Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[F:9][C:10]1([F:24])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:24][C:10]1([F:9])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC(F)(F)C1
Reactant: Fc1ccc(I)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2)CC(F)(F)C1
Yield: 11.6 %

Procedure:
To a toluene solution (2.0 mL) of 1-fluoro-4-iodobenzene (62.6 mg, 0.282 mmol), tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (100 mg, 0.423 mmol), cesium carbonate (184 mg, 0.564 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23.3 mg, 0.0423 mmol), and palladium acetate (II) (6.30 mg, 0.0282 mmol) were added and the resultant mixture was stirred under nitrogen atmosphere at 110° C. for 4 hours. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain a compound (10.2 mg, yield 11%) in Reference Synthesis Example 260 and a compound (6.30 mg, yield 7%) in Reference Synthesis Example 261 as the title compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10])#[N:33]
Reactant: N#Cc1ccccc1CBr
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccccc2C#N)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and alpha-bromo-o-tolunitrile. MS (M−H, 435.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.664 (s, 2H), 4.348 (s, 2H), 4.498 (s, 2H), 6.728 (d, 2H, J=8.4 Hz), 7.036 (d, 2H, j=8.4 Hz), 7.352 (t, 2H, J=9.2 Hz), 7.548 (t, 1H, J=7.6 Hz), 7.640 (d, 1H, J=7.6 Hz), 8.003 (d, 2H, J=8 Hz), 8.139 (d, 2H, J=8.4 Hz), 13.559 (s, broad, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([C:42](F)(F)[F:43])=[N:20][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:22]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([CH2:42][F:43])=[N:20][NH:21][CH:22]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccnc3ccc(-c4c[nH]nc4CF)cc23)CC1
Yield: 52.8 %

Procedure:
123 mg 4-(4-methylpiperazin-1-yl)-6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 170 and 0.7 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 35 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:9]2)=[O:5].C(N(CC)CC)C.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1.C(Cl)(Cl)Cl>C1COCC1>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:28]([C:25]1[CH:26]=[CH:27][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:23][CH:24]=1)=[O:29])[CH2:9]2)=[O:5]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(C(=O)c1ccc(-c3ccccc3)cc1)C2
Yield: 85.1 %

Procedure:
2,3-Dihydro-1H-isoindole-5-carboxylic acid methyl ester compound with hydrobromic acid (0.80 g), triethylamine (1.30 mL) and biphenyl-4-carbonyl chloride (0.67 g) are stirred in THF (35 mL) at ambient temperature. After 1.5 h the mixture is treated with CHCl3 washed, dried and evaporated until a solid starts to separate. The product is fully crystallized by adding heptane. 0.94 g of the title compound is obtained with MP 172-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.C(O)(=O)C.[OH:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O>CN(C=O)C>[OH:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[C:7]1[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]1=[O:1]
Reactant: Oc1cc(O)nc(S)n1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(O)cc1O
Temperature: 80 °C
Reaction time: 0.02 h

