenched with 7 mL of 2N HCl, extracted into ethyl acetate (2×2 mL), washed with water (3×4 mL) and then sat. NaHCO3 (1×4 mL). The organic phase was passed through a Waters solid phase extraction column (5 g silica gel) onto which was added Na2SO4 to act a drying agent. Elution with ethyl acetate gave the title compound: NMR (DMSO-d6 ; 300 MHz) δ 10.46 (s, 1H), 8.88 (t, 1H), 8.84 (s, 1H), 7.74-7.81 (m, 3H), 7.50-7.70 (m, 6H), 7.30 (t, 1H) 7.22 (d, 1H), 6.87 (s, 1H), 6.69 (t, 2H), 4.31 (d, 2H), 3.73 ppm (s, 3H). Mass spectrum (MALDI-TOF; gentisic acid matrix) cald. for C27H20N2O5S: 435.1 (M+Na). Found: 435.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][NH2:34])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12])[CH3:30]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 59.1 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 2-ethoxyethylamine (18 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 480.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.41 (bs, 1H), 8.47 (t, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.66 (s, 3H), 3.56-3.39 (m, 6H), 1.13 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:18](=[O:21])[CH:19]=[CH2:20])[CH:5]=1
Reactant: C=CC(=O)Cl
Reactant: CNc1cccc(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)CNc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred mixture of 3-methylaminobenzoic acid methyl ester (3.11 g, 18.8 mmol) and sodium bicarbonate (3.16 g, 37.6 mmol) in DCM (20.0 mL) at 0° C. was added 2-propenoyl chloride (2.29 mL, 28.2 mmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.12 g, 100% yield), which was used in the next reaction without further purification.
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:10][CH2:9][S:8][CH:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>C1COCC1.C(OCC)C>[C:20]([CH2:19][CH2:18][CH2:17][C:7]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:8][CH2:9][CH2:10][S:6]1)#[N:21]
Reactant: N#CCCCBr
Reactant: CCOC(=O)C1SCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1(CCCC#N)SCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (6.5 mL, 1.6 M in hexane) was added to a solution of ethyl 1,3-dithiolane-2-carboxylate (1925 mg, 10 mmol) in THF (10 mL) at −78° C. under N2. The reaction mixture was stirred for 30 min at −78° C. and then 4-bromobutanenitrile (1469 mg, 10 mmol) in THE (10 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. It was diluted with diethyl ether and washed with 1 N HCl and H2O, and dried. Evaporation and purification by column chromatography afforded ethyl 2-(3-cyanopropyl)-1,3-dithiolane-2-carboxylate: LCMS tR=1.86 Min (5 min run, UV254nm), Mass calculated for, M+259.0, observed LC/MS m/z 260.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:23][C:22]([F:25])([F:24])[CH2:21]2)=[C:16]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[N:15]=1)=[O:13])[C:5]1[N:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:32]I.[H-].[Na+]>>[CH3:32][N:11]([CH:4]([C:5]1[N:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:2]([CH3:31])[CH3:1])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][C:22]([F:25])([F:24])[CH2:23]2)=[C:16]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[N:15]=1)=[O:13]
Reactant: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)CC(c1cccnn1)N(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procure described in Example 16 b), (+)-6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide was reacted with methyl iodide (CAN 74-88-4) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=446.2 [MH]+.
Reaction SMILES: C(Cl)Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[C:23](Cl)(=[O:25])[CH3:24].[Cl-].[Na+]>C(N(CC)CC)C>[C:23]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:9][CH:10]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a 10 ml dried methylene chloride solution of 0.57 g (2.24 mmol) of 1-(4-aminophenyl)-3-(3-pyridyl)-2-imidazolidinone in a 100 ml round-bottomed flask were added 0.34 ml (1.1 eg.) of triethylamine, and, after stirred for 15 minutes, 0.17 ml (1.1 eg.) of acetyl chloride were added dropwise under cooling with ice. After dropwise addition, the mixture was stirred for 8 hours at room temperature. To this reaction mixture were added 10 ml of saturated aqueous solution of sodium chloride, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then solvent was distilled off under reduced pressure to obtain 0.16 g (yield 24%) of 1-(4-acetylaminophenyl)-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CCO>[CH:19]1([NH:22][CH2:2][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Reactant: NC1CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CNC2CC2)c1
Reaction time: 24 h
Yield: 86.7 %

Procedure:
23.7 g of tert-butyl 3-(bromomethyl)-4-nitrobenzoate are suspended in 400 ml of EtOH and treated at 0° C. with 9.0 g of cyclopropylamine. The mixture is stirred for 24 h, concentrated, and the residue is crystallized from petroleum ether. The mother liquor is chromatographed and crystallized. 19 g of the title compound are obtained. MS (DCI) 293 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([O-])([O-])=O.[K+].[K+].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:14]=1[C:15]#[N:16]>C(Cl)(Cl)Cl>[C:15]([C:14]1[C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH3:5])#[N:16]
Reactant: COc1ccc(N)c(C#N)c1OC
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(OC)c(OC)c1C#N
Yield: 50.2 %

