Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S-:21].[Na+].O>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([S:21][CH3:20])[CH:17]=1)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(NC(=O)OC(C)(C)C)c1cncc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(NC(=O)OC(C)(C)C)c1cncc(SC)c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of [1-(5-bromo-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (6.3 g, 19 mmol) and sodium thiomethoxide (2.7 g, 38 mmol) in anhydrous THF (27 mL) is heated at 70° C. After 2 hours the reaction is cooled to room temperature and water (200 mL) is added. The resultant mixture is extracted with ethyl acetate (3×200 mL). The combined organic layers are combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluted with 0 to 60% EtOAc/hexanes) to afford [1-(5-methylsulfanyl-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (3.9 g, 68%) as a thick light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.CCN(CC)CC>O1CCOCC1.[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:13][C:14]1[N:19]=[C:18]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([NH2:12])=[O:11])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C#Cc1ccccc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1CC(N)=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-ethynylphenyl)acetamide (I8) (5.40 g, 33.9 mmol), 2,4-dichloro-5-methylpyrimidine (6.63 g, 40.7 mmol) and CuI (0.129 g, 0.678 mmol) in 1,4-dioxane (180 mL) and Et3N (14.2 mL, 101 mmol) was placed under nitrogen. PdCl2(PPh3)2 (0.238 g, 0.339 mmol) was added and the resulting mixture was stirred at 70° C. for 20 minutes, then adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 120 g SiO2 Cartridge, 0-5% MeOH in DCM) to give the title compound I9 as a yellow solid (5.01 g, 51%); 1H NMR (300 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.35-7.52 (m, 4H), 6.97 (brs, 1H), 3.71 (s, 2H), 2.42 (s, 3H). LCMS-B: rt 5.689 min; m/z 286 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH:18](OCC)(OCC)OCC>>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[N:1]=[CH:18][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)Nc1ccccc1
Reactant: CCOC(OCC)OCC
Product: O=c1c2cc(Br)ccc2ncn1-c1ccccc1
Temperature: 130 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
A mixture of 2-amino-5-bromo-N-phenylbenzamide (2.82 g, 9.7 mmol) and triethyl orthoformate (20 mL) was stirred at 130° C. for 15 h. The reaction mixture was cooled to RT and petroleum ether was added. After filtration, the filtrate was extracted with ethyl acetate (100 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=5:1) to give 6-bromo-3-phenylquinazolin-4(3H)-one (1.5 g, yield: 50%) as white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 7.87˜7.90 (m, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.55˜7.58 (m, 2H), 7.51˜7.53 (m, 1H), 7.41˜7.43 (m, 2H). MS (M+H)+:301/303.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:27]=1)=[O:20])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=1)=[O:20]
Reactant: CC(C)c1ccc(N(Cc2cnn(-c3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2cnn(-c3ccccc3)c2)C(=O)C2CCCc3c(O)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
To a solution of 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.04 g) in methanol (10 mL) were added 10% palladium carbon (0.10 g) and ammonium formate (0.59 g), and the mixture was stirred at room temperature for one day. The reaction mixture was filtrated, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)c3cccs3)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g, 1.7 mmol) in tetrahydrofuran (10 mL) was added 2-thiophenecarbonyl chloride (0.36 mL, 3.4 mmol), and triethylamine (0.52 mL, 3.7 mmol) was added to the obtained mixture. The reaction mixture was stirred at room temperature for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was dissolved in conc. hydrochloric acid (5 mL) and the mixture was stirred at 40° C. for 14 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) and crystallized from isopropyl ether-hexane to give the title compound (0.56 g, yield 82%).
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].Cl>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:5]=[C:4]([Br:8])[CH:3]=1
Reactant: Brc1cccc(Br)c1Br
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc(Br)c1
Temperature: -55 °C
Reaction time: 0.58 h