Procedure:
To a solution of 0.144 9 (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine and 2 ml of acetic acid in 2 ml of DMF was added a solution of 2,4-dihydroxybenzaldehyde (1 mmol) in 2 ml of DMF. The suspension was heated to 80° C. under nitrogen for 16 hours. Upon cooling to room temperature, the reaction was poured into water and the precipitate collected by filtration. The crude product was washed with water, and the solid boiled in methanol for 1 minute. Filtration provided 2.6 mg of product.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([CH3:36])[N:29]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[N:31]=[C:30]([CH3:36])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:16])=[O:17])=[O:25])[N:33]=1
Reactant: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cc2nnc(SC)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
By the procedure of Example 4, 0.3 g of the sulfonamide prepared in Example 3 was reacted with 0.29 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.15 g of "DBU" in 10 ml of p-dioxane. After stirring two hours at room temperature the solution was diluted with about 75 ml of water and acidified with concentrated hydrochloric acid (red to litmus paper). Following filtration, the residue was washed with water (2×20ml) then with ether (1×20ml) and suction-dried to give 0.15 g of the subject compound; m.p. 140°-146° C. NMR (CDCl3): δ2.6(d,6H,SCH3, OCH3); 4.1 (S, 3H, CH3); 4.9(S, 2H, CH2); 7.4-7.7(m, 4H, Ar+NH); 8.3(d, 1H, Ar).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[CH3:19][C:20]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)([CH3:30])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:34]1[CH:33]=[CH:32][C:31]([C:20]([CH3:30])([CH3:19])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 31.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (200 mg, 0.62 mmol) was reacted with tert-butyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (350 mg, 0.93 mmol) to afford the desired product (95 mg, 62%) as a brown solid: ESI MS m/z 493 [C28H32N2O4S+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44]>C(Cl)Cl.O>[CH2:46]([O:45][C:43]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7](=[O:8])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=1)(=[O:26])=[O:25])=[O:44])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 3-[3-(2-imidazol-1-ylacetyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (50.5 mg, 0.110 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.22 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. CH2Cl2 (30 mL) was added to the residue and this was washed with water. The organic phase was dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (52.4 mg, 0.495 mmol), water (2 mL) and butyl chloroformate (34.3 μL, 0.270 mmol), and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound as a white solid in 32% yield, over two steps, (18 mg, 0.036 mmol).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8]OC1C(OC)=CC(I)=CC=1C=O)(C)(C)C.C([Si](C)(C)OCCOC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si](N[Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.[CH2:62]([N:64](CC)CC)C.C(Cl)(=O)C>>[CH3:1][Si:5]([CH3:22])([CH3:21])[O:6][C:7](=[CH2:8])[N:64]=[CH2:62]
Reactant: CCN(CC)CC
Reactant: COc1cc(I)cc(C=O)c1OCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde (4.58 g, 11 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.18 mL, 11 mmol), n-butyllithium (2.5 M, 4.2 mL, 11 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give crude 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][CH2:12][C:13]1[C:25](Cl)=[CH:24][C:16]([C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=1)[CH2:8]2.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Cl>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][CH2:12][C:13]1[C:25]([CH:28]3[CH2:30][CH2:29]3)=[CH:24][C:16]([C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=1)[CH2:8]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(COC2C3CC4CC(C3)CC2C4)cc1F
Temperature: 100 °C
Yield: 62.6 %

Procedure:
To a solution of 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamide (0.30 g, 0.72 mmol), cyclopropylboronic acid (0.40 g, 4.65 mmol) and potassium phosphate (2.55 g, 12.00 mmol) in toluene (10 mL) and water (0.5 mL) was bubbled with a nitrogen atmosphere for 10 min, tricyclohexylphosphine tetrafluoroborate (0.17 g, 0.48 mmol) and palladium acetate (0.05 g, 0.22 mmol) was added to this reaction mixture. The reaction mixture was heated to 100° C. for 18 h under a nitrogen atmosphere and then cooled to ambient temperature. 5% aqueous hydrochloric acid (20 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3), the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (10% to 30% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (0.19 g, 62%): 1H NMR (300 MHz, CDCl3) δ 8.81 (br s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.40 (d, J=13.5 Hz, 1H), 4.71 (s, 2H), 3.60 (br s, 1H), 3.41 (s, 3H), 2.16-2.03 (m, 4H), 1.90-1.51 (m, 11H), 0.97-0.90 (m, 2H), 0.68-0.62 (m, 2H); MS (ES−) m/z: 420.35 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[O:12].C[Si]([N:17]=[N+:18]=[N-:19])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]1[C:11](=[O:12])[NH:19][N:18]=[N:17]1
Reactant: Cc1cc(N=C=O)c(Cl)cc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: Cc1cc(-n2nn[nH]c2=O)c(Cl)cc1Cl
Yield: 27.3 %

