Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH:22]3[CH2:24][CH2:23]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:32]([OH:35])[C:33]#[CH:34]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]#[C:33][CH2:32][OH:35])[CH:17]=3)[N:12]([CH:22]3[CH2:24][CH2:23]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(C#CCO)cc2c1=O
Reaction time: 8 h

Procedure:
To a dry flask under an atmosphere of argon gas containing 0.24 g of N-(4-chlorobenzyl)-1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 20, 0.01 g of copper (I) iodide and 0.04 g of dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (1.5 mL) and propargyl alcohol (0.04 mL). After 3 hours reaction is diluted with DMF (0.5 mL) and left to stir overnight. The reaction is concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol, and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0.17 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:27]([OH:30])[OH:28])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)c1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran (1.42 g, 7 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (8.25 mL, 14 mmol) and trimethyl borate (1.5 mL, 14 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran can be prepared as described by Janusz et al. in J. Med. Chem. 1998, 41, 1124-1137.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([CH:34]=1)[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:28]([C:27]3[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:34]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:35])=[CH:25][C:26]=3[Cl:33])=[O:29])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with H2O, 1N HCl, H2O, 1M NaHCO3, brine and dried Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137°-140° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([CH3:29])[CH:18]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[C:27]([CH3:28])[C:17]([O:16][CH3:15])=[CH:18][C:19]=3[CH3:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CC)c1=O
Yield: 52.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.9 g (13.9 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.43 g (yield 52% ) of Compound 74 as white crystals.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[F:25])C(=O)OC(C)(C)C)=[O:8]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:25][C:18]1[C:17]2[NH:9][C:7](=[O:8])[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:22]=2[CH:21]=[C:20]([O:23][CH3:24])[CH:19]=1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)C(=O)c2sccc2Br)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1
Yield: 82.9 %

Procedure:
Following Step 3 from General Procedure A, tert-butyl 3-bromothiophene-2-carbonyl(2-fluoro-4-methoxyphenyl)carbamate (2.0 g, 4.6 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (100 mg, 0.20 mmol) to afford the desired product (950 mg, 80%) as a dark brown solid: ESI MS m/z 250 [C12H8FNO2S+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([C:11]([O:13]CC)=O)[CH2:5]1)(=[O:3])[CH3:2].Cl.[C:17]([NH2:23])(=[NH:22])[CH2:18][CH2:19][CH2:20][CH3:21].C[O-].[Na+]>C(O)C.CO>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:22]=[C:17]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:23][C:11](=[O:13])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C1CN(C(C)=O)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(C)=O)CC2
Yield: 96.9 %

Procedure:
A mixture of 1.5 g of ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate and 1.0 g of valeramidine hydrochloride in 15 ml of anhydrous ethyl alcohol is treated with 7.5 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a colorless syrup which is stirred with 50 ml of ether for 2 hours then filtered. The tacky cake is dried under high vacuum at 56° C. to afford 1.7 g of the desired product, m.p. 106°-113° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:7]3[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=3)[C:1]#[N:2])[C:21]=12
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(C#N)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 41.2 %

Procedure:
A solution of 3-Cyanophenylboronic acid (23 mg, 0.15 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA39 (14.9 mg, 41% yield). ESI-MS (M+H)+ m/z calcd 279.1, found 279.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>ClCCl.CO>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([Cl:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1N

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 4.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL, 12.92 mmol), and 3-chloro-4-methylaniline (7.0 mL, 57.69 mmol). Chromatography on silica gel in 95:5 dichloromethane/methanol gave the product, (2.72 g), m.p. 153-157° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C:4]1([CH:18]([CH2:26][CH2:27][S:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:34])[CH2:3][C:4]1([CH:18]([CH2:26][CH2:27][S:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:19]([OH:21])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: CC(C)CC1(C(CCSc2cccs2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(C(CCSc2cccs2)C(=O)O)CCN(CCc2ccccc2)C1=O
Yield: 95.6 %

