Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Brc1ccc2ccccc2c1
Product: COc1ccc(-c2ccc3ccccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (0.31 g, 1.50 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.31 g, 1.80 mmol) according to method A to yield 0.30 g (79%) of a white solid: mp 108-110° C.; 1H NMR (CDCl3): δ (3.96, 3H, s), 7.04-7.10 (1H, m), 7.43-7.52 (4H, m), 7.68 (1H, dd, J=1.81 Hz, J=8.57 Hz), 7.84-7.92 (3H, m), 7.97 (1H, d, J=1.05 Hz).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:32])=[O:31])=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(N)(=O)=O)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(=O)(=O)NC(=O)CCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 390 mg (1.00 mmol) of 3-heptyloxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 9 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 412 mg (yield: 84.4%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[Cl:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:5]=1[Cl:11]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
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: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To the mixture of 2,6-dichloro-nicotinic acid methyl ester (4.0 g, 19 mmol) synthesized in Example 23 and tetrahydrofuran (39 ml), phenyl boronic acid (2.5 g, 19 mmol), potassium carbonate (8.0 g, 58 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 0.97 mmol) were added, and the obtained reaction mixture was stirred for 16 hours while being heated to reflux. The reaction mixture was cooled to room temperature, and then insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, and then water and ethyl acetate were added to the obtained residue, followed by extraction. The organic layer and the aqueous layer were separated, and the aqueous layer was further extracted using ethyl acetate. The organic layers were mixed, washed with saturated saline, and dried using anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=10:1 to 3:1). The obtained crude compound was recrystallized using the mixed solvent of heptane-diethyl ether, thereby obtaining the entitled compound (2.2 g, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[C:17]([O:25][C:26]([F:29])([F:28])[F:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([CH:33]1[CH2:38][N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:36][CH2:35][NH:34]1)(=[O:32])[NH2:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:29][C:26]([F:28])([F:27])[O:25][C:17]1[CH:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[CH2:21][C:22]([N:34]1[CH2:35][CH2:36][N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:38][CH:33]1[C:30](=[O:32])[NH2:31])=[O:24]
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OC(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid (0.50 g, 1.15 mmol) from Step 9 above and 2-carbamoyl-4-(2-methyl-phenyl)piperazine (0.28 g, 1.1 mmol) from Step 4 of Example 1 in DMF (20 mL) was added HOBT (0.175 g, 1.15 mmol), EDC (0.53 g, 1.8 mmol), and DIEA (0.26 mL, 1.5 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (75 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure to give 1-(1-(2-trifluoromethoxy-4-(N-tert-butyoxycarbonyl-4-piperidinyloxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine as an amorphous solid (HPLC retention time=11 min (method A); TLC Rf =0.5 (7:3 EtOAc:hexanes).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.CN1CCOCC1.[O:42]1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=[O:48]>C1COCC1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:43]([OH:48])=[O:42])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)O1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCC(=O)O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
A mixture of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) and 4-methyl-morpholine (300 mg, 30.0 mmol) in THF (3 mL) was treated with dihydro-furan-2,5-dione (250 mg, 2.50 mmol) and heated at 120° C. under microwave irradiation for 4 hrs and then thermally at 60° C. for four days. The crude reaction mixture was purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM. The fractions containing product were concentrated in vacuo affording the title compound as a colorless glass which solidified in a white solid by standing (182 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]#[N:22])=[C:4]([CH:3]=1)[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(Cl)ccc1OCC#N
Reaction time: 48 h

