Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[N:19]([CH:24]1[CH2:26][CH2:25]1)[CH:18]=[C:17]([C:27]([OH:29])=[O:28])[C:16]2=[O:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[N:19]([CH:24]1[CH2:26][CH2:25]1)[CH:18]=[C:17]([C:27]([OH:29])=[O:28])[C:16]2=[O:30]
Reactant: CC(C)(C)OC(=O)NCCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Yield: 133.7 %

Procedure:
A solution of intermediate 11 (100 mg) in 10% TFA/DCM (1 mL) was stirred at room temperature for 2 h. The solvent was partially evaporated under reduced pressure. For five times the residual was diluted in DCM (2 mL) and concentrated under reduced pressure. Final solvent evaporation afforded the title compound (103 mg).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([OH:17])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O[C@@H]1CCCOC1
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1O[C@@H]1CCCOC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and (R)-tetrahydro-pyran-3-ol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.Cl.[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37].C(P(C#N)(CC)=O)C>ClCCl>[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH:37][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1cccc(N)c1C
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Yield: 25.4 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath for 3 hours. The mixture is washed with H2O, 1M NaCHO3, H2O, 1N HCl, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness under vacuum and the residue crystallized from dichloromethane-hexane to give 0.11 g of crystals, m.p. 239°-240° C.
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([Cl:22])=[O:21]>C(O)(C(F)(F)F)=O>[Cl-:22].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)=[O:21]
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) and 2,2-dimethylpropionic acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 74 mg (56%) of a white solid. M.p. 176-177° C. 1H NMR (CDCl3, TMS): δ 1.33 (s, 9H), 1.69-1.78 (m, 1H), 2.16-2.25 (m, 1H), 2.74-2.88 (m, 3H), 3.23 (dd, 1H), 3.57 (qui, 1H), 6.83 (dd, 1H), 6.89 (s, 1H), 6.93 (s, 1H), 7.16 (d, 1H), 8.85 (s, 1H), 14.38 (s, 1H), 14.47 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]3[CH2:20][C@@H:19]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH2:18][NH:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:29]1[N:30]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:29]1[N:30]([CH2:34][C:35]([N:17]2[CH2:18][C@H:19]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:20][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)=[O:15])=[O:36])[N:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccs2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccs2)CN1C(=O)Cn1nccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
A flask was charged with (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide (84 mg, 0.21 mmol), 2-(2H-1,2,3-triazol-2-yl)acetic acid (29 mg, 0.23 mmol), DIEA (0.5 mL, 2.9 mmol), HATU (81 mg, 0.21 mmol) and DMF (3 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 64, (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide (6.1 mg, 0.012 mmol, 6% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 9.15 (s, 1H), 7.72 (s, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.18-7.16 (m, 1H), 7.03-6.82 (m, 8H), 5.29 (s, 2H), 4.86 (d, J=8.0 Hz), 3.63-3.58 (m, 1H), 3.25-3.20 (m, 1H), 3.12 (dd, J=13.6, 4.8 Hz, 1H), 3.01-2.87 (m, 2H), 2.73 (dd, J=12.4, 5.2 Hz, 1H), 1.75-1.68 (m, 1H). MS (EI) for C26H24FN5O3S. found 506.2 (MH+).
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(Cc1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 77.4 %