Procedure:
In the manner of Example 1, Step A, the reaction of 3.4 g (0.016 mole) of 2,4-dichloro-5-methylphenyl isocyanate and 3.6 g (0.031 mole) of trimethylsilyl azide produced 1.07 g of 1-(2,4-dichloro-5-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, mp 135°-137° C.
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:8]=1)(C)(C)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.FC(F)(F)C(O)=O.ClCCl>[CH2:24]([N:13]([S:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:5])=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2cccnc2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A solution of 3-(Pyridine-3-sulfonylamino)-benzoic acid tert-butyl ester (99 mg, 0.3 mmol), benzyl bromide (39 μL, 0.32 mmol) and Cesium Carbonate (145 mg, 0.4 mmol) in dimethylformamide (5 ml) was stirred for 16 hrs. The reaction was diluted with ethyl acetate (50 ml) and washed with water (6×100 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was dissolved in trifluoroacetic acid/dichloromethane (1:5 v/v) (10 ml), stirred for 3 hrs and then concentrated in vacuo to afford the title compound as a white solid (58.7 mg). HPLC retention time 4.31 min. Mass spectrum (APCI+) m/z 369 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 46.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.25 g, 0.53 mmol) obtained in step 2 and ethanesulfonamide (0.32 g, 2.63 mmol), the title compound (0.14 g, 47%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N)cc1O
Temperature: 0 °C

Procedure:
4-Amino-5-chlorosalicylic acid (24 g) is added to a stirred solution of thionyl chloride (30 ml) in methanol (300 ml) cooled to 0° C., and the mixture is stirred under reflux for 18 hours. The reaction mixture is evaporated and the residue is recrystallized from EtOH-H2O to give methyl 4-amino-5-chlorosalicylate which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: Oc1ccc2c(c1)C[C@@H](NC[C@@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Yield: 67.5 %

Procedure:
(2S)-2-(4-Benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (2.50 g) was dissolved in tetrahydrofuran (31 ml), and borane-dimethyl-sulfide complex (1.76 ml) was added to the solution. After the mixture was heated under reflux for 4 hours, a solution of triethanolamine (4.62 g) in tetrahydrofuran (4.6 ml) was added to the reaction mixture and the mixture was heated under reflux for 11 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate/ethanol=7/1) gave (1S)-1-(4-benzyloxy-phenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethanol (1.63 g) as an amorphous.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH:19]4[CH2:21][CH2:20]4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH:19]4[CH2:21][CH2:20]4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(C3CC3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCCC1)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide (94 mg, 0.23 mmol) was dissolved in CH2Cl2 (0.9 mL). Trifluoroacetic acid (0.7 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (0.9 mL) and ethylenediamine (0.9 mL) was added. The reaction mixture was stirred at room temperature for 2 h then H2O and EtOAc were added. The resultant suspension was filtered, rinsing with H2O and EtOAc and dried under high vacuum to afford 55 mg (85%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide as a white solid. MS: (M+H)+=285; mp>300.0.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([CH3:18])[C:13](=O)[NH:14]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:12]([CH3:18])=[N:11][C:10]2[C:15]([N:14]=1)=[CH:16][C:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[CH:8][CH:9]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(Cn3ccnc3)cc2[nH]c1=O
Product: Cc1nc2ccc(Cn3ccnc3)cc2nc1Cl
Reaction time: 2 h
Yield: 59.4 %

Procedure:
A mixture of 6 parts of 7-(1H-imidazol-1-ylmethyl)-3-methyl-2(1H)-quinoxalinone and 40 parts of phosphoryl chloride was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated to dry. The residue was taken up in 300 parts of ice water and the whole was neutralized with potassium carbonate. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.6 parts (59.4%) of 3-chloro-6-(1H-imidazol-1-ylmethyl)-2-methylquinoxaline; mp. 115.8° C. (comp. 22).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([CH:28]([CH2:30][CH3:31])[CH3:29])[CH:21]=2)=[C:14]([Cl:32])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:28]([CH2:30][CH3:31])[CH3:29])[CH:21]=2)=[C:14]([Cl:32])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(O)c(C(C)CC)c2)c(Cl)c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of {[4-(3-sec-butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (0.8 g, 1.6 mmol) in CH2Cl2 (16 mL) was cooled to −60° C. under nitrogen atmosphere. To that 1M BBr3 solution (4.8 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25° C. over 5 h. then diluted with more CH2Cl2 (25 mL) and quenched with H2O. After stirring at 20-25° C. for 30 min, organic phase was separated, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (Hexane:Ethylacetate 90:10) to afford the pure product {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (0.77 g, 99% Yield)