Procedure:
To a solution of 25.0 grams of 4-chloro 2-acetamidophenol (0.135 mole) in 500 ml of acetone is added 18.7 grams of potassium carbonate (0.135 mole). To the resulting suspension is added 10.20 grams of chloroacetonitrile (0.135 mole). The suspension is stirred for 48 hours at reflux. The reaction mixture is then filtered and the solvent removed under reduced pressure to yield a dark solid residue. Recrystallization of the residue from methylene chloride-petroleum ether (1:1) followed by recrystallization twice more from methanol yields refined 5'-chloro 2'-(cyanomethoxy) acetanilide mp; 146°-149° C.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:12]([CH3:26])[C:11]3[C:10]([OH:27])=[CH:9][CH:8]=[C:7]([F:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43]>O>[CH3:45][O:44][C:42](=[O:43])[CH2:41][O:27][C:10]1[CH:9]=[CH:8][C:7]([F:28])=[C:6]2[C:11]=1[C:12]([CH3:26])=[C:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:5]2
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.040 g), potassium carbonate (0.044 g) and N,N-dimethylformamide (0.21 mL) was treated with methyl bromoacetate (0.011 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), extracted with ethyl acetate (3×10 mL), and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume) to afford the title compound as a yellow oil (0.034 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:16]
Reactant: Cc1cccnc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncccc1C
Temperature: -20 °C

Procedure:
3-Methyl-pyridine-2-carboxylic acid (1 g, 7.29 mmol) was dissolved in EtOH (50 mL) and cooled to −20° C. Thionyl chloride (1.1 mL, 14.6 mmol) was added, and the resulting white suspension was refluxed for 5 h, then concentrated to dryness. Water (10 mL) was added and solid Na2CO3 was added to neutralize the solution. The resulting mixture was extracted with ether. The organic layer was dried over MgSO4, and the solvent was removed by distillation to give 1.25 g of the title compound as an oil. 1H NMR (CDCl3, 200 MHz): δ=8.54 (d, 1H, J=3.9 Hz), 7.59 (d, 1H, J=7.8 Hz), 7.26-7.40 (m, 1H), 4.45 (q, 2H, J=7.0 Hz), 2.59 (s, 3H), 1.45 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:21](=[O:32])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19]>C(OCC)(=O)C>[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][C:24]([NH:23][C@@H:22]1[C:21](=[O:32])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:12]([CH2:11][O:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:13][S:14][C@H:15]12)=[O:31]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Reaction time: 0.67 h

Procedure:
Trichloroacetylisocyanate (4.3 ml) was added rapidly to a stirred suspension of (6R,7R)-3-hydroxymethyl-7-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (10.62 g) at 6° in ethyl acetate (70 ml). The reaction mixture was stirred at 5° for 40 min. Petroleum ether was added dropwise during 15 min. The mixture was stirred for 30 min, filtered and the solid was washed with petroleum ether and dried to give the title compound as a solid (16.48 g), [α]D22 +73° (c 1.2 in Me2SO).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH2:29][C:30]#[N:31]>C1COCC1>[C:30]([CH2:29][CH2:28][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)#[N:31]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#CCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCC#N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of ethyl N-Boc-piperidine-4-carboxylate (10.0 g, 38.86 mmol) in THF (200 mL) was added LDA (2 M solution in Hexane, 38.86 mL, 77.72 mmol) at −78° C. and stirred for 30 min. 3-bromo propionitrile (6.25 g, 46.63 mmol) was then added at −78° C. The resulting reaction mixture was stirred at −60° C. for 4 h and quenched with saturated NH4Cl solution. Ethyl acetate was added and the organic layer was extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using 10% ethyl acetate in hexane to yield the title compound as a pale yellow liquid (5.0 g, 40%). [1H-NMR (DMSO-d6, 300 MHz): δ 4.15 (q, 2H), 3.78-3.54 (m, 2H), 2.93-2.72 (m, 2H), 2.43 (t, 2H), 2.02-1.78 (m, 4H), 1.45-1.29 (m, 11H), 1.22 (t, 3H); HPLC RtA=4.703 min (93%); LCMS RtA=1.881, [M+H-Boc]+=211.1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N#N.[CH:33]([N:36]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[N:37]1)([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15]1[CH:16]=[C:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:39]4[CH:38]=[N:37][N:36]([CH:33]([CH3:35])[CH3:34])[CH:40]=4)[CH:3]=[C:4]3[N:10]=[CH:9]2)[CH:12]=[C:13]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:14]=1
Reactant: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reactant: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C(C)C)c4)cnc32)c1
Yield: 52.1 %