Procedure:
A suspension of 9 mg of (Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-5-yl}-acrylic acid in 2 ml of methanol and 1 ml of dichloromethane and 6 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (2 h). The mixture was filtered, the filtrate evaporated and the residue was purified by HPLC (RP-18, CH3CN/H2O, gradient) to give 7 mg of the title compound as a colorless oil. MS: (M−H)− 403.3.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][C:55]([NH2:59])([CH3:58])[CH2:56][NH2:57]>CN(C=O)C>[NH2:59][C:55]([CH3:58])([CH3:54])[CH2:56][NH:57][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:18]
Reactant: CC(C)(N)CN
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (0.30 mmol), 145 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.45 mmol) and 122 mg of 4-methylmorpholine (1.20 mmol) were initially charged in 1.9 ml of DMF. 53 mg of 2-methylpropane-1,2-diamine (0.60 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 94 mg of the title compound (78% of theory).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[OH:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].ClCCl>CCOCC>[C:9]([C:8]1[CH:12]=[C:13]([S:1]([OH:3])(=[O:5])=[O:2])[CH:14]=[C:15]([OH:16])[C:7]=1[OH:6])([OH:11])=[O:10]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
Concentrated sulphuric acid (1 ml) and 2,3-dihydroxybenzoic acid (0.5 g) were heated at 60° C. for 1 hour. The mixture was cooled, taken up in ether (20 ml), poured into dichloromethane (200 ml) and cooled to give as crystals, 3-carboxy-4,5-dihydroxybenzenesulphonic acid (0.31 g); δ(DMSO-d6); 7.34(d,1H); 7.61(d,1H). To a suspension of this acid (1 g) in acetonitrile (10 ml) was added triethylamine (2.4 ml), followed by isobutyryl chloride (1.5 ml). The solution was stirred at room temperature for 1 hour, the solvent was evaporated and the residue purified by chromatography on Diaion HP 20 SS resin (aqueous methanol containing 1% acetic acid) to give 3-carboxy-4,5-di-isobutyroxybenzene sulphonic acid (1.2 g); δ(DMSO-d6): 1.19(s,6H); 1.27(s,6H); 2.90-3.15(m,2H); 7.63(d,1H); 8.04(d,1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:17][CH2:18][N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][N:19]3[C:20](=[O:30])[CH2:21][C:22]4([CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:27][C:28]3=[O:29])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: COc1ccc(F)cc1C1CCNCC1
Product: COc1ccc(F)cc1C1CCN(CCN2C(=O)CC3(CCCC3)CC2=O)CC1
Temperature: 165 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
A mixture of 4-(5-fluoro-2-methoxyphenyl)piperidine (20 mg, 0.096 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 165° C. for 1 hour. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (2.6 mg, 0.0065 mmol, 7%): ESI-MS m/z 403 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([C:23](Cl)=[O:24])[CH2:20][C:19]1([F:22])[F:21]>[Cu]Br.C1(C)C=CC=CC=1>[F:21][C:19]1([F:22])[CH2:20][C:18]1([C:23]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:24])[CH3:17]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cu]Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C(=O)C#Cc2ccc(Cl)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
13.7 g (0.1 mol) of p-chlorophenyl-acetylene are added to a mixture of 10.1 g (0.1 mol) of triethylamine, 1.4 g (0.01 mol) of copper(I) bromide and 55 ml of toluene, and the mixture is stirred for 30 minutes at room temperature under argon. After the reaction mixture has been heated to 55° C., 15.5 g (0.1 mol) of 1-methyl-2,2-difluorocyclopropanecarbonyl chloride are added dropwise. After this, the mixture is stirred for 8 hours at 90° C., and then cooled and filtered. The filtrate is washed with dilute aqueous hydrochloric acid and water in succession and concentrated under reduced pressure. 19.2 g of a dark oil remain which is distilled using a bulb tube. A yellow oil, which solidifies on standing, distils over at 0.1 mbar and a jacket temperature of 120° C. 8.4 g (33% of theory) of 2-(4-chlorophenyl)-ethin-1-yl 2,2-difluoro-1-methyl-cycloprop-1-yl ketone of melting point 67°-68° C. are obtained. ##STR54##
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[I:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(I)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 68 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-iodobenzenesulfonyl chloride under the conditions used in example 2 giving 68% of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Yield: 73 %

Procedure:
The title compound (73 mg, 73%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine and acetic anhydride similarly to the procedure used for example 166. 1H NMR (400 MHz, CDCl3) δ 1.31-1.34 (m, 3H), 1.48-1.53 (m, 5H), 1.82-1.85 (m, 4H), 1.99 (s, 3H), 2.02-2.07 (m, 4H), 2.13-2.17 (m, 4H), 2.28 (s, 2H), 2.58-2.64 (m, 4H), 2.70 (t, 2H), 3.20 (t, 2H), 3.41-3.43 (m, 2H), 4.01 (t, 2H), 6.83 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 428.3264 [MH]+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[S:10](=[O:12])(=[O:11])[C:4]=2[CH:3]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Li]CCCC.Cl>C1COCC1>[C:16]([O:15][C:13]([N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:20]=[CH:21][C:2]([B:22]([OH:27])[OH:23])=[CH:3][C:4]=2[S:10]1(=[O:12])=[O:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2S1(=O)=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2S1(=O)=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product obtained in Step F above (21.6 g, 57.3 mmol) and 40 ml of triisopropyl borate in 210 ml of THF, cooled to −65° C. and under N2, there are added dropwise 90 ml (143 mmol) of 1.6M nBuLi solution. The reaction mixture is stirred for 1 hour at −65° C. and allowed to return to ambient temperature. After stirring for 1 hour, the solution is cooled in an ice bath and hydrolysed by adding 320 ml of 0.5M HCl solution. After extracting 3 times with CH2Cl2, the organic phase is washed with brine, dried over MgSO4 and evaporated. The residue is taken up in heptane and, after evaporation, is triturated in heptane and filtered to yield the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:4])=[O:3].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1ccccc1C(=O)Cl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccccc2S(C)(=O)=O)sc1C(=O)NCc1ccccc1
Yield: 9 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-methanesulfonylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 9% yield; m.p. 239-242° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.64 (t, J=5.8 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.33-7.19 (m, 6H), 4.38 (d, J=5.8 Hz, 2H), 3.26 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([NH2:9])[N:3]=1.[Cu][C:11]#[N:12]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:11]#[N:12])[CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc(N)nc(N)c1
Temperature: 230 °C
Yield: 74 %

