Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reaction time: 5 h
Yield: 98.2 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propenoate (12.13 g), 5% palladium-carbon (10.22 g) and tetrahydrofuran (100 ml) was stirred for 5 hours under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (9.52 g, yield 98%) as a colorless oily substance.
Reaction SMILES: Cl.[CH3:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1.CCOC(C)=O>O>[CH3:2][NH:3][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Reactant: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To melted methylamine hydrochloride (Aldrich, 73.7 g, 1090 mmol) at 235° C. (oil bath) was added 6-(2-chloropyridin-4-yloxy)-1-naphthoic acid (6.54 g, 21.8 mmol). The reaction mixture was stirred for 3 min and cooled to RT. The brownish solid was treated with EtOAc and water and stirred until all residue was either in solution or suspended. The precipitate was filtered off, washed with EtOAC and purified by silica gel chromatography using 0-100% of a 85:15:0.5 mixture of DCM:MeOH:AcOH. The product obtained was washed with water, filtered and dried under vacuum to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(=O)Cl)c(OCc2ccccc2)c1)OCc1ccccc1

Procedure:
Thionyl chloride (1.55 ml) and dimethylformamide (2 drops) were added to a solution of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid (7.1 mg) in dichloromethane (50 ml), and the mixture was refluxed under heating for 1.5 hours. After the reaction, the solvent was evaporated under reduced pressure to give 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (50 ml), and the solution was dropwise added to a solution of 4-aminopyridine (1.42 g) and diisopropylethylamine (5.27 ml) in acetonitrile (50 ml) under ice-cooling. The mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give N-(4-pyridyl)-2-benzyloxy-4-benzyloxycarbonylaminomethylbenzamide as crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Cl:11][CH2:12][CH2:13][CH2:14]Br.O>CN(C)C=O>[Cl:11][CH2:12][CH2:13][CH2:14][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: Nc1ccccc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1OCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 50% oil dispersion) in dimethylformamide (250 ml), under nitrogen, was added, dropwise, 2-aminophenol (25.0 g, 230 mmol) dissolved in dimethylformamide (125 ml). After complete addition, the reaction was stirred at ambient temperature for 1 hour, and then it was cooled to 5° C. (ice bath). 3-Chloro-1-bromopropane (36.2 g, 230 mmol) in dimethylformamide (50 ml) was added, dropwise, so that the temperature did not go above 8° C. The reaction. was stirred for 4 hours and then permitted to stand at ambient temperature for 16 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 25.4 g of a reddish, dark oil. About 12.0 g of the oil was chromatographed on HPLC columns. Concentration of the largest fractions gave 5.4 g of 2-(3-chloropropoxy) aniline as an oil.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C([Si](C)(C)O[CH2:22][CH2:23][O:24][CH3:25])(C)(C)C.C([SiH](CC)CC)C>C(#N)C>[CH3:1][C:2]1([C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH2:3][CH2:4][CH:5]([O:8][CH2:22][CH2:23][O:24][CH3:25])[CH2:6][CH2:7]1
Reactant: CC(C)COC(=O)C1(C)CCC(=O)CC1
Reactant: COCCO[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: COCCOC1CCC(C)(C(=O)OCC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A solution of isobutyl 1-methyl-4-oxocycylohexanecarboxylate (D67, 12.7 g, 59.8 mmol), t-butyl dimethyl 2-methoxyethoxy silane (11.4 g, 59.9 mmol), and anhydrous ferric chloride (250 mg, 1.541 mmol) in acetonitrile (150 mL) at 0° C. was treated with triethylsilane (12 mL, 75 mmol). The mixture was stirred for 1 h at room temperature, then partitioned between saturated sodium bicarbonate and dichloromethane, and the organic layer was dried and evaporated to give isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (27 g, 49.6 mmol, 83% yield) as a cis/trans mixture containing one equivalent of t-butyldimethyl triethyl siloxane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH:21][C:32](=[O:33])[C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc2c(c1)OCCO2
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
2-((2S,3S)-2-Amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.255 g, 0.80 mmol), (2R)-tert-butoxycarbonylamino-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetic acid (prepared according to the procedure of Bohme, E. H. W. et al., J. Med. Chem. 1980, 23,405-412), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (0.364 g, 0.96 mmol) and diisopropylethyl amine (0.56 mol, 3.2 mmol) were dissolved in N,N-dimethylformamide (3 mL) in an ice bath. 1-Hydroxybenzotriazole (0.13 g, 9.6 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. Stirring was continued for 30 min at 0° C. The reaction mixture was diluted with ethyl acetate and the mixture was washed with water and brine. The organic layer was diluted with an equal volume of dichloromethane, filtered through a pad of silica gel with a layer of sodium sulfate on the top and eluted with 1:1 ethyl acetate/dichloromethane. Evaporation of the solvents gave a white solid which was triturated with ether/hexane to give crude 2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 65 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.02 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.95 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH2:19][CH2:20][C:21]1([O:34][CH2:33][CH2:32][O:31]1)[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO.[Cl-].[Na+].O>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][CH2:22][C:21]1([O:34][CH2:33][CH2:32][O:31]1)[CH2:20][CH2:19][C@@H:11]1[C@@H:12]2[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]2)[CH2:18][C@H:10]1[OH:9]
Reactant: O=C1C[C@@H]2[C@@H](CCC3(COc4cccc(Cl)c4)OCCO3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](CCC3(COc4cccc(Cl)c4)OCCO3)[C@H](O)C[C@@H]2O1
Reaction time: 3.5 h
Yield: 78.4 %

