Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](OCC)([O:20]CC)[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2Cc3cccc(OC)c3C2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc2c1C(=O)N(C[C@H]1CC(=O)CCN1[C@@H](C)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-(R)-(7-Methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1 (1-(S)-phenyl-ethyl)-piperidine (2.0 g, 4.4 mmol) was dissolved in a ice cold mixture of trifluoroacetic acid and water (10 ml, 9:1) and stirred or 0.5 hour on an ice bath. The reaction mixture was poured on aqueous sodium carbonate (100 ml) and extracted with dichloromethane (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo, affording 1.67 g (100%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4-oxo-1 (1-(S)-phenyl-ethyl)-piperidine.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.37 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.11 g, 22%). MS (ISP) 498.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][C:28](O)([CH3:31])[CH2:29][OH:30]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][C:28]([CH3:31])([CH3:27])[CH2:29][OH:30])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)(O)CO
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Product: CC(C)(CO)OCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
Using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5, formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material, and 2-methyl-propane-1,2-diol obtained in Step A instead of ethylene glycol used as a reagent in Step G of Example 1, synthesis similar to that in Step G of Example 1 was performed. The resultant cyclic acetal was subjected to reduction condition similar to that in Step H of Example 1 to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][N:21]([CH2:30][CH2:31][OH:32])[N:20]=2)=[CH:15][CH:14]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][CH2:30][N:21]1[CH:22]=[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][N:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[N:20]1)(=[O:42])=[O:41]
Reactant: OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ncccc4n3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ncccc4n3)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of Intermediate 5B, 2-(3-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol in DCM is cooled at 0° C. Pyridine (12 equivalents) and methanesulfonyl chloride (8 equivalents) are added and the reaction mixture is stirred at 0° C. for 1 h. The mixture is quenched with water and extracted with more DCM. The organic solvent is separated, dried (MgSO4), and concentrated under reduced pressure. The crude residue is purified by silica gel column chromatography. The desired fractions are collected and concentrated under reduced pressure to yield 2-(3-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11]1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11]1)#[N:28]
Reactant: BrCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
2-(8-Bromooctyl)-4,5-diphenyltriazole (7 g) in dimethylsulphoxide (220 ml) was added to a suspension of sodium cyanide (1 g) in dimethylsulphoxide (60 ml) over 15 minutes. The reaction mixture was stirred at 24° C. for 1 hour and at 50° C. for 2 hours. The cooled reaction mixture was poured into water (600 ml), extracted with diethyl ether (4×200 ml). The extracts were combined, washed with water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-cyanooctyl)-4,5-diphenyl-triazole (5.6 g, 92%) as an oil.
Reaction SMILES: CO[C:3](=O)[NH:4]/[C:5](/SC)=[N:6]/[C:7](=[O:10])[O:8][CH3:9].[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH2:26])C(N)=[CH:23][CH:24]=1>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:3]2[N:4]=[C:5]([NH:6][C:7](=[O:10])[O:8][CH3:9])[NH:26][C:21]=2[CH:20]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reactant: COC(=O)/N=C(/NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Yield: 64.5 %