Procedure:
A mixture of 1.00 g 2.6-diamino-4-bromopyridine and 0.992 g copper(I)cyanide in 10 ml dimethylformamide was heated under microwave irradiation to 230° C. for 1000 sec. The resulting mixture was partitioned between 10% aqueous ammonium chloride and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were washed with water and brine, dried over magnesium sulfate dihydrate and evaporated. The solid residue was dissolved in hot ethyl acetate and passed through a filter. To the clear mother liquor was added heptane until crystallization started. The mixture was cooled to room temperature and the crystals were collected by filtration to yield 0.528 g of the title compound as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.CC([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:39]2[CH2:40][CH2:41][CH:37]([C:34]3[CH:35]=[CH:36][C:31]([CH2:30][NH2:26])=[CH:32][CH:33]=3)[CH2:38]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: NCc1ccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)cc1

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.95 g, 3.2 mmol) and 1,1 dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (0.75 g) as a yellow solid, mp 225°-227° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:4]([CH2:17][CH3:18])[N:3]=1
Reactant: CCI
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)c2ccccc2)c(N)n1
Reaction time: 1 h

Procedure:
To a vigorously stirring solution of (3-amino-1H-pyrazol-4-yl)-phenyl-methanone (0.1 g, 0.53 mmol) in dry DMF at RT is added sodium hydride (0.023 g, 0.57 mmol). After 1 h, ethyl iodide (0.042 mL, 0.53 mmol) is added and stirring is continued for 4 h. The reaction mixture is diluted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate. The organic filtrate is concentrated and the crude is chromatographed on silica gel using 50% ethyl acetate in hexanes to provide (3-amino-1-ethyl-1H-pyrazol-4-yl)-phenyl-methanone.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1C=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:26])=[O:27])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: NCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluoroctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.12 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:3]=1.C(OC([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)=O)(C)(C)C>>[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:3]=1
Reactant: COc1cc(C(=O)c2cc(I)ccc2NC(C)=O)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: COc1cc(C(=O)c2cc(-c3ccc[nH]3)ccc2NC(C)=O)cc(OC)c1OC

Procedure:
In the same manner as in the synthesis of Compound 457, Compound 19 shown in Reaction 5 and (1-(tert-butoxycarbonyl)-1H-pyrrole-2-yl)boronic acid were subjected to the Suzuki reaction to obtain N-(4-(1H-pyrrole-2-yl)-2-(3,4,5-trimethoxybenzoyl)phenyl)acetamide. Thus obtained N-(4-(1H-pyrrole-2-yl)-2-(3,4,5-trimethoxybenzoyl)phenyl)acetamide (20 mg, 0.05 mmol) was dissolved in methanol (3 ml), and NaOMe (30 μl, 0.5 mmol, 1.0 M/tetrahydrofuran) was added thereto at room temperature. The mixture was refluxed with stirring for 3 hours at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature, and diluted with an EtOAc solution. The organic layer was washed with water, and brine. The extracted organic layer was dried over anhydrous MgSO4, and the solid substance was filtered off. The filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=2/1→1/2) to obtain Compound 597 (8 mg, 45%) in a form of a yellow solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C[O:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([N+:31]([O-])=O)[CH:30]=1)[C:16]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].CCO>[Pd].CN(C=O)C>[OH:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([NH2:31])[CH:30]=1)[C:16]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17]
Reactant: O=C(NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cc(O)cc(C(=O)NNC(=O)c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
A mixture of 1-{3-[(2-naphthyl)methoxy]-5-nitrobenzoyl}-2-benzoylhydrazine (0.34 g, 0.77 mmol), Pd/C (10%, 0.35 g), EtOH (10 mL), and DMF (10 mL) was hydrogenated in Parr apparatus (H2 pressure—30 psi) at room temperature for 1.5 h. Catalyst was filtered off, and filtrate concentrated in vacuo to give a slurry of white needles, which were filtered and washed with EtOH (3×25 mL). Yield 0.20 g (96%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.37 (s, 1H); 10.12 (s, 1H); 9.20 (s, 1H); 7.91 (d, J=7.0 Hz, 2H); 7.62-7.48 (m, 3H); 6.54 (s, 1H); 5.46 (s, 1H); 6.19 (s, 1H); 5.18 (br.s, 2H).