Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[F:26][C:23]([F:24])([F:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1

Procedure:
A mixture of 5-nitro-2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridine (1.6 g, 4.4 mmol) and 10% Pd/C (300 mg) in EtOAc (100 mL) was hydrogenated at 50 psi overnight. The catalyst was filtered off through celite. The filtrate was removed in vacuo to give the title compound as a light brown gum.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.Cl.Cl.[NH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[NH2:19].C([O-])(=O)C.[Na+]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Reactant: NNc1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (10.2 g, 50.0 mmol), 3-hydrazinopyridine dihydrochloride (9.10 g, 50.0 mmol) and sodium acetate (9.84 g, 120 mmol) in ethanol (100 mL) was heated under reflux for 1 hour. The solution was cooled to room temperature, and the reaction solvent was evaporated under reduced pressure. The residue was poured into water, and organic matter was extracted with a mixed solvent of chloroform/methanol. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate/diethylether/hexane to give the title compound (10.1 g, 69% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[CH2:6][NH:7]2.[C:15]([O-])([O-])=[O:16].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:11]([O:16][CH3:15])=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[CH2:6][NH:7]2
Reactant: COc1cc2c(c(OC)c1)C(=O)CN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c(OC)c1OC)C(=O)CN2
Yield: 21 %

Procedure:
Compound (9) was synthesized from (8) in the same manner as described for the synthesis of (6) using 2-amino-4,5,6-trimethoxy-a-chloroacetophenone (1.05 g, 4.0 n-mmol), K2CO3 (838 mg, 6.1 mmol), a little KI, and dry acetone (50 ml). Purification by column chromatography (eluent: CH2Cl2/MeOH: 9/1) afforded (9) (190 mg, 21%) as red crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCl>[CH:29]([O:28][C:26]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:31])[CH3:30]
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 4-aminopiperidine-1-carboxylate (100 mg) and triethylamine (190 μL) are dissolved in dichloromethane (2 mL), treated with isopropyl chloroformate (920 μL, 1 M solution in toluene) and stirred for 2 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=1[N:34]=[C:35]=[O:36]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:35]([NH:34][C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:33])=[O:36])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Product: Cc1cccc(C)c1NC(=O)Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
1-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-3-(2,6-dimethyl-phenyl)-urea was prepared according to the procedure outlined in Example 60, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (100 mg) and 2,6-dimethylphenyl isocyanate (0.040 mL). The resultant white solid was recrystallized using isopropyl alcohol. 1-{2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-3-(2,6-dimethyl-phenyl)-urea was isolated in 100% purity @ 254 nm; LCMS (APCI): 500 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[CH:37]1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)c1

Procedure:
Compound A31 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μL), 1-methyl-1H-imidazole-4-sulfonyl chloride (9 mg, 0.050 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.32 (m, 2H), 3.53 (m, 2H), 3.79 (s, 3H), 5.55 (m, 1H), 7.46 (s, 1H), 7.53 (s, 1H), 7.85 (d, 2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.16 (s, 1H). Exact mass calculated for C20H23N7O7S2 537.11, found 538.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3,5-dimethylpyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C=O)c(O)cc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,4,5-Trimethoxybenzaldehyde (20 g) was dissolved in dichloromethane (20 ml) and aluminum chloride (34.1 g) was added in small portions. The resulting mixture was stirred at room temperature for 5 hours and then poured in acidic ice water. The dichloromethane layer was separated and the water phase extracted with ethyl acetate. The combined organic layers were extracted with 1 N NaOH. The water phase was acidified with HCl and the precipitate was filtered. The product was recrystallized from toluene.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Product: COc1ccc(C(OC(C)=O)C(=O)Nc2ccccn2)cc1

