Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][NH2:6].F[C:9]1[C:22]2C(=O)[C:20]3[CH:19]=[N:18][CH:17]=C[C:15]=3[C:14](=[O:24])[C:13]=2[C:12]([O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:11][CH:10]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C1COCC1.O>[C:32]1([CH3:35])[CH:31]=[CH:30][C:29]([S:26]([O:25][C:12]2[CH:11]=[CH:10][C:9]3[NH:6][N:5]=[C:4]4[C:3]5[CH:17]=[N:18][CH:19]=[CH:20][C:15]=5[C:14](=[O:24])[C:13]=2[C:22]=34)(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: CN(C)CCNN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2ccncc2-4)cc1

Procedure:
Under a nitrogen atmosphere a solution of N-[2-(dimethylamino)ethyl]hydrazine (J. Med. Chem. 7, 493, 1964) (1.86 g) in anhydrous THF (6.0 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy) benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy) benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (2.4 g) in THF (24 mL) containing N,N-diisopropylethylamine (1.10 mL). A slightly exothermic reaction ensures, and the reaction temperature increases from 20° C. to 25° C. After one hour at room temperature the reaction mixture is poured in water (240 mL) and the suspension obtained is stirred for 30'. The solid is separated by suction, washed with water and dried at 40° C. to give 2-[2-(dimethylamino)ethyl)]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (1.44 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34])=[C:21]=[O:22]>C(Cl)Cl.CN(C=O)C>[CH3:34][O:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:23]=1[NH:20][C:21]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=1)=[O:22]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1cccc(Cn2ccnc2-c2ccncc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(Cn2ccnc2-c2ccncc2)c1

Procedure:
To a solution of 3-(2-Pyridin-4-yl-imidazol-1-ylmethyl)-phenylamine (50 mg, 0.2 mmol) in DCM (4.0 mL) and DMF (1.0 mL) is added 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (43 mg, 0.2 mmol) and allowed to react overnight. The resulting crude was concentrated under reduced pressure and the residue is purified by column chromatography (DCM:MeOH) to afford 1-(2-methoxy-5-trifluoromethyl-phenyl)-3-[3-(2-pyridin-4-yl-imidazol-1-ylmethyl)-phenyl]-urea as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:23])[CH:7]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:26][CH:27]=2)=[O:32])=[CH:7][C:6]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:19])=[O:20])=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN1C(=O)N(c2cc(N)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
0.2 g 3-(5-Amino-2-chloro-phenyl)-7-methanesulfonyl-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one were dissolved in 50 mL of dichloromethane. 0.137 g Biphenyl-4-carboxylic acid and 0.042 g 4-dimethylaminopyridine (DMAP) were added. The solution was cooled to 0° C. and 0.128 g N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCl), dissolved in 20 mL dichloromethane were slowly added. The reaction mixture was stirred for 24 h under nitrogen. The reaction was quenched by extraction with 100 mL of an aqueous solution of potassium carbonate. The phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (n-heptane/ethyl acetate (EtOAc)) to give the title product in 28% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH2:14][C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC2CCC3=C(CCC(=O)N3)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC2CCC3NC(=O)CCC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (1.5 g) (prepared according to Example 9) was dissolved in dichloromethane (50 ml) and cooled to 0° C. Triethylsilane (0.9 ml and trifluoroacetic acid (5 ml) were added and the mixture was stirred for 2 hours. The reaction mixture was then evaporated under reduced pressure, crystallised by addition of ether and recrystallised from acetonitrile to give the title compound (0.7 g), mp 194°-196° C.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[C:10]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[C:9]([CH3:16])[C:8]([O:17][CH3:18])=[C:7]([O:19][CH3:20])[C:6]=1[O:21][CH3:22]>>[CH3:3][O:4][C:5]1[C:10]([CH2:11][CH2:15][CH2:14][CH2:13][OH:12])=[C:9]([CH3:16])[C:8]([O:17][CH3:18])=[C:7]([O:19][CH3:20])[C:6]=1[O:21][CH3:22]
Reactant: COc1c(C)c(C2CCCO2)c(OC)c(OC)c1OC
Solvent: CI
Product: COc1c(C)c(CCCCO)c(OC)c(OC)c1OC
Yield: 98.2 %

Procedure:
By the same procedure as described in Reference Example 58, 2,3-dimethoxy-5-methyl-6-(tetrahydrofur-2-yl)-1,4-benzohydroquinone (27 g, 0.106 mole) was methylated with methyl iodide, thereby being derived into 1,2,3,4-tetramethoxy-5-methyl-6-(tetrahydrofur-2-yl)benzene (28.5 g, 98%, bp1.0 135° to 138° C.). The catalytic reduction of the compound afforded 1,2,3,4-tetramethoxy-5-methyl-6-(4-hydroxybutyl)benzene (28.2 g, 99%, oily substance).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:11][C:9]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C=CN(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 76.2 %

