Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[NH2:18]
Reactant: NN
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: O
Solvent: CO
Product: NNC1=NS(=O)(=O)c2cnccc2N1
Temperature: 70 °C

Procedure:
3-Methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (1.0 g) was added to hydrazine hydrate (0.8 ml) and the mixture was heated to 70° C. for 30 min. After cooling, the reaction mixture was supplemented with methanol (10 ml) and the solvents were removed by distillation under reduced pressure. The residue was dissolved in NaOH 2M (20 ml), treated with charcoal, filtered, and the filtrate was adjusted to pH 6-7 with HCl 1M. The precipitate so obtained was collected by filtration, washed with water an dried (yield: 0.8 g); m.p. 290°-292° C. (Compound 1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26](O)=[O:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]([NH:32][O:30][CH3:31])=[O:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: COc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OC)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-methoxypyrimidine-4-carboxylic acid (Example 311) and methoxylamine hydrochloride.
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[O:23]>CN(C)C=O>[OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:26](=[O:27])[CH2:25][CH2:24][S:22]([CH3:21])=[O:23])=[CH:7][CH:6]=1
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: CS(=O)CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)CCC(=O)Nc1ccc(OCC(O)CO)cc1
Yield: 80.4 %

Procedure:
A 1.83 g quantity of 4-(2,3-dihydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 30 ml of dimethylformamide. To the solution was added 1.55 g of 3-(methylsulfinyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from ethanol was effected, giving 2.42 g of N-[4-(2,3-dihydroxypropoxy)phenyl]-3-(methylsulfinyl)propionamide in a yield of 80.4%. M.p. 139° to 141° C.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@H](N)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (626 mg, 4630 μmol) in benzene (10 mL) was added 4-chlorobenzaldehyde (651 mg, 4630 μmol) and MgSO4 (1000 mg, 8308 μmol) and the suspension stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-chlorobenzylidene)-1-phenylpropan-2-amine, which was carried on into the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.Br[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55]>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Yield: 80 %

Procedure:
t-Butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in a mixture of dry THF-DMPU 60:40 (2.5 mL) at −78° C. was treated with a 2.0 M LDA solution (0.23 mL, 0.46 mmol) and the mixture was stirred for one h at the same temperature. 2-Fluoro-5-methoxybenzyl bromide (35, 100 mg, 0.46 mmol) in dry THF (2.5 mL) was added dropwise at −78° C. and then the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (10 mL), and the product was extracted with diethyl ether (2×15 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×10 mL), dried over sodium sulfate, filtered and evaporated to give 40 as a crude yellow oil (110%). When examined, the pure product 40 was made in 80% yield (175 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 35 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49 as a yellow solid (14 mg, 4% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:21]2[CH2:22][CH:23]3[CH2:26][CH2:27][CH:19]([CH2:25][CH2:24]3)[CH2:20]2)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CC2CCC1CNC2
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CCC(CC3)C2)cc2ccccc12
Yield: 63.1 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (861 mg, 3.02 mmol) and 3-azabicyclo[3.2.2]nonane (379 mg, 3.02 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml) and the mixture was stirred at room temperature for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aq HCl. The EtOAc was then washed with saturated aq NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 1% acetone in CHCl3 to provide the pure product as a white foam (712 mg, 63% yield): 1H NMR (CDCl3) δ 1.52-1.84 (8H, m, 4×CH2), 2.02-2.13 (2H, br s, 2×CH), 2.46 (3H, s, CH3CO), 3.31 (4H, d, J=4.2 Hz, 2×CH2), 7.56-7.71 (3H, m, ArH), 7.92-8.02 (2H, m, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(F)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(F)cc1

Procedure:
Example 17 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-fluoro-4-isocyanatobenzene (15.5 μl) to give the title compound (0.031 μg). LC-MS (System A): Rt 2.30 mins, Mass Spectrum m/z 421 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cnc(Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(NCc2ccc(OC)cc2OC)cc1OC
Temperature: 120 °C
Reaction time: 19 h
Yield: 64.6 %