Procedure:
Methyl chloroformate (18.6 g, 19.7 mmol) was added to a suspension of K2CO3 (2.71 g, 19.6 mmol) and 2-amino-5,6-dimethoxybenzonitrile (7.0 g, 39.3 mmol) in 70 ml of CHCl3. The resulting mixture was heated at reflux for 2 hours before using filtered and evaporated to a residual solid. Recrystallization of the crude material from MeOH yielded 4.64 g (50.2% of product in good purity.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].[C:18]([O:21][C:22](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:18][O:21]/[CH:22]=[C:7]1\[C:6](=[O:14])[N:5]([C:15](=[O:17])[CH3:16])[N:4]([C:1](=[O:3])[CH3:2])[C:13]2[C:8]\1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1C(=O)Cc2ccccc2N1C(C)=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: CO/C=C1\C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 1,2-diacetyl-1,4-dihydro-3(2H)cinnolinone (0.34 g, 1.5 mmol) in dimethylformamide (3.6 mL) is added acetic anhydride (5 mL), followed by trimethylorthoformate (0.64 mL). The mixture is heated at reflux for 12 hours. After cooling to room temperature, the mixture is purified by semi-preparative reverse-phase HPLC, employing a gradient elution from 5% acetonitrile in water with 0.1% trifluoroacetic acid to 100% acetonitrile over 60 minutes. The desired fractions were concentrated under reduced pressure to afford 0.18 g of (Z)-1,1′-(4-(methoxymethylene)-3-oxo-3,4-dihydrocinnoline-1,2-diyl)diethanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: COc1cccc(C(=O)Cl)c1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(OC)c4)c3)csc12

Procedure:
3-[3-(3-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and m-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: C([O:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=O)[C@H:6]1[C@H:19]([O:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH3:20])(=O)C.[C:28]1([S:34][C:35]([O:37][Si](C)(C)C)=[CH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:25]([O:24][C:22]([O:21][C@@H:19]([C@@H:6]1[C@@H:7]([CH2:36][C:35]([S:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:37])[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]1=[O:4])[CH3:20])=[O:23])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)O[C@H](C)[C@@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1OC(C)=O
Reactant: C=C(O[Si](C)(C)C)Sc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 377 mg of (3S, 4R)-4-acetoxy-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-1-(p-methoxybenzyl)-2-azetidinone in 2 ml of dry methylene chloride were added 448 mg (2 mmole) of 1-phenylthio-1-(trimethylsilyloxy)ethylene and then the mixture was stirred at room temperature, A catalytic amount of trimethylsilyltrifluoromethanesulphonate was added to the mixture, which was then left to stand at room temperature overnight. The precipitate produced was dissolved in 200 ml of ethyl acetate, and the resulting solution was washed successively with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulphate and subjected to Lobar column chromatography eluted with a 1:1 by volume mixture of cyclohexane and ethyl acetate, to afford 430 mg (yield 91%) of the title azetidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(Oc1ccccc1C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 1.1 g of methyl 2-(2-methylphenoxy)-3-methoxyacrylate, 0.95 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux in carbon tetrachloride for 4 hours. The solid was filtered, and the solvent evaporated to give a crude sample of methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude sample together with 0.6 g of o-cresol, and 1.0 g of potassium carbonate was heated at reflux in acetonitrile for 20 hours. The solid was filtered, the solvent evaporated, and the residue purified by silica gel chromatography to give methyl 2-[2-(2-methylphenoxy)methylphenoxy]-3-methoxyacrylate (0.47 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:27])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:8]=1[CH3:26]>C1COCC1.CO>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:27])=[O:4])=[C:8]2[CH3:26])=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+ 326)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][C@H:2]1[C:3]([O:5][CH3:6])=[O:4].C(N[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])CC>>[CH3:6][O:5][C:3]([C@@H:2]1[CH2:7][CH2:8][CH2:9][N:1]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:15])=[O:16])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Pro-OMe following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)C>[OH:1][C@@H:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CCO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Yield: 53.8 %

Procedure:
(S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (50 g) and 4-(naphthalen-2-yl)piperidine (43 g) were dissolved in ethanol (500 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the obtained crystals were collected by filtration. The crystals were recrystallized once from acetonitrile and once from a mixed solvent of ethyl acetate and ethanol to give the title compound (50 g), melting point 138-140° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>O>[CH2:5]1[C:6]2[NH:15][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:1]=2[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCCCC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Temperature: 115 °C
Reaction time: 8 h

Procedure:
Cyclohexanone (2.0 ml., 0.020 mole), phenylhydrazine hydrochloride (2.88 g., (0.020 mole) and 6.0 ml. of freshly distilled pyridine are combined, heated at reflux (115° C) for 3 hours, then allowed to cool to room temperature and allowed to stir overnight. About 25 ml. of water is added and the precipitated solids are collected by decantation. After washing again with water, the solids are dissolved in a mixture of 20 ml. of ethanol and 5 ml. of water and set aside. The resulting crystals are collected by filtration, washed with aqueous ethanol and dried to afford 2.65 g. (77.5% of theory) of the title compound, M.P. 119°-120° C. A mixture of the product and an authentic sample of 1,2,3,4-tetrahydrocarbazole also melted at 119°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:28][CH3:29])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 103 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 17.3 g. of sodium hydride (50% dispersion in oil) in 1 liter of absolute dimethylformamide was stirred at room temperature for 4 hours and subsequently treated with 56.2 g. of ethyl iodide with stirring and ice-cooling. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. Then, 1 liter of water was added to the residue and the mixture was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 700 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained N-ethyl-2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester having a melting point of 85°-86° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:8]([CH3:21])[N:9]=[C:10]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11]2.O1CCCC1>C(N(CC)CC)C>[CH3:21][N:8]1[C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[C:15]2[C:10]([N:11]=[C:12]([C:17]([CH3:18])([CH3:20])[CH3:19])[NH:13][C:14]2=[O:16])=[N:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N(S(C)(=O)=O)S(C)(=O)=O

Procedure:
Methanesulphonyl chloride (12.9 g) was added slowly to a stirred mixture of 3-amino-2-methyl-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (11 g) prepared as in Example 1, tetrahydrofuran (85 ml) and triethylamine (21 ml), causing the mixture to boil. The mixture was heated under reflux for 3 hours, and was then cooled and filtered. The filtrate was then evaporated to dryness, and the residue was washed with 80:20 ethanol/water to give the title compound, m.p. 258°-259° C.