Procedure:
A solution of N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide (0.2 g, 0.405 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N2 bubbling for 5 min. 1-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.191 g, 0.810 mmol, 2.0 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.032 g, 0.040 mmol, 0.1 eq.) and aqueous sodium carbonate (0.17 g, 1.012 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to yield the product in 52.1% yield (0.11 g). 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.94 (s, 1H), 8.75 (d, 1H), 8.44-8.42 (dd, 2H), 8.05 (s, 1H), 7.95 (s, 1H), 7.77-7.70 (m, 2H), 7.48-7.43 (m, 2H), 7.30-7.26 (m, 1H), 4.54-4.51 (m, 1H), 4.13-4.11 (m, 1H); 3.28-3.26 (m, 2H), 3.17-3.16 (d, 1H), 1.48-1.46 (d, 6H), 1.28-1.25 (t, 3H), LC-MS (ESI): Calculated mass: 522.57 Observed mass: 523.0 [M+H]+ (rt: 1.52 min).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:51][OH:52])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([CH:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]5)=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH:38]5[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]5)=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[C:18]=1[CH2:51][OH:52])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Yield: 65.6 %

Procedure:
tert-butyl 4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (85 mg, 120 μmol) was deprotected by treatment with 50% trifluoro acid in dichloromethane (10 mL) for 2 hr. The reaction mixture was concentrated to dryness, then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting crude product was further purified by crystallization from hot isopropylacetate/hexanes. A crystalline product was collected by filtration, providing the desired product as a white solid (48 mg, 65.7%). (M+H)+=610 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.63 (s, 1H), 8.27-8.33 (m, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.44-7.72 (m, 6H), 6.94 (d, J=8.5 Hz, 1H), 4.46 (s, 2H), 3.88-3.96 (m, 3H), 3.35-3.44 (m, 2H), 2.85-2.99 (m, 2H), 2.65-2.78 (m, 1H), 1.83-1.97 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(Oc2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)CC1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 1-(4-hydroxy-piperidin-1-yl)-ethanone in analogy to Example 9c): MS (ISP): 521.2 and 523.2 (M+H)+; MS (ISN): 519.1 and 521.2 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[N-:26]=[N+:27]=[N-:28].[Na+].C(OCC)C>CS(C)=O>[N:26]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[N+:27]=[N-:28]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN=[N+]=[N-])ccc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 93.5 %

Procedure:
To a solution of 600 mg of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-24-b in 4 ml dimethyl sulfoxide was added 162 mg of sodium azide, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 25 ml of diethyl ether. The mixture was sequentially washed with water (×3) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 571 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18]C=O)[C:15]([F:21])=[CH:14][C:13]=1[F:22])[CH:9]=[C:8]([C:23]([O:25]CC)=[O:24])[C:7]2=[O:28].Cl>C(O)(=O)C>[NH2:18][C:16]1[CH:17]=[C:12]([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:29])=[C:3]([F:30])[C:2]=3[Cl:1])[C:7](=[O:28])[C:8]([C:23]([OH:25])=[O:24])=[CH:9]2)[C:13]([F:22])=[CH:14][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Yield: 89.1 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(2,4-difluoro-5-formylaminophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.8 g) was added to 5 ml of hydrochloric acid and 20 ml of acetic acid. The solution was heated at reflux for 3 hours. The reaction solution was allowed to cool down and concentrated in vacua, and ethanol was added to the residue. The solid was collected by filtration and washed with diethyl ether to give 1.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[Br:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Br)ccc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,4-dibromonitrobenzene and dimethyl sulfoxide, ethyl 2-(5-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[C:40]([F:42])[CH:41]=[C:36]([Cl:35])[CH:37]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)cc(Cl)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chloro-5-fluorophenylboronic acid.