Procedure:
To a solution of methyl 6-chloro-4-methoxypyridine-3-carboxylate (1.09 g) in N,N-dimethylacetamide (12 mL), 2,4-dimethoxybenzylamine (1.35 g) and potassium carbonate (2.24 g) were added at room temperature, and the mixture was stirred at 120° C. for 19 hours. The reaction solution was cooled to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to obtain the title compound (1.16 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][S:17](=[O:21])(=[O:20])[NH:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C1C(=O)N([Br:30])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:30][C:9]1[CH:10]=[C:11]([CH:14]2[CH2:19][NH:18][S:17](=[O:21])(=[O:20])[NH:16][CH2:15]2)[CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CNS(=O)(=O)NC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
[4-(1,1-Dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 100 mg, 0.305 mmol) was dissolved in TFA (1 mL). The resulting solution was stirred at RT for 30 min and concentrated in vacuo. The residue obtained (74.3 mg) was dried in vacuo for 1 h and dissolved in HOAc (2 mL). The resulting mixture was cooled to 0° C. and NBS (42.6 mg, 0.239 mmol) was added. The resulting mixture was stirred for 30 min, washed with aq NaHCO3 (2 mL) and concentrated. The residue was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (49 mg, 52%): 1H-NMR (CD3OD; 400 MHz): δ 7.23 (d, 1H, J=2.0 Hz), 6.93 (dd, 1H, J=8.2, 2.0 Hz), 6.78 (d, 1H, J=8.2 Hz), 3.63 (m, 2H), 3.32 (m, 2H), 2.82 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:8]([CH:7]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ncc[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2nccn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 422.1 %

Procedure:
A solution of diethyl 5-(1H-imidazol-2-yl)isophthalate (0.0689 g, 0.239 mmol, 1 eq) in anhydrous THF (2 ml) was added dropwise to a stirred suspension of NaH (60% dispersion in oil, 0.0105 g, 0.263 mmol, 1.1 eq) in anhydrous THF (3 ml) at 0° C. under Ar. After 1 h the reaction was warmed to room temperature. After 1 h the reaction was cooled to 0° C. and MeI (0.016 ml, 0.037 g, 0.263 mmol, 1.1 eq) was added dropwise. The reaction was stirred at 0° C. to room temperature overnight. The reaction was quenched with water and diluted with EtOAc. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.305 g (0.1.1 mmol, 42% yield) of diethyl 5-(1-methyl-1H-imidazol-2-yl)isophthalate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=O)=[CH:30][CH:29]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH3:42].CO>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH2:42])=[O:36])=[CH:39][CH:40]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(=O)OCC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Reactant: N
Solvent: CO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(N)=O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 70 °C
Reaction time: 43 h
Yield: 35 %

Procedure:
Ethyl (4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate (300 mg) was added to a 7N ammonia-methanol solution (15 ml) and then stirred at 70° C. for 43 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:19:1→ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane, giving a pale yellow powder of 2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide (100 mg, yield: 35%)
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Mg]Br.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[S:3][C:4]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1
Reactant: Br[Mg]c1cccs1
Reactant: Brc1cnc(Br)s1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: c1csc(-c2cnc(-c3cccs3)s2)c1
Yield: 5.8 %