Procedure:
add 728 mg of dimethyl[(Z)-(methylsulphanyl)methylylidene]biscarbamate to a solution of 1 g of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in a mixture of 60 cm3 of methanol and 212 mg of glacial acetic acid. The mixture is refluxed for 5.5 hours then concentrated under reduced pressure (0.2 kPa). The residue is taken up in 80 cm3 of a saturated aqueous solution in sodium hydrogen carbonate and the mixture obtained is extracted five times with 150 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is taken up in 25 cm3 of acetonitrile, washed twice with 5 cm3 of acetonitrile, then dried under reduced pressure over sodium hydroxide. We obtain 834 mg of methyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate in the form of a white powder, which has the following characteristics:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=1.[C:12]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[C:18]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(B(O)O)cc1C(C)(C)C
Reactant: CCOC(=O)c1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(-c2ccc(OC)c(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
260 mg (0.5 mmol) of tetrakis(triphenylphosphine)palladium(0), 50 ml of toluene and 2.59 g (10.9 mmol) of ethyl 2-bromo-4-thiophenecarboxylate are introduced into a three-necked flask under a stream of nitrogen and the mixture is stirred at room temperature for 20 minutes. 3.7 g (16.5 mmol) of 3-tert-butyl-4-methoxyphenylboronic acid and 11 ml of aqueous sodium carbonate solution (2 N) are then added and the mixture is refluxed for 8 hours. The reaction medium is evaporated to dryness, the residue is taken up in water and ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (10/90% by volume). 3.53 g (69%) of ethyl 2-(3-tert-butyl-4-methoxyphenyl)-4-thiophenecarboxylate are obtained.
Reaction SMILES: C([C:8]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[O:11][C:10](=[O:27])[CH:9]=1)[N:18]([C:22](=[O:24])[CH3:23])[C@@H:17]([CH3:25])[CH2:16][C@H:15]3[NH2:26])C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([N:18]1[C:19]2[C:14](=[C:13]3[CH:8]=[CH:9][C:10](=[O:27])[O:11][C:12]3=[CH:21][CH:20]=2)[C@H:15]([NH:26][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:16][C@@H:17]1[CH3:25])(=[O:24])[CH3:23]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](N)C[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccc3oc(=O)ccc3c2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
[Step 5] 22 mg of the cis-benzyl-7-acetyl-10-amino-8-methyl-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-3-one and 19 mg of 4-chlorophenylboronic acid were dissolved in 10 mL of dichloromethane followed by adding 29 mg of divalent copper acetate and 34 μL of triethylamine and stirring for 18 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite and water was added followed by extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 7 mg of the target compound in the form of a yellow solid (23%).
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])([CH3:4])[CH3:3].[Na].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.Cl>C(O)C.C(O)(=O)C>[O:18]=[C:19]1[NH:10][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:2]([CH3:4])[CH3:3])=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)Oc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OC(C)C)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-Isopropoxybenzamidine hydrochloride (10.0 g., 0.0465 mole) was added to a stirred, cooled (ice-water) solution of sodium 2.14 g., 0.093 g-atom) in ethanol (100 ml.). To this cooled, stirred solution was added dropwise a solution of diethyl ethoxymethylenemalonate (10.1 g., 0.0465 mole) in ethanol (30 ml.) over a 10 minute period. The mixture was refluxed for 2 hours and stored at 22° for 18 hours. The mixture was then poured onto ice-water containing acetic acid (10 ml.) and concentrated HCl (10 ml.) to precipitate the desired product. The precipitate was washed and dried to give 15.5 g. of the title product, m.p. 123° 124°. Recrystallizations from ethyl acetate and then cyclohexane gave colorless crystals of the ester, m.p. 128°-130°.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 95.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(cyclohexyl{2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methyl)amino]benzoic acid (355 mg) as well as ethyl 3-(methylamino)propanoate (118 mg) to give the title compound (401 mg, 96%) as an amorphous compound.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:15]=[C:16](C(C)(C)C)[C:17]=1[OH:18])C=C1CCNC1=O)(C)(C)C.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25].[H-].[Na+]>C(OCC)(=O)C>[CH3:23][N:24]([C:26]([O:18][C:17]1[CH:5]=[CH:6][CH:7]=[CH:15][CH:16]=1)=[O:27])[CH3:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 301 mg of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (1.0 mmole) dissolved into 5 ml of DMF, NaH (60% in mineral oil, 85 mg, 2.1 mmole) was added under ice-cooling. The resulting mixture was stirred at room temperature for 30 min, then the solution was cooled again. N,N-Dimethylphenylcarbamate (282 mg, 1.71 mmole) which was prepared according to the method described in J. Org. Chem., p660, 21, 1956, was added thereto, then the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate, which was washed with 1N-HCl, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=2:1) and recrystallized from ether-n-hexane, whereby 190 mg of the objective compound was obtained in 51% yield. The physical constants are described on Table 1.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].O.[NH2:16][NH2:17]>CO>[C:8]1([S:5]([CH2:4][C:3]([NH:16][NH2:17])=[O:2])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of 5.0 g (0.023 mol) of benzenesulfonyl-acetic acid methyl ester in 10 mL of MeOH at RT, 3.50 g (0.070 mol, 3 eq) of hydrazine hydrate were added. After one hour, the solvent and the excess of hydrazine were removed under reduced pressure, yielding 4.90 g (quantitative) of benzenesulfonyl-acetic acid hydrazide as a colorless oil, MS: 232 (MNH4+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15](=O)[NH:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15]([Cl:32])=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Cl)c12
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of (4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl)-acetic acid ethyl ester (1.78 g, 6.17 mmol, 1 equiv, from step 3) in toluene (15 mL) were added diisopropylethylamine (1.18 mL, 6.79 mmol, 1.1 equiv) and phosphorous oxychloride (0.63 mL, 6.79 mmol, 1.1 equiv) at 0° C. under argon. The flask was equipped with a reflux condenser and heated at 80° C. for 5 h. The reaction mixture was cooled to rt and quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (20% EtOAc/hexane) to yield 1.12 g (3.6 mmol, 56%) of a light yellow solid. 1H-NMR (DMSO-d6) δ 9.01 (s, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.15 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 4.10 (q, 2H), 3.92 (s, 2H), 1.20 (t, 3H), LCMS RT=3.19 min, [M+H]+=307
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 78.2 %

