Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([O:35]C)=[O:34])=[N:31][CH:32]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O>[OH:1][C:2]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[N:31][CH:32]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(C(=O)O)nc3)s2)c1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
The product of Step 2 (95 mg, 0.184 mmol) was taken up in MeOH (2.0 ml) in a microwave vial, and sodium hydroxide (1.0 M in H2O, 0.369 ml, 0.369 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4), filtered and evaporated to afford the title compound (85 mg, 0.169 mmol, 92% yield) as an off-white foam. MS ESI: [M+H]+ m/z 502.1. 1H NMR (600 MHz, DMSO-d6) δ 13.12 (s, 1H), 10.23 (s, 1H), 8.89 (d, J=1.9, 1H), 8.80 (d, J=4.9, 1H), 8.09 (dd, J=2.3, 8.2, 1H), 7.99 (d, J=8.2, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=4.9, 1H), 7.13 (d, J=4.5, 2H), 2.28 (s, 3H), 1.95 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42]Cl)[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: O=C1OC2(CCN(C(=O)c3cn(CC4CN(Cc5ccccc5)CCO4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with commercially available 4-benzyl-2-(chloromethyl)morpholine gave the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:16])=[O:6])[CH2:12][CH2:11]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.5 %

Procedure:
A solution of 1-(1,1-Dimethylethyloxycarbonyl)-4-piperidine carboxylic acid (11.3 g, 49.3 mmol), N,O-dimethylhydroxylamine hydrochloride (5.77 g, 59.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (11.33 g, 59.1 mmol), 4-dimethylaminopyridine (602 mg, 4.93 mmol) and triethylamine (14.96 g, 148.0 mmol) in dichloromethane (200 mL) was stirred at room temperature for 18 h. The mixture was concentrated to ca. 25 mL, then was poured into 1M hydrochloric acid (75 mL) and extracted with ethyl acetate (3×75 mL). The organic extracts were washed sequentially with 1M hydrochloric acid (50 mL), 10% (w/v) aqueous sodium carbonate (2×50 mL) and brine (50 mL), combined, dried over Na2SO4, filtered and evaporated to afford the title compound as a clear syrup (12.0 g, 44.1 mmol, 89%). 1H NMR CDCL3 : δ4.2 (brm, 2H, eq-H--C(2)), 3.72 (s, 3H, ° CH3), 3.19 (s, 3H, NCH3), 2.8 (brm, 3H, ax-H--C(2), H--C(4)), 1.7 (brm, 4H, H--C(3)), 1.46 (s, 9H, (CH3)3C).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>CN1CCCC1=O.[OH-].[Na+]>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.151 mL, 1.00 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→75/25), and precipitated from diisopropyl ether to give the title compound (195 mg, 98%) as a white powder.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].[H][H]>[Pt].CO>[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)/C=C(/C)N
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC(C)N

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrous methanol, 1.5 equivalent of sulfuric acid and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 2 hours at approximately 25° C. under 3-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.13 g of pure methyl (RS)-3-aminobutyrate sulfate were obtained as an oil. The hydrogensulfate can be prepared correspondingly.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)ncc3c2=O)c(OC)c1
Yield: 42.7 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.068 mmol), glycine (675 mg, 8.9 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting precipitate was isolated by filtration. The crude solid was further purified by silica gel chromatography (10-90% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 414.31 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]([CH2:9][C:10]([OH:12])=O)[C:4](=[O:13])[N:3]=1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][CH2:34][CH2:35][CH3:36])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:23]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][CH2:34][CH2:35][CH3:36])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:10](=[O:12])[CH2:9][N:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[N:3][C:4]3=[O:13])[C:23]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: Cc1cn(CC(=O)O)c(=O)nc1O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Cn1cc(C)c(O)nc1=O
Yield: 19.6 %

Procedure:
Using the general method of Example 105 2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetic acid (0.12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.06 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamide as a solid, m.p. 242-244° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].C(O)(=O)C.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:31]1([CH2:34][NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:33][CH2:32]1
Reactant: O=CC1CC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 378.6 %

Procedure:
cis-N-(2-Amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) (200 mg, 0.05 mmol) was dissolved in 10 mL methanol. Acetic acid (0.156 mg, 2.6 mmol) and cyclopropanecarboxaldehyde (73 mg, 1 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (221 mg, 1 mmol) was added at stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Crystallization with diisopropylether and a small amount of dichloromethane yielded cis-N-[2-(cyclopropylmethyl-amino)-cyclohexyl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide as a white solid (83 mg, 36%), MS: m/e=439.3 [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([S:25][CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: SCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 120, Step 1, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzyl mercaptan.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[CH2:13][CH3:14].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:3][C:4]1[N:8]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[CH2:13][CH3:14]
Reactant: CCc1c(C(=O)OC)c[nH]c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 91 %

