Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 38a. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (25 mg, 0.076 mmol) was reacted with 3-chloropropane sulfonyl chloride (30 uL, 0.242 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CCOCCO.[Cu]>[O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Product: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1.8 Grams of 6-(1-oxo-2-piperazinylbutyl)-3,4-dihydrocarbostyril, 2.0 g of p-bromonitrobenzene, 1.2 g of potassium carbonate and 0.1 g of copper powder were dispersed in 80 ml of ethyl cellosolve and stirred at 120°-150° C. by heating for 5 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was added water and extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was separated and purified by a separative thin layer chromatography and recrystallized from ethanol to obtain 0.2 g of 6-{1-oxo-2-[4-(4-nitrophenyl)-1-piperazinyl]-butyl}-3,4-dihydrocarbostyril in yellow powdery crystals.
Reaction SMILES: C[O-].[Na+].[CH:4]([NH2:6])=[NH:5].C[O:8][C:9](=O)[CH:10]([C:14](=O)[CH3:15])[CH2:11][CH2:12][CH3:13].C(O)(=O)C>CO>[CH2:11]([C:10]1[C:9](=[O:8])[NH:5][CH:4]=[N:6][C:14]=1[CH3:15])[CH2:12][CH3:13]
Reactant: CCCC(C(C)=O)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1c(C)nc[nH]c1=O
Reaction time: 0.25 h

Procedure:
NaOMe (1.30 g, 24 mmol) is added to a stirred solution of formamidine (12 mmol) in MeOH (75 ml) at room temperature. The mixture is stirred for 15 minutes. 2-Acetyl-pentanoic acid methyl ester (10 mmol) is added and the mixture is stirred at room temperature overnight. Acetic acid (0.72 g, 12 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and it is extracted with 2-butanone (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid (100), which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:30]([CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[O:31])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C(Cl)C1CCOCC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CCOCC3)C2)cc1

Procedure:
62 mg (0.18 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 41 mg (0.27 mmol, 1.5 eq.) of tetrahydro-2H-pyran-4-carbonyl chloride were reacted according to General Method 2. Yield: 67 mg (88% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>ClCCl>[Si:14]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)CC(O)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A dry dichloromethane (10 mL) solution of 3-(dimethylamino)-1,2-propanediol (98%, 1.00 g, 8.39 mmol, 1.0 equiv) and imidazole (0.57 g, 8.39 mmol, 1.0 equiv) was stirred at 0° C. under argon for 15 minutes. Solid tert-butyldimethylsilyl chloride (1.26 g, 8.39 mmol, 1.0 equiv) was added to the mixture and the resultant was stirred for 2 hours at 0° C. The mixture was then diluted with 20 mL of dichloromethane and poured into deionized water (15 mL). The organic layer was separated and the aqueous layer was extracted with two additional portions of dichloromethane (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol, a thick clear oil, which was used without further purification.
Reaction SMILES: ClC(Cl)(Cl)C(O)=O.S(=O)(=O)(O)O.[N+:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH2:21][CH2:20][C:19]2=[O:26])([O-:15])=[O:14].[N-:27]=[N+]=[N-].[Na+]>>[N+:13]([C:16]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][CH2:20][C:19](=[O:26])[NH:27][C:18]=2[CH:17]=1)([O-:15])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCOc2ccc([N+](=O)[O-])cc2N1
Temperature: 70 °C
Yield: 22 %

Procedure:
Trichloroacetic Acid (39 g, 0.24 mol), Sulfuric acid (3 mL, 0.05 mol), and 6-Nitro-chroman-4-one (5.000 g, 0.026 mol) were combined and heated to 70° C. Sodium azide (3.36 g, 0.052 mol) was added slowly. The resulting solution was heated for 2 h, poured onto ice. Title compound isolated as a beige solid in 22% yield. 95% purity, LCMS: 209.15 (M+1) 1H NMR (400 MHz, DMSO, d6) δ 10.13, (s, 1H), 8.06 (dd, J=1.5 Hz, 1H), 7.85-7.82 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.47-4.44 m, 2H), 2.88-2.85 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][N:14]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][N:14]=2)=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: Cn1ncnc1-c1ccc(F)cc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cn1ncnc1-c1ccc(F)cc1C=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-phenyl]-methanol plus regiosiomer (600 mg, 2.90 mmol) in CH2Cl2 (20.0 mL) is added MnO2 (750 mg, 8.63 mmol). The reaction mixture is stirred at room temperature for 72 hours and is filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 6% MeOH in CH2Cl2 as the eluent to afford 5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-benzaldehyde plus regioisomer (475 mg, 80%).
Reaction SMILES: C=O.[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:28])[N:17]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:18]4=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:5]=1.[CH3:29]C([O-])=O.[Na+]>CC(O)=O.O>[CH2:29]=[C:22]1[C:18]2=[N:19][C:20]3[C:15]([C:16](=[O:28])[N:17]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1)=[O:11])[CH:21]=3
Reactant: Cc1cnc(NC(=O)c2ccc3c(=O)n4c(nc3c2)CCCCCC4)s1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=C1CCCCCn2c1nc1cc(C(=O)Nc3ncc(C)s3)ccc1c2=O
Yield: 144 %