Procedure:
To a solution of 9 (1.15 g, 2.36 mmol) in methanol (40 mL) was added potassium carbonate (389 mg, 2.81 mmol). After 3.5 h, saturated ammonium chloride (45 mL) and saturated brine (25 mL) were added, the mixture was extracted with ethyl acetate (3×60 mL), dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 14 cm tall×41 mm diameter silica gel column eluting with 4:1 ethyl acetate:hexane to afford 10 (708 mg,81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH3:26])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)ccc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was added to a mixed liquid of a 40% aqueous solution (103 mg) of methylamine and pyridine (1 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethanol was added to the residue. Solids formed were collected by filtration and washed with hexane to obtain the title compound (85 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].CO.[CH:21](=O)[CH2:22][CH3:23]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH:21][CH2:22][CH3:23])=[O:14])[CH3:2]
Reactant: CCC=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: CO
Solvent: O
Product: CCC=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 58 μl of propanal were added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 127 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-propylidenehydrazine ((40-b)-(15)-3).
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.N#N.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1>N1C=CC=CC=1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CN(C)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino -2-butynoic acid (0.9 g, 3.8 mmol ) and N-methylmorpholine (0.384 g , 3.8 mmol ) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol ) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; : mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:17])[C:7]=2[CH:6]=[C:5]([CH3:18])[C:4]=1[CH3:19].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:17])[C:7]=2[CH:6]=[C:5]([CH3:18])[C:4]=1[CH3:19]
Reactant: CCOC(=O)c1oc2c(OC)c(C)c(C)cc2c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1oc2c(O)c(C)c(C)cc2c1C
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 7-methoxy-3,5,6-trimethylbenzofuran-2-carboxylate (97.2 g, 0.37 mole) (from Step 2) in dichloromethane (1 L) cooled to -78° C., was added a solution of BBr3 (1.1 L, 1 M in dichloromethane). The reaction was warmed to -5° C. for and left for 15 mins. Quenching with 25% NH4OAc buffer, extraction with EtOAc and drying (Na2SO4), followed by removal of solvent, afforded the product which was used as such for the following step.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3](=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: COC(=O)C(C(=O)OC)=C1CCSC1
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)=C1C=CSC1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A solution of 0.50 g (2.31 mol) of dimethyl 2-(3-tetrahydrothienylidene)malonate in 10 ml of toluene was treated with 0.32 g (2.35 mmole) of sulfuryl chloride in 1 ml of toluene under nitrogen at ice bath temperature. The mixture turned dark, and starting material could not be observed by tlc after 5 min. Nitrogen was bubbled through the solution for 5 min., and the dark color faded. Pyridine (1 ml) was added. After 15 min. at room temperature, the solution was worked up as in Example 1 and molecular distillation gave 0.45 g (93%) of dimethyl 2-(3-thienylidene)malonate, containing minor impurities by glc (SE-30, 200° ).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:28]1[C:32]2[CH:33]=CC=C[C:31]=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[CH:32]([NH:28][C:24]([CH:12]1[CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:26])([CH3:33])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(C)N
Product: CC(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid 47-1 (0.40 g, 1.10 mmol), 1-hydroxybenzotriazole (0.20 g, 1.32 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g, 1.43 mmol), 4-methylmorpholine (0.0.44 g, 4.39 mmol) and isopropyl amine (0.071 g, 1.21 mmol) were dissolved in DMF and stirred at 25° C. for 18 hours. The DMF was then removed under reduced pressure and the residue partitioned between ethyl acetate and dilute aqueous KHSO4. The aqueous phase was drawn off and the organic layer was washed with dilute aqueous NaHCO3, brine, dried, filtered and evaporated to afford 47-2.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: COC(=O)[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=O)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][NH:31][NH2:32])=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>CC(O)C>[CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=[N:32][NH:31][CH2:30][C:29]1[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNN)cc1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCC(=NOCc1ccccc1)C(=NNCc1ccc(OC)cc1)C(=O)N1CCOCC1
Yield: 82.2 %

Procedure:
1.0 g (3.3 mmol) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine was dissolved in 20 ml of 2-propanol and 1.24 g (6.6 mmol) of 4-methoxybenzylhydrazine hydrochloride, 1.08 g (13.2 mmol) of sodium acetate and 1 ml of acetic acid were added and the mixture was refluxed for 15 hours. After distilling the solvent off under reduced pressure, 20 ml of water was added and the mixture was extracted three times with 30 ml of diethylether. After washing with 1N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate, water and then a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.19 g (yield: 83%) of 4-(3-benzyloxyimino-2-(4-methoxybenzylhydrazono)valeryl)morpholine as a yellow oil.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 74 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU23##
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccc5)c(C)c4)c23)CC1
Yield: 61 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and N-ethylpiperazine to give the title compound in 61% yield; NMR Spectrum: 0.95 (t, 3H), 2.22 (s, 3H), 2.24 (q, 2H), 2.22-2.55 (m, 8H), 2.77 (t, 2H), 4.41 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 488 (MH+).