Procedure:
Using sodium hydride (60% in oil, 393 mg), methyl 5-bromo-4-ethyl-1H-pyrrole-3-carboxylate (2.00 g) and benzenesulfonyl chloride (1.25 mL), a procedure as in Reference Example 41 was performed to give the title compound as white crystals (yield 2.93 g, 91%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:27])([F:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: O=C(Cl)C(F)(F)c1ccccc1
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccccc2)c1F
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of DIEA (1.49 mL, 8.55 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (690 mg, 2.85 mmol), as prepared in the preceding step, in DCM (6 mL) was added a solution of 2,2-difluoro-2-phenylacetyl chloride (0.99 g, 5.20 mmol), as prepared according to the procedure of step 3 of Example 1, in DCM (3 mL). After stirring for 24 hours, the mixture was concentrated, and partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to give the title compound (1.04 g, 92% yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 8.49-8.43 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 6.68 (d, J=7.1 Hz, 2H), 7.55-7.49 (m, 3H), 4.35 (t, J=6.4 Hz, 2H), 3.37 (dt, J=6.3, 2.3 Hz, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
To a stirred solution of tert-butyl 3-methyl4-(N′-phenylureido)phenylacetate (1.12 g, 3.29 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3 to give 3-methyl4-(N′-phenylureido)phenylacetic acid (680 mg, 73%) as white needles. 1H-NMR (DMSO-d6) δ 2.22 (s, 3 H), 3.46 (s, 2 H), 6.93–7.05 (m, 3 H), 7.25–7.29 (m, 2 H), 7.43–7.46 (m, 2 H), 7.72–7.74 (m, 1 H), 7.90 (s, 1 H), 8.98 (s, 1 H), 12.26 (br s, 1 H); Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.47; H, 5.68; N, 9.73.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.C1(C)C=CC=CC=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: FC(F)(F)COc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)COc1ccccc1Nc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 3, Step A) in 39 Ml of toluene was added 0.136 g (0.118 mmol) of tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of 3-aminophenylboronic acid, 47 Ml (94.1 mmol) of a 2M solution of sodium carbonate and 8 Ml of ethanol and the reaction mixture was heated at 90° C. for 22 hr. The reaction mixture was cooled to RT, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with water and brine and dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:1 hexanes:EtOAc) to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32].CN1C=CN=C1>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:32][C:28]3[S:27][CH:31]=[CH:30][N:29]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride (Intermediate DDDD; 2.040 g, 5.06 mmol) and thiazol-2-amine (2.54 g, 25.3 mmol) in 40 mL of MeCN was treated with 1-methylimidazole (0.496 ml, 5.06 mmol) and was heated to reflux with a heat gun, and then allowed to stir at room one hour. The reaction mixture was concentrated and the material was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) to yield 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (1.230 g, 2.64 mmol, 52.1% yield). 1H NMR (acetonitrile-d3) δ ppm: 9.42 (s, 1H), 8.52 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.45-7.51 (m, 2H), 7.01 (d, J=4.8 Hz, 1H), 6.64 (d, J=4.7 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 467.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][C:32]([F:35])([F:34])[F:33])=[C:12]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH2:20][C:19]5[C:25]([C:28]([NH2:30])=[O:29])=[N:26][NH:27][C:18]=5[C:17]=4[N:16]=3)[CH:13]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][CH2:44][Cl:45].O>CN(C=O)C>[Cl:45][CH2:44][CH2:43][N:27]1[C:18]2[C:17]3[N:16]=[C:15]([NH:14][C:12]4[CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=[CH:10][C:11]=4[O:31][C:32]([F:33])([F:35])[F:34])[N:24]=[CH:23][C:22]=3[CH2:21][CH2:20][C:19]=2[C:25]([C:28]([NH2:30])=[O:29])=[N:26]1
Reactant: ClCCBr
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3[nH]nc(C(N)=O)c3CC4)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCCl)CC4)c2)CC1
Yield: 96 %

Procedure:
A suspension of 8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (488 mg, 1.0 mmol) and Cs2CO3 (490 mg, 1.5 mmol) was suspended in DMF (1 mL) and treated with 1-bromo-2-chloro-ethane (0.1 mL, 1.2 mmol) at room temperature. After 2 h the reaction mixture was poured into water and filtered, washed with water and dried to give the title compound (529 mg, 96% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
5-{4-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.63) (0.35 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.22 g) which was subsequently deprotected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][OH:27]>C(O)C>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[NH:17])[NH:26][OH:27])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C#N)c1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(=N)NO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
To a solution of {tert-butoxycarbonyl-[3-cyanobenzyl]-amino}-acetic acid tert-butyl ester (3.5 g, 0.010 mol) in Ethanol (100 mL) under N2, was added hydroxylamine (1.66 mL, 0.0505 mol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford the title compound as a pale yellow viscous liquid (3.8 g, 99%). 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 7.53-7.56 (m, 2H), 7.29-7.33 (m, 1H), 7.24-7.26 (m, 1H), 5.76 (s, 2H), 4.37-4.39 (s, 2H), 3.74 (s, 2H), 1.35-1.37 (s, 18H). LC/MS (Method A): 380.0 (M+H)+. HPLC (Method B) Rt 5.91 min (Purity: 90.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[S:23](=[O:26])(=[O:25])[NH2:24])(=[O:12])=[O:11])=[C:4]([O:27][CH3:28])[CH:3]=1.[CH3:29]O>S(Cl)(Cl)=O>[CH3:29][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([NH:13][S:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:27][CH3:28])(=[O:12])=[O:11])=[C:15]([S:23](=[O:25])(=[O:26])[NH2:24])[CH:16]=1
Reactant: CO
Reactant: COc1cc(Cl)ccc1CCS(=O)(=O)Nc1ccc(C(=O)O)cc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NS(=O)(=O)CCc2ccc(Cl)cc2OC)c(S(N)(=O)=O)c1
Yield: 97 %

Procedure:
To a solution of 4-[2-(4-chloro-2-methoxy-phenyl)-ethanesulfonylamino]-3-sulfamoyl-benzoic acid (0.18 g, 0.40 mmol) in anhydrous methanol (15 mL), thionyl chloride (1 mL) was added and the mixture was heated at reflux for 18 hours. The volatiles were removed under reduced pressure to give 0.18 g (97% yield) of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:9]2[S:18][N:19]=[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-Hydroxy-3-phenyl-7-pyridin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 407.1 (M+1).