Procedure:
42.4 g of Tribromobenzene (134.6 mmol) was dissolved in 600 mL Et2O. The solution was chilled to −55° C., at which temperature starting material precipitated. 54 mL of n-BuLi (2.5 M in hexanes, 135 mmol) were added within 20 minutes. After stirring for 35 minutes at −52° C., 20 ml TMSCl (158 mmol) and 20 mL Et2O were added within 7 minutes. The suspension turned into a solution at −42° C., and a fine precipitate appeared at −30° C. The suspension was stirred overnight at room temperature. 100 mL 2M HCl were used to hydrolyze the mixture. After stirring for 30 minutes, the Et2O-phase was dried with MgSO4, filtered, and solvent evaporated until compound crystallized out of solution. The flask was stored overnight at +4° C. The crystalline compound was filtered, washed with a small amount cold pentane, and dried under vacuo. A second fraction of crystalline compound was obtained from the filtrate. Yield: 31.9 g (103.5 mmol, 77%). 1H-NMR (CHCl3=7.24 ppm): δ7.62 (t, 1H), 7.49 (d, 2H), 0.25 (s, 3×3H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccc(C=O)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: BrCCCCCc1ccccc1
Product: CC(=O)NC(CCc1ccc(C(O)CCCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 69.2 %

Procedure:
2-Acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-formylphenyl)ethyl)propane (3.0 g) and 1-bromo-5-phenylpentane (4.1 g) were reacted and treated in the same manner as in Working example 1(6) to give the title compound (2.7 g) as a pale yellow oily substance.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2].[CH3:41]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][N:33]([CH3:41])[CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCNC3)cc1)C2c1ccc(Cl)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCN(C)C3)cc1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of Example 45 (TFA salt, 7 mg, 0.01 mmol) in DCM (0.5 ml) were successively added AcOH (0.001 ml, 0.021 mmol), formaldehyde (37% in water, 0.002 ml, 0.021 mmol) and NaBH(OAc)3 (4.4 mg, 0.021 mmol) at RT. The reaction mixture was stirred at RT for 1 h, then diluted into DCM and washed with a 2M aqueous Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt, 7.4 mg, 0.01 mmol, quant.) as a colorless solid. HPLC: AtRet=2.11 min; LC-MS: m/z 576.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 0.83-0.92 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.10-1.20 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.44-1.67 (m, 4H), 1.69-1.87 (m, 2H), 2.04-2.19 (m, 1H), 2.65-2.81 (m, 5H), 2.84-2.93 (m, 3H), 3.08-3.19 (m, 1H), 3.22-3.41 (m, 3H), 3.56 (d, J=20.0, 1H), 3.72 (s, 3H), 3.91 (d, J=20.0, 1H), 4.17-4.27 (m, 1H), 5.91-5.96 (m, 1H), 6.58-6.63 (m, 2H), 6.83 (s, 1H), 6.88-6.94 (m, 2H), 6.98-7.02 (m, 1H), 7.32-7.37 (m, 4H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C)(C)(C)C.Cl.C(OCC)(=O)C>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCCc1ccccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.2 %

Procedure:
N-[2-(2-(Phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamic acid tert-butyl ester (547 mg, 1.4 mmol) was dissolved in dichloromethane (5 ml). 3.1 N hydrogen chloride in ethyl acetate (3 ml, 9.3 mmol) was added. The solution was stirred at room temperature for 1 h. Another portion of 3.1 N hydrogen chloride in ethyl acetate (5 ml, 15.3 mmol) was added. The solution was stirred for another 3.5 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silcia (7 g), using dichloromethane/methanol/25% aqueous ammonia 50:10:1 as eluent, to give 521 mg of N-[2-(2-(methylamino)ethyl)phenyl]benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.[F:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:18][CH2:17][CH2:16][F:15])[N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1
Reactant: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Yield: 57.9 %

Procedure:
A stirred solution of 4.7 g (0.022 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one, 4.0 g (0.028 mole) of 3-fluoropropyl bromide and 4.0 g (0.028 mole) of potassium carbonate in 60 ml of dimethylformamide was heated at 60° C. for 16 hours. The reaction mixture was poured into water and the mixture extracted with diethyl ether. The combined ether extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 3.5 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 62°-63° C. The reaction was repeated several times.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=1)(=[O:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl.O>[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39]([O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][S:3]([C:2]([F:1])([F:14])[F:15])(=[O:5])=[O:4])[CH:12]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Oc1cc(O)ccn1)C(F)(F)F
Reactant: O=S(=O)(Cl)CCCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CCCC(F)(F)F)Oc1ccnc(OS(=O)(=O)C(F)(F)F)c1