Procedure:
A solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-α-[2-(2-thienylthio)ethyl]-3-pyrrolidineacetate (338 mg, 0.674 mmol), trifluoroacetic acid (3 mL), and CH2Cl2 (3 mL) is stirred at 0° C. for 15 minutes and at room temperature for 1.5 hour. Concentration and aqueous workup (CH2Cl2, MgSO4) gives 287 mg (96%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[C:16](=[C:17]([CH:22]=C)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=[O:12])=[O:11].I([O-])(=O)(=O)=[O:25].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:25])[C:16]=2[CH:15]=[CH:14]1)(=[O:12])=[O:11]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cc(C)ccc1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
OsO4 (10 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-methylphenyl)sulfonyl]-4-vinyl-1H-indole (262 mg, 0.80 mmol; Intermediate 7) and 2,6-2,6-lutidine (186 μL, 0.46 mmol) in dioxane (9 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.684 g, 3.2 mmol) in water (3 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 30 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and concentrated to give the title compound (290 mg, 110%, still some dioxane according to HNMR) as a black solid. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([NH2:13])=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[NH2:13][C:10]1[C:11]2[S:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:9]=1
Reactant: COC(=O)c1cc2[nH]nc(N)c2s1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(N)c2sc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
To an ice-cooled suspension of 3-amino-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (35.5 mmol, 7.0 g) and N,N′-diisopropylethylamine (0.21 mol, 36.5 mL) in 71 mL of tetrahydrofuran were added, dropwise, 3.5 mL of ethyl chloroformate (36.6 mmol). After 1.5 hours, the cold suspension was concentrated under vacuum and diluted with dichloromethane. The organic phase was washed with buffer pH 4, sodium hydroxide 1 N, brine and dried over Na2SO4. The filtrate was evaporated to dryness and triturated with dichloromethane to give 6 g 1-ethyl 5-methyl 3-amino-1H-thieno[3,2-c]pyrazole-1,5-dicarboxylate (7)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][C:18]([CH2:20][C:21]([CH:23]([F:25])[F:24])=[O:22])=O>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:17])[C:20]([C:21](=[O:22])[CH:23]([F:25])[F:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C(F)F
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)F
Yield: 36 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1,1-difluoroacetylacetone according to the procedure of example 1, except that the residue was purified by chromatography on aminated silica gel with heptane/ethyl acetate (5:1). Yield: 36%. MS: m/z=377 (M).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[C:16]([CH3:25])([CH3:24])[CH2:15]1>ClCCl.O>[CH3:24][C:16]1([CH3:25])[CH2:15][CH:14]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18][CH:17]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1CCC(O)CC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (2.6 g, 22 mmol) and triethylamine (2.4 g, 22 mmol) were added to a solution of methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (1.38 g, 7.4 mmol) in dichloromethane (30 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. Then the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3): δ 5.30-4.78 (m, 1H), 3.65 (s, 3H), 3.05 (s, 3H), 2.25-2.21 (m, 1H), 2.19-2.13 (m, 2H), 1.90-1.88 (m, 1H), 1.79-1.75 (m, 2H), 1.63 (s, 1H), 1.06 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OC)=O)=[CH:26][CH:25]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
Yield: 32.1 %