Procedure:
was prepared from intermediate 79a and 2-aminopyridine following Method A. 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.31–8.23 (m, 2H), 7.81–7.75 (m, 1H), 7.43 (d, 2H, J=8.59 Hz), 6.90 (d, 2H, J=8.59 Hz), 6.14 (s, 1H), 3.79 (s, 3H), 2.25 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 301, found 301.
Reaction SMILES: [F-].[K+].C(O[C:6](=[O:15])[C:7](Br)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[SH:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>CN(C)C=O>[CH2:11]([O:10][C:8]([C:7]1([CH3:13])[C:6](=[O:15])[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: Nc1ccccc1S
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a suspension of KF (3.016 g, 52 mmoles) in anhydrous dimethyl formamide (14 ml), diethyl-2-bromo-2-methyl-malonate (3.90 ml, 20 mmoles) was added and the mixture was stirred for 15 minutes at room temperature. Subsequently, 2-mercaptoaniline (2.50 g, 20 mmoles) was added and the mixture was stirred for 6 hours at the temperature of 60° C. and overnight at room temperature. The reaction mixture was admixed with a mixture of water and ice (80 ml), the product which separated was filtered off by suction and recrystallized from absolute ethanol. Thus there were obtained 3.80 g (75.7%) of the title product in the form of white crystals, m.p. 109°-111° C.
Reaction SMILES: C(OC(N[CH2:9][P:10]([CH2:15][NH:16][C:17](OC(C)(C)C)=O)(=[O:14])[O:11][CH2:12][CH3:13])=O)(C)(C)C.Cl.[C:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[NH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:33]1([C:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:32][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
The tert-butoxycarbonyl protective group is removed from the ethyl phosphinate 2 (100 mg; 0.28 mmol) using 3N methanolic hydrochloric acid (30 ml) (check via DC). The reaction solution is evaporated under reduced pressure. Diphenylmethanimine (0.100 ml; 0.60 mmol) is added dropwise to the suspension of the crude product in methylene chloride (20 ml) under an atmosphere of nitrogen. The reaction solution is filtered after being stirred for 16 hours at room temperature. The filtrate is evaporated under reduced pressure. The crude product is taken up in ether, filtered and extracted with water (2×20 ml). The organic phase is dried over Na2SO4 and evaporated under reduced pressure. The diphenylmethylene phosphinate 3 (71 mg, 53% of theory) is obtained after purification on silica gel using column chromatography (ethyl acetate/heptane=1/1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18](=[O:24])[CH2:19][Si](C)(C)C)([CH3:16])([CH3:15])[CH3:14].[CH3:25][C:26]1([C:29](N2C=CN=C2)=[O:30])[CH2:28][CH2:27]1.Cl>O1CCCC1>[CH3:25][C:26]1([C:29](=[O:30])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:24])[CH2:28][CH2:27]1
Reactant: CC1(C(=O)n2ccnc2)CC1
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)C1(C)CC1
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium (2.5M in hexane, 36 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (9.09 g) in dry tetrahydrofuran (i.e. tetrahydofuran) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred for 0.25 hour and t-butyltrimethylsilylacetate (16.9 g) was added dropwise with stirring whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour. A suspension of 1-(1-methylcyclopropylcarbonyl)-imidazole (13.5 g) in dry tetrahydrofuran (120 ml) was added dropwise whilst maintaining the temperature below -60° C. The mixture was stirred at -78° C. for 3 hours and the temperature was allowed to rise to room temperature. Hydrochloric acid (2M, 100 ml) was added cautiously and the mixture was extracted with ether (2×100 ml). The combined extracts were washed with hydrochloric acid (2M, 3×50 ml) and water (3×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 3-(1-methylcyclopropyl)-3-oxopropionate as an orange oil NMR (CDCl3) 0.65(m,2H), 1.1(m,2H), 1.25(s,3H), 1.4(s,9H), 3.2(s,2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7-hydroxyquinoline (67 mg, 0.46 mmol) in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue taken up in 2N. aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and the solution filtered through phase separating paper. The filtrate was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(quinolin-7-yloxy)quinazoline (122 mg, 63%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[S:23][C:22]([S:24]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:21][CH:20]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[S:23][C:22]([S:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)(=[O:25])=[O:26])=[CH:21][CH:20]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1)n1cccc1
Yield: 93 %

Procedure:
N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C from 3,5-bis(trifluoromethyl)benzeneboronic acid (619 mg, 2.26 mmol) and N-[5-bromothiophene-2-sulfonyl]pyrrole (60 mg, 2.05 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide as a white solid in 93% yield.
Reaction SMILES: O.[C:2]1([CH:8]([CH3:26])[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC)=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([CH:8]([CH3:26])[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)C(C)c3ccccc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)Nc1nc2c(s1)CCCC2C(=O)O)c1ccccc1

Procedure:
Water (20 mL) and MeOH (80 mL) were added to ethyl 2-(2-phenylpropionylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (R) (4.95 g, 13.8 mmol) and NaOH (5.52 g, 0.138 mol), and the resultant mixture was stirred at RT under a blanket of nitrogen as inert gas until completion of the reaction. Following removal of MeOH, 2N hydrochloric acid solution in water (250 mL) and DCM (250 mL) were added. The phases were separated, and the aqueous phase was extracted a number of times with DCM (a total of 200 mL). Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(2-phenylpropionylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (S) in a yield of 4.6 g (corresponding to 100% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11](=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]1=[O:16]
Reactant: O=C1CCCCCC1c1cc(Cl)ccc1Cl
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCCC(c2cc(Cl)ccc2Cl)C1=O

Procedure:
2-(2,5-Dichloro-phenyl)-cycloheptanone (157 mg, 0.61 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (197 mg) as a red solid which was used directly in the next step. MS ISP (m/e): 312.0 [(M+H)+].
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (1.0 g, 3-09 mmol) was dissolved in dimethyl sulfoxide (60 ml), then at room temperature, triethylamine (560 μl, 4.02 mmol) was added, followed by heating at 150° C. 4-Methoxybenzylamine (525 μl, 4.02 mmol) was added to the solution all at a time, followed by stirring for 1.5 hours. The reaction liquid was cooled to room temperature, and the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=98:2, v/v) to obtain the entitled compound (665 mg, 49%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23]>>[CH3:20][O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)[CH:29]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: COC(=O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Yield: 70 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (370 mg) was reacted with 3-methoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a white solid (70% yield). M.p. 211° C., LCMS: m/z=374.17 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 3.95 (s, 3H), 4.48 (s, 2H), 5.35 (s, 2H), 7.23-7.35 (m, 2H), 7.38-7.40 (m, 2H), 7.50-7.58 (m, 2H), 7.60-7.66 (m, 2H), 7.84 (s, 1H), 7.9-8.1 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]([CH3:29])=[CH:17]3)=[CH:10][CH:9]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]([CH3:29])=[CH:17]4)=[CH:10][CH:9]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1nc2ccc(-c3ccc(O)cc3)cc2cc1C
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2cc1C
Reaction time: 18 h
Yield: 44 %

Procedure:
Cesium carbonate (71.7 mg, 220.1 μmol) was added to ethyl 6-(4-hydroxyphenyl)-3-methyl-2-quinolinecarboxylate (61.5 mg, 200.1 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (67.0 mg, 220.1 μmol) in N,N-dimethylformamide (4 mL) at room temperature. The resulting suspension was stirred for 18 hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 50.7 mg (44%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.32 (s, 1H), 8.14 (s, 1H), 8.08-8.01 (m, 2H), 7.72 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=8 Hz, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.89 (s, 2H), 4.41 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 2.55 (s, 3H), 1.36 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(C)ccc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cccc(C)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.428 ml, 3.609 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 135 (1.1 g, 3.609 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (930 mg of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).