Procedure:
A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 1), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5%-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M++1: calc'd 576.2, found, 576.3.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29])=[NH:6]>[Ni].CO.O>[ClH:28].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N

Procedure:
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 1.0 g (2.024 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-chlorophenyl)-irnidazole dihydrochloride in 35 ml of methanol and 20 ml of water, and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then diluted with 50 ml of methanol and filtered. The filtrate is adjusted to pH 3 with a small amount of 3N methanolic hydrochloric acid and is concentrated to a volume of approximately 30 ml. After cooling in an ice-bath, the product that has crystallized out is filtered off, washed with a small amount of methanol and diethyl ether and dried under a high vacuum at 120° C. The title compound is obtained in the form of the monohydrate, m.p. 245°-250° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.33 (d, 1H); 8.12 (s, 1H); 7.79-7.87 (m, 3H); 7.67 (t, 1H); 7.57 (d, 2H); 3.38 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:33][CH3:34])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[CH:41]=1>>[CH2:36]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[C:15]([O:33][CH3:34])[CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:41]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 505.29 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[C:8]1([CH3:17])[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:17])[C:15]1=[S:16])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: Cc1ccccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccccc2C)C1=S
Yield: 31 %

Procedure:
The tide compound was prepared by the procedure described in Example 7 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (3.6 g) was obtained as a creamy solid, m.p. 105°-108° C. Anal. Calcd. for. C12H14N2O S: C, 61.51; H, 6.02; N, 11.93. Found: C, 61.22; H, 5.96; N, 11.89. Mass spectrum (EI, M.+) m/z 234.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Cl)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: COc1cc(Cl)cc(C=O)c1
Reaction time: 1.25 h
Yield: 77.1 %

Procedure:
A mixture of 3-chloro-5-methoxybenzyl alcohol (5.0 g, 28.9 mmol) and pyridinium chlorochromate (20% on alumina, 40 g, 37.8 mmol) was allowed to stir for 1.25 hr. Diethyl ether (200 ml) was then added followed by filtration of precipitate. The filtrate was concentrated under reduced pressure and the resulting residue was purified via silica gel chromatography using 40% dichloromethane, 60% petroleum ether as eluant, to give 3.8 g of 3-chloro-5-methoxybenzaldehyde (78%). 1H-NMR (CDCl3): 3.84 (s, 3H) 7.13 (s, 1H), 7.28 (s, 1H), 7.41 (s, 1H), 9.89 (s, 1H).