Procedure:
When a three-neck 50-ml flask fitted with a reflux condenser, a stirrer, and a calcium chloride tube was charged with 6.45 g (40 m.mols) of 2-bromothiophene and 29 ml of dehydrated ether and then 1.06 g (44 m.mols) of a magnesium metal was added thereto, the resultant reaction mixture produced 2-thienyl magnesium bromide with evolution of heat. Under an atmosphere of nitrogen, 4.0 g (16 m.mols) of 2,5-dibromothiazole, 0.179 g (0.33 m.mol) of dichloro[1,3-bis(diphenylphosphino)propane]nickel, and 29 ml of dehydrated ether were added to the 2-thienyl magnesium bromide. The resultant mixture was placed and refluxed for 16 hours in a three-necked 100-ml flask fitted with a reflux condenser, a stirrer, and a calcium chloride tube. The reaction mixture was treated with 1N hydrochloric acid and the water layer separated from the organic layer was extracted with ether. The organic layer was added to the water layer extracted with ether. The resultant liquid was washed with water, cleaned with a saturated aqueous sodium hydrogen carbonate solution, and then washed again with water. The washed liquid layer was dried with anhydrous sodium sulfate, treated with activated carbon, and recrystallized twice with n-hexane, to produce 237 mg (5.8%) of yellow leaflike crystals of 2,5-di(2-thienyl)thiazole having a melting point of 93.0° to 93.8° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1.COC(C1C=NC(OC2C=CC3CCN(C4CCC4)CCC=3C=2)=CN=1)=O>>[CH3:27][O:26][C:24]([C:21]1[CH:22]=[N:23][C:18]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
The title compound was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and methyl 6-chloro-3-pyridine carboxylate in an analogous manner to that described for E122; MS (ES+) m/e 353 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[C:16]([CH3:26])[CH:15]=2)[CH2:13][CH2:12]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:13][CH2:12]4)=[CH:15][C:16]=3[CH3:26])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C2CC2)ccc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 15 and using 4-bromo-2-methylaniline (3 g), N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (5.65 g) and cyclopropylboronic acid (721 mg), 1-(4-cyclopropyl-2-methylphenyl)piperazine (640 mg) was obtained. To a solution (7 mL) of 6-bromonicotinic acid (132 mg) in methanol were added 1-(4-cyclopropyl-2-methylphenyl)piperazine (150 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (217 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (260 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:12].CC(C)=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])=[CH:7][C:6]=1[CH3:12]
Reactant: COC(=O)Cc1ccc(N)cc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 2-methyl-4-amino phenylacetic acid methyl ester (5.3 mmol) in acetone (10 mL) dry pyridine (7.95 mmol) and phenylsulfonyl chloride (6.36 mmol) have been added and the resulting solution has been left stirring overnight at room temperature. Acetone has been evaporated and the residue diluted with CHCl3 (15 mL), washed with 1N HCl (2×10 mL), water (3×20 mL), dried over Na2SO4 and evaporated under vacuum to give {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid methyl ester as colourless oil (5.0 mmol) pure to be used in the following reaction. Following the procedure described for Example 1 and starting from the methyl ester (5.0 mmol) pure {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid has been synthesised (4.75 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[S:27]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2)(=[O:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1,1-dimethylethyl 6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.146 g; 0.586 mmol) and Et3N (0.17 mL; 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Tf2O (0.11 mL; 0.67 mmol (dropwise over 2 min. The mixture was stirred overnight, gradually warming to room temperature, diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum which slowly solidified. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.87 (t, J=5.7 Hz, 2H), 3.66 (br. t, J=5.5 Hz, 2H), 4.59 (s, 2H), 7.04-7.12 (m, 2H), 7.18 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1-c1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
4-{(2,2-Dimethyl-propyl)-[4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile (200 mg, 0.5 mmoles), 1-methyl imidazole (0.2 ml, 2.5 mmoles), triphenylphosphine (26 mg, 0.10 mmoles) and CsCO3 (160 mg, 0.5 mmoles) are dissolved in 3 ml of DMF and Pd(OAc)2 (10 mg, 0.05 mmoles) is added at rt. The mixture is stirred at 120° C. for 18 h. Water is added and the organic layer is extracted with AcOEt washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 104 mg of desired 4-{(2,2-dimethyl-propyl)-[4-(3-methyl-3H-imidazol-4-yl)-benzyl]-amino}-pyrimidine-2-carbonitrile in 59% yield.