Procedure:
Paraformaldehyde (10 mg), N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide (60 mg, 0.16 mmol) and NaOAc (3 mg, 0.0365 mmol) in 5 mL HOAc was stirred at 120° C. overnight in a sealed tube. The completion was monitored by TLC and LC-MS. The sealed tube was then placed in water until cool. The suspension was diluted with water (30 mL) and adjusted pH to 8, then extracted with ethyl acetate (3×50 mL). The organic phase was concentrated to give crude product and 20 mg of the desired product was obtained by column chromatography. MS (ESI): 381 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.45-8.42 (d, J=8.22 Hz, 1H), 8.27 (s, 1H), 8.04-8.00 (dd, J=8.39, 1.61 Hz, 1H), 7.28 (s, 2H), 5.52 (s, 1H), 5.30 (s, 1H), 4.39-4.33 (m, 2H). 2.72-2.59 (m, 2H), 2.42 (s, 3H), 1.96-1.88 (m, 2H), 1.72-1.68 (m, 2H), 1.56-1.51 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[Cl:23])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[Cl:23])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Nc2nc3c(Cl)cccc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3c(Cl)cccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.7 %

Procedure:
In THF (5 ml) was dissolved methyl (4-(4-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetate (556 mg, 1.51 mmol). To the resulting solution was added 1N NaOH (4.5 ml, 4.50 mmol), followed by stirring at room temperature for 20 hours. The mixture was poured in ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(4-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetic acid (468 mg, 88%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)CC1=O.C(=O)C1C=CC=CC=1.CN(C)CCN(C)C.C([Li])CCC.[CH3:49][S:50]SC>O1CCCC1.O>[CH3:49][S:50][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: O=C1Nc2ccccc2C1Cc1ccccc1
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: O=C1Cc2ccccc2N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
3-Phenylmethyl-1,3-dihydro-2H-indol-2-one (4 g, 18.25 mmol) (prepared from 1,3-dihydro-2H-indol-2-one and benzaldehyde by the method of Daisley and Walker J. Chem. Soc. (C) (1971) page 1373) and tetramethylethylenediamine (4.5 g, 38.7 mmol) was dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75° C. in an acetone/dry ice bath. n-Butyllithium (2.5M, 20 ml, 50 mmol) was added and the mixture was stirred at -75° C. for 30 minutes. Dimethyl disulfide (1.65 g, 17.6 mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent ethyl acetate/hexane) gave 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][N:10]=1>N1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[N:6][C:5]([NH:2][NH2:3])=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2ccc(F)cc2)nn1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
Hydrazine hydrate (0.28 mL, 0.0057 mol) was added to a suspension of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (400 mg, 0.002 mol) in pyridine (4 mL) at 0° C. and stirred at 0° C. until a precipitate formed. The mixture was then heated at 65° C. for 30 min. The solvent was evaporated under reduced pressure. The residue was triturated with water, filtered, and washed with water. The crystalline solid was collected and dried under high vacuum to give the desired product (360 mg, 91.9%). Analytical LCMS: (M+H)+=206.1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O>C(O)(=O)C>[CH:17]1[C:16]2[C:21](=[C:12]3[C:13](=[CH:14][CH:15]=2)[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[S:8](=[O:10])(=[O:9])[NH:11]3)[N:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccccc21
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
2-Amino-N-(quinolin-8-yl)-benzenesulfonamide (Example Compound 8) (100 mg, 0.32 mmol) was dissolved in acetic acid (2 ml) and stirred at 10° C. for 5 min. The solution was cooled to −10° C. before tert-butyl nitrite (36 μl, 0.08 mmol) was added dropwise, the mixture was allowed to warm to room temperature and stirred for 10 minutes. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with a sat. sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with MeOH/DCM/NH3 (1:100:2 drops) as the eluent to give the title compound (50 mg, 53%).
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN2CCC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (1 g), 4-methylphenethyl bromide (0.72 g) , anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rbombs, yield 1 g, m.p. 110°-113° C. [α]D25 +14.7 (c 1.0 CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(4-bromophenyl)acetic acid (10 g, 0046 mol) in MeOH (100 mL) was added sulfuryl dichloride (8.3 g, 0.069 mol) dropwise. The reaction mixture was stirred overnight at 80° C., allowed to cool to rt and concentrated under reduced pressure to afford compound 68a as a colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C9H9BrO2: 228.0 (M). found: 228.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.CI.[C:19]([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:19])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C(C)C2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: COc1ccc(-c2cc(C)c(=O)n(C)n2)cc1