Procedure:
To a solution of 2-acetylamino-4-methyl-5-nitropyridine (33.8 g, 0.173 mol) in dry DMF (300 mL) was added dimethylformamide dimethyl acetal (50.7 mL, 0.381 mol) and the mixture heated at 90° C. for 90 min. The solvent was evaporated in vacuo using toluene as an azeotrope. The residue was triturated with ether and the solid collected by filtration to give the title compound (33 g, 76%) as an orange solid. mp 193°-196° C. 1H NMR (250 MHz, CDCl3) δ 2.23 (3H, s), 3.04 (6H, s), 6.12 (1H, d, J=13.1Hz), 7.43 (1H, d, J=13.1Hz), 8.17 (1H, br s), 8.27 (1H, s) and 8.83 (1H, s).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[NH:6][NH3+:7].CO[CH:14](OC)[CH2:15][C:16](=O)[CH3:17]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:6]2[CH:14]=[CH:15][C:16]([CH3:17])=[N:7]2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: [NH3+]Nc1ccc(F)c(Br)c1
Reactant: COC(CC(C)=O)OC
Agent: [Cl-]
Solvent: CCO
Product: Cc1ccn(-c2ccc(F)c(Br)c2)n1
Yield: 20.7 %

Procedure:
To a solution of (3-bromo-4-fluoro-anilino)ammonium chloride [CAS: 1166990-89-1](5412 mg, 22.41 mmol) in ethanol (30 mL) was added 4,4-dimethoxybutan-2-one (3.12 mL, 23.53 mmol), and the reaction was heated to reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was loaded onto silica (50 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 25%. Fractions containing the faster running desired product were combined and concentrated in vacuo to give one of the isomers 1-(3-bromo-4-fluoro-phenyl)-3-methyl-pyrazole (D86) (1249 mg, 4.65 mmol, 20.8% yield) (1.26 g);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccccc2C)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2C)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-methylphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 10, Part C) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:35]=O)=[C:32]([CH3:34])[CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:16])/[CH:7]=[CH:35]/[C:31]1[S:30][C:29]([C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:33][C:32]=1[CH3:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Cc1cc(C(=O)OCc2ccccc2)sc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OCc2ccccc2)sc1/C=C/C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A solution of diethylphosphonoacetic acid tert-butyl ester (0.44 g, 1.74 mmol) in tetrahydrofuran (3 ml) was added dropwise to a suspension of 60% sodium hydride (0.055 g, 1.38 mmol) in tetrahydrofuran (15 mL) with stirring at 0° C. After stirring at room temperature for 30 minutes, a solution of 5-formyl-4-methylthiophene-2-carboxylic acid benzyl ester (0.3 g, 1.15 mmol) obtained in step 2 in tetrahydrofuran (3 mL) was added dropwise at 0° C. After stirring at room temperature for 2 hours, the mixture was worked up according to a conventional method, and purified by silica gel column chromatography to give the title compound (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: COc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-6-methoxybenzamide (1.7 g) in methylene chloride (20 ml) is added pyridine (1.6 ml), and thereto is added dropwise acetoxyacetyl chloride (1.1 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 2 hours, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and then are recrystallized from ethanol to give the title compound (2.1 g) having the following physical properties.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]2[S:29][CH:28]=[C:27]([CH3:30])[N:17]2[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:30][C:27]1[N:17]2[C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:14]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:13])[N:15]=[C:16]2[S:29][CH:28]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3ccncc3)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccncc3)c(=O)n12

Procedure:
A mixture of 6-bromo-9H-purine (0.064 g, 0.32 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.046 g, 0.16 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.32 mmol) in ethanol (0.5 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the product as the free base. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.1.
Reaction SMILES: [CH2:1]([NH:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:22])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>C(O)C>[CH2:1]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[CH:30][CH:31]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC=CCCCNc1ccc(C(=O)NCC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)NCC(=O)O)cc1