Procedure:
Under argon, 550 mg (2.26 mmol) of 4-hydroxy-2-pyridinyl trifluoromethanesulfonate (Example 39A) are suspended in 15 ml of dichloromethane at room temperature. 2 ml of a 40% strength solution of tetrabutylammonium hydroxide in water are added dropwise to this. Then 476 mg (2.26 mmol) of 4,4,4-trifluoro-1-butanesulfonyl chloride are added and allowed to react for 20 minutes. Working up takes place by adding water, extracting with ethyl acetate, washing, drying and evaporating in a rotary evaporator. The residue is purified by chromatography on 20 g of silica gel (0.04-0.063 mm) with cyclohexane/ethyl acetate 2:1 to 1:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Br[CH2:12][C:13]1([CH3:39])[CH:17]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:15]2[S:14]1>P([O-])([O-])([O-])=O.O1CCOCC1>[Cl:25][C:22]([Cl:23])([Cl:24])[CH2:21][O:20][C:18]([CH:17]1[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:15]2[S:14][C:13]1([CH2:12][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH3:39])=[O:19]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Sc1nc2ccccc2s1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(CSc2nc3ccccc3s2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
Benzothiazole-2-thiol (0.20 g) was dissolved in a mixture of pH 6.7 phosphate buffer (15 ml) and dioxane (15 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 7 hours at room temperature. After the reaction was completed, dioxane was distilled off and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% potassium carbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.15 g) from the second fraction of fractions each of which was separated into 30 ml.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].Cl.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.74 g) was added to a solution of 8-bromooctanoyl chloride (3 g) in benzene (20 ml), and the mixture was stirred at room temperature for 1.5 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.36 g of 8-bromo-1-phenyl-1-octanone.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.B(F)(F)F.CCOCC>>[NH2:9][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=[C:11]2[CH2:12][CH2:13][CH2:14][C:10]=12
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCCC1
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)CCC2

Procedure:
Anthranilonitrile (5.0 g, 42.3 mmol), cyclopentanone (4.1 g, 46.7 mmol), boron trifluoride diethyl etherate (1M, 10 ml, 81.8mmol) were treated according to the general procedure to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].[OH-].[Na+]>ClCCl>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1)=[O:33]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.0 g (20.7 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 2.1 g (20.7 mmol) TEA are dissolved in 30 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.95 g (20.7 mmol) 2-naphthoyl chloride are dissolved in 40 ml absolute dichloromethane and added dropwise under ice cooling. The mixture is stirred for two hours at RT without further cooling. Subsequently, the batch is made alkaline with 10% sodium hydroxide solution and washed twice with a small amount of water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically purified over silica gel with CHCl3/CH3OH (96/4). Yield of colorless resin 5.4 g (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Yield: 133.4 %

Procedure:
A mixture of 2-chloro-4-nitrotoluene (0.20 g, 1.17 mmol), N-bromosuccinimide (0.228 g, 1.28 mmol) and benzoyl peroxide (0.014 g, 0.058 mmol) in tetrachloromethane (7 mL) was irradiated (500 W lamp) at reflux overnight. The reaction mixture was concentrated to give a yellow oil/solid (0.391 g) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1Nc1nc(Cl)nc2ccccc12
Reactant: CI
Product: COc1ccccc1N(C)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide by a procedure similar to example 7 (72% yield). 1H NMR (CDCl3): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)=[CH:9][CH:8]=1)[CH3:6].C(N(CC)CC)C.[Cl:26][C:27]1[N:32]([CH3:33])[C:31](=[O:34])[CH:30]=[C:29]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[N:28]=1>O1CCCC1>[ClH:26].[ClH:1].[ClH:26].[CH3:6][N:5]([C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[NH:14][CH2:15][CH2:16][N:17]([C:27]3[N:32]([CH3:33])[C:31](=[O:34])[CH:30]=[C:29]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[N:28]=3)[CH2:18]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CN(C)c1ccc([C@H]2CNCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCN2)cc1
Reaction time: 10 h
Yield: 163.7 %

Procedure:
To a suspension of (S)-2-(4-(N,N-dimethylamino)phenyl)piperazine trihydrochloride (115 mg, 0.365 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.28 mL, 2.0 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (74 mg, 0.33 mmol) at room temperature. After stirring for 10 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and saturated sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to yield crystals, which were washed with diisopropyl ether. After the crystals were dissolved in ethyl acetate, the solution was treated with 4 N hydrogen chloride in ethyl acetate. White precipitate was collected and dried in vacuo to afford (S)-2-(3-(4-(N,N-dimethylamino)phenyl) piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one trihydrochloride (135 mg, 81%).