Procedure:
The product of step 2 (6-(4-methoxy-phenyl)-2,4-dimethyl-2H-pyridazin-3-one) was prepared as described for example 22 step 2 using 6-(4-methoxy-phenyl)-4-methyl-4,5-dihydro-2H-pyridazin-3-one, MeI and Cs2CO3.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Br:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:28][C:29]1[CH:34]=[C:33]([N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])[CH:32]=[CH:31][CH:30]=1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2cccc(Br)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-bromophenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.00 g, 70%).
Reaction SMILES: [F:1][C:2]1[C:20](I)=[C:19]([CH3:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)=[O:5].[CH3:23][NH:24][C:25]1[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:20]([C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([NH:24][CH3:23])[N:34]=[CH:33]3)=[C:19]([CH3:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)=[O:5]
Reactant: Cc1ccc(C(=O)Nc2cccc(OC(C)C)c2)c(F)c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CNc1ncc2cc(-c3c(C)ccc(C(=O)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 2-fluoro-3-iodo-N-(3-isopropoxyphenyl)-4-methylbenzamide (630 mg, 1525 μmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (522 mg, 1830 μmol) and sodium carbonate (2 M aqueous solution) (1525 μL, 3049 μmol) in DME (25 mL) was flushed with nitrogen and then tetrakis(triphenylphosphine)palladium (0) (176 mg, 152 μmol) was added. The mixture was refluxed for 24 h and then cooled to RT. Solvent was removed in vacuo and the residue was purified by flash chromatography eluting with EtOAc/hexane (25-60%) to give the title compound (387 mg, 57%). MS (M+H)+ 445.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O.S(=O)(O)[O-].[Na+].[CH:26]([CH:28]=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[CH:13]=[C:14]4[C:15](=[CH:16][CH:17]=3)[N:18]=[CH:28][CH:26]=[N:19]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccc(Sc2cccc3cnccc23)cc1N
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: c1cc(Sc2ccc3nccnc3c2)c2ccncc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
4-(5-Isoquinolylsulfanyl)-1,2-benzenediamine 200 mg (0.7 mmol) was dissolved in water 10 ml, a water solution 6 ml of glyoxal-sodium bisulfite hydrate 580 mg (2.3 mmol) was added, and the mixture was stirred for 1 hour at 80° C. Potassium carbonate was added to the reaction solution to alkalize the solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:acetone=1:10), and 6-(5-isoquinolylsulfanyl)quinoxaline 90 mg (41.2%) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH2:16][NH:17][C:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][N:21]2[CH:25]=[N:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:22]2)=[CH:11][C:10]=1[CH2:37][OH:38])C1C=CC=CC=1>[Pd].CO.O1CCCC1>[OH:36][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:37][OH:38])[CH:11]=1)[CH2:16][NH:17][C:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][N:21]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[N:22]1
Reactant: COc1ccc(-c2ncn(CCC(C)(C)NCC(O)c3ccc(OCc4ccccc4)c(CO)c3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ncn(CCC(C)(C)NCC(O)c3ccc(O)c(CO)c3)n2)cc1

Procedure:
3.8 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethanol are hydrogenated with 0.6 g of palladium on charcoal (5%) as catalyst in 75 mL methanol and 75 mL tetrahydrofuran. Then the catalyst is suction filtered and the filtrate is evaporated down. The residue is dissolved in 15 mL 15% m acetonitrile, acidified with formic acid and combined with a crystallisation aid. The precipitated product is separated off and washed. Yield: 2.8 g (81%, formate); m.p.=142-145° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH:6]1[CH2:10][N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8](=[O:21])[NH:7]1)[CH3:5].Cl[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:21]=[C:8]1[N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[CH2:10][CH:6]([CH:4]([CH3:3])[CH3:5])[N:7]1[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)=[O:25]
Reactant: O=C(CCl)Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)C1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Sodium hydride (60%, 22 mg) was added to a solution of 4-(propan-2-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (50 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. After 2-chloro-N-[3-(trifluoromethyl)phenyl]acetamide (52 mg) was added thereto, the resulting mixture was stirred at room temperature for 21 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, followed by extraction with chloroform. The organic layer was separated out by phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography (NH cartridge, and silica gel cartridge, hexane/ethyl acetate) and preparative HPLC to afford the title compound (79 mg).