Procedure:
A mixture of 26.4 g. of ethyl N-[4-(4-pentadecenylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution, and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The gaseous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)[C:30]=3[C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=4)[C:30]=3[C:22]=2[CH:21]=1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(S(C)(=O)=O)cc3)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed and the residue was purified on preparative HPLC to give the product as a pale white solid (89% yield); mp: 194-195° C.; 1HNMR (DMSO+TFA-d, 400 MHz) δ: 10.29 (s, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J=2.1, 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.08 (dd, J=3.0, 8.9 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 3.89 (d, J=12.8 Hz, 2H), 3.51 (d, J=12.8 Hz, 2H), 3.23(s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin assay for the compound of Example 126 is shown in Table 2.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1[CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15]([C:26]3[C:34]([F:35])=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][NH:30]4)=[N:14][C:13]=2[CH:12]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(Cl)Cl>[F:35][C:34]1[C:26]([C:15]2[N:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:18]3[S:19][C:11]([CH2:10][N:2]4[CH2:3][C:4]5([CH2:9][CH2:8][N:7]([C:41]([NH2:40])=[O:42])[CH2:6][CH2:5]5)[CH2:1]4)=[CH:12][C:13]=3[N:14]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2
Reactant: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2sc(CN3CC4(CCNCC4)C3)cc2n1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)N1CCC2(CC1)CN(Cc1cc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 6-(2,7-diaza-spiro[3.5]non-2-ylmethyl)-2-(5-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (125 mg, 0.254 mmol) in anhydrous DCM (10 mL) was added trimethylsilyl isocyanate (35 μL, 0.254 mmol). The reaction mixture was stirred at RT for 1 h, then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC to give the title compound as a white solid (41 mg, 30%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH2:25]([Sn](CCCC)(CCCC)C#CC)[CH2:26][CH2:27]C>O1CCOCC1.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>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:25]#[C:26][CH3:27])=[CH:12][N:13]=2)[CH2:3]1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 96 °C
Reaction time: 40 h
Yield: 76.1 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (Example 1) (120 mg, 0.31 mmol) and tributyl(1-propynyl)tin (140 μL, 0.46 mmol) were stirred in dioxane (5 mL) in a flask purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) was added, and the solution stirred at 96° C. for 40 h. Concentration in vacuo and purification by silica gel chromatography (16% MeOH/CHCl3) gave 82 mg (76%) of the title compound as a clear oil. 1H NMR (400 MHz, MeOD-d4): δ 7.82 (s, 1H), 7.64 (d, 1H, 7.6 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.36 (t, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 5.30 (s, 2H), 3.40-3.48 (m, 1H), 3.21-3.30 (m, 1H), 2.78-2.89 (m, 2H), 2.58-2.66 (m, 1H), 1.91 (s, 3H), 1.85-1.93 (m, 1H), 1.52-1.74 (m, 2H), 1.18-1.27 (m, 1H). MS (ES) [m+H] calc'd for C20H21N5O, 348; found 348.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH3:36]>O1CCCC1>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:36])=[O:19]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)=C(C)C1=O
Reactant: N
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(CCCCCC(N)=O)c2ccccc2)=C(C)C1=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of p-nitrophenyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2yl)-7-phenyl-heptanate (0.71 g, 1.5 mmoles) in tetrahydrofuran (7 ml) was added concentrated ammonia (1.0 ml) at room temperature and kept stirring for 4 hours. After the reaction was completed, the solvent was evaporated in a reduced pressure. To the residue was added aqueous potassium carbonate and then extracted with ethylacetate. The organic layer was washed with water, dried over magnesium sulfate. Evaporation of the solvent gave 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanamide (0.46 g, 87%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[Cl:56][C:57]1[CH:58]=[CH:59][C:60]2[CH:64]=[C:63]([CH2:65]O)[S:62][C:61]=2[CH:67]=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:65][C:63]2[S:62][C:61]3[CH:67]=[C:57]([Cl:56])[CH:58]=[CH:59][C:60]=3[CH:64]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2cc3ccc(Cl)cc3s2)NS(=O)(=O)c2cccnc2)n1
Yield: 104.5 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (100 mg, 0.209 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using (6-chlorobenzo[b]thiophen-2-yl)methanol (see WO 99/37304A, 41.5 mg, 0.209 mmol) in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (144 mg) substantially quantitatively as a slightly yellow liquid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.[OH-].[K+]>C1C=CC=CC=1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:12]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Reactant: CCCCN=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
8.9 g. of 3-trifluoromethyl-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.06 ml. of triethyl amine in 45 ml. of dry benzene are heated up to 50° C. under stirring, and the reaction mixture is kept at the same temperature for one additional hour. The progress of the reaction is monitored by thin layer chromatography. When the reaction is complete, the mixture is cooled to room temperature, the benzene solution is shaken with a 5% aqueous potassium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The solid residue is crystallized from a mixture of ethyl acetate and n-hexane. 11.4 g. of the named compound are obtained, melting at 99° to 100° C.