Procedure:
10 mg (0.032 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.087 mmol) of methyl 4-bromophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5 mg (53%) of a solid, Rf=0.69 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:4]([F:19])[CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[N:10]([CH3:20])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:13]=2)=[C:4]([F:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
First, 2.93 g of 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1005) was dissolved in 15 ml of N,N-dimethylformamide, to which 2.07 g of potassium carbonate and 1.25 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=6:1), which afforded 1.98 g (yield, 65%) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-11; m.p., 83.2° C.).
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)C.O=[S:21](Cl)Cl>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:5]1[N:4]=[N:3][S:21][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(N=C(Cc1cccs1)c1cccs1)C(=O)[O-]
Product: c1csc(-c2nnsc2-c2cccs2)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
Acylhydrazine 31 (14.13 g, 14.04 mmol) was added to SOCl2 (60 ml) at 0° C. The reaction was allowed to warm to room temperature. The reaction was complete (by TLC) after 2 hours. SOCl2 was removed under reduced pressure. The dark residue was chromatographed on SiO2 (300 g), eluting with CH2Cl2. The isolated oil was bulb to bulb distilled at 0.2 mm (Hg) at 150° C. to yield 29 (2.3 g, 66.0%).
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:4]1[C:5]2[C:10](=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc2c([N+](=O)[O-])cccc2c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2c([N+](=O)[O-])cccc2c(Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3-methyl-5-nitro-isoquinoline-2-oxide (12 g) was added to phosphorus oxychloride (60 ml) and the mixture was refluxed with stirring for 1 hour, and then allowed to cool to room temperature (20°C). The reaction mixture was then poured onto ice, and the crude product, weighing 6.2 g, was isolated by filtration. This product was then recrystallized twice from acetone to yield 1-chloro-3-methyl-5-nitro-isoquinoline melting at 112°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](F)[CH:13]=2)[NH:8][CH:7]=1.F[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[CH:17][CH:18]=4)[NH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:7]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: Fc1ccc2[nH]cc(CCCCCl)c2c1
Product: c1ccc2c(CCCCN3CCC(c4c[nH]c5ccccc45)CC3)c[nH]c2c1

Procedure:
of 3-(4-chlorobutyl)-5-fluoroindole with 4-(5-fluoroindol-3-yl)piperidine:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([CH:36]=[CH:10][C:8]([O:7][CH3:6])=[O:9])=[CH:38][CH:39]=2)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=O)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=CC(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of a 1.6 N butyllithium solution are added dropwise to a solution of 6.4 ml of trimethyl phosphonoacetate in 50 ml of dry tetrahydrofuran at 0° C. in the course of 10 minutes. Stirring is carried out for 1.5 hours at 0° C. and a solution of 10.3 g of crude 4-[(trans-4-heptylcyclohexyl)methoxy]benzaldehyde in 50 ml of dry tetrahydrofuran is then added dropwise in the course of 5 minutes at the same temperature. The mixture is then slowly warmed up to room temperature and is allowed to react for 15 hours. The reaction mixture is then partitioned between methylene chloride and 1 N hydrochloric acid and the organic phase is washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated down. Chromatography over silica gel using ethyl acetate/hexane (1:9) and subsequent repeated crystallization from hexane/ethyl acetate give methyl 4-[(trans-4-heptylcyclohexyl)methoxy]cinnamate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:31])[NH:12][C:13]1[S:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)([CH3:10])[CH3:9])(C)(C)C.Cl>CCOC(C)=O>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C:13]1[S:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
{1-[4-(4-Fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester was stirred overnight in freshly prepared HCl (g)/EtOAc solution. Evaporation to dryness afforded the title compound as the hydrochloride salt. 1H NMR (400 MHz, DMSO-D6) 1.63 (s, 6H) 2.81-2.89 (m, 4H) 3.70-3.78 (m, 4H) 7.23-7.29 (m, 2H) 8.10-8.16 (m, 2H) 8.62 (s, 3H) 12.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)[C:11]2=O)[CH:5]=[N:6][C:7]=1[Cl:8].CN>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(Cl)c(Cl)c1
Agent: CN
Solvent: CCO
Product: CNCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 2-(5,6-dichloro-pyridin-3-ylmethyl)-isoindole-1,3-dione from step (b) above (307 mg, 1.0 mmol) and methylamine (1.0 mL, 2.0 mmoL, 2.0 M in THF, Aldrich) in EtOH (10 mL) was stirred at room temperature for 4 days. The solvent was removed in vacuo to give the title compound, which was used in the next step without additional purification.