Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([CH3:20])[CH3:19])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
A reaction mixture solution prepared by suspending 2.18 g of 4-bromo-2-nitrophenol and 2.07 g of potassium carbonate in 40 mL of dimethylformamide and adding 2.04 g of isopropyl iodide was heated under stirring at 110° C. for 14 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene. (2) A suspension was prepared by adding 1.05 g of potassium hydrogen carbonate, 22 mg of palladium chloride (II) and 102 mg of a copper bromide (I) dimethylsulfide complex to 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene obtained above, followed by suspending the mixture in 15 mL of toluene. Subsequently, a reaction mixture solution prepared by adding 1.02 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 46.2 μL of isobutyric acid and 114 mg of di-t-butylcyclohexylphosphine to the suspension was heated at 120° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was celite-filtered to remove insoluble matter, water was added to the filtrate, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 1.38 g of ethyl 4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]2.[CH3:25][S:26]SC.Cl>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[C:17]([S:26][CH3:25])=[CH:16]2
Reactant: CSSC
Reactant: Cc1ccc2cc(C=O)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cc2cc(C)ccc2cc1C=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
A 200 ml three-neck flask equipped with a dropping funnel was heated and dried, and air in the flask was replaced with nitrogen. N,N,N′-trimethyldiamine (1.22 ml, 9.6 mmol) and anhydrous THF (40 ml) were added into the flask and cooled down to −30° C. A butyllithium hexane solution (1.57 M, 6.14 ml, 9.6 mmol) was added thereto and stirred for 15 minutes. The temperature in the flask was brought back to −20° C., and an anhydrous THF (40 ml) solution of 6-methyl-2-naphthaldehyde (1.0 g, 5.9 mmol) was slowly dropped therein and stirred for 15 minutes. Further, after a butyllithium hexane solution (1.57 M, 11.2 ml, 0.017 mol) was added therein and stirred for 3.5 hours, dimethyldisulfide (2.6 ml, 0.029 mol) was added. The temperature was increased to a room temperature, and an obtained solution was stirred for 2 hours. Then, 1 M hydrogen chloride was added to stop the reaction, an obtained reaction solution was extracted with methylene chloride, and an organic layer was dried with anhydrous magnesium and filtrated. A filtrate was concentrated by use of a rotary evaporator. A residue was purified by silica gel column chromatography by use of a mixture solvent of hexane and ethyl acetate (hexane:ethyl acetate=9:1) as a mobile phase, so as to obtain 6-methyl-3-methylthio-2-naphthaldehyde (386 mg, 1.8 mmol, 30%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)CCC>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.C1(C)C=CC=CC=1>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccco2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (1.13 g, 4.0 mmol), 2-(tributylstannyl)furan (1.71 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL of toluene is heated under argon at reflux of 30 min. The reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark oil. Purification by flash column chromatography on silica gel (1% ethyl acetate-hexane) yields about 0.47 g (43%) of the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:24])=[CH:3][CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6](=[O:20])[CH:5]1C(O)=O>C(C(C)=O)C(C)C>[F:24][C:2]([F:1])=[CH:3][CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6](=[O:20])[CH2:5]1
Reactant: COc1ccc(CN2CC(C=C(F)F)C(C(=O)O)C2=O)c(OC)c1
Solvent: CC(=O)CC(C)C
Product: COc1ccc(CN2CC(C=C(F)F)CC2=O)c(OC)c1
Temperature: 116 °C

Procedure:
A suspension of (K) in methyl isobutyl ketone (MIBK-5 L) is heated at 116° C. overnight. Evaporation of the solvent gives 564 g of (IIIc). The product is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+]([O-])=O)[CH:14]=[N:13][CH:12]=2)[C:4]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[O:24][C:19]3[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=3)=[CH:14][N:13]=[CH:12][C:11]=4[C:5]=2[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cncc3cccc([N+](=O)[O-])c23)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1OC)Oc1cccc3cncc-2c13
Temperature: 80 °C

Procedure:
Phenol 5 (4.65 g, 0.014 mol) was dissolved in 100 ml of dry N,N-dimethylformamide. The solution was degassed with argon for thirty minutes. Potassium carbonate (5.80 g, 0.042 mol) was added to the yellow solution in one portion. After heating at 80° C. for one hour, the mixture had turned brown and no more starting material remained. After the solution was cooled to room temperature, 200 ml of water was added. The aqueous layer was extracted with dichloromethane (3×500 ml), this organic extract was washed with water (3×500 ml), dried (Na2SO4), and concentrated. A white powder (3.65 g 92%) was obtained that was used in the next reaction without further purification. An analytical sample was recrystallized from ethyl acetate:hexane: mp 195-196° C.; 1H NMR: (300 MHz, CDCl3): 9.02 (s, 1H); 8.82 (s, 1H); 7.87 (d, 1H, J=8.7 Hz); 7.62 (m, 3H); 7.32 (dd, 1H, J=6.0, 1.5 Hz); 6.95 (d, J=9.6 Hz); 3.88 (s, 3H); 3.82 (s, 3H). CIMS m/z: 280 (M+H+, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-])=O>CC(O)=O.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1

Procedure:
tert-Butyl 5-nitropyridin-2-ylcarbamate (750 mg, 3.14 mmol) was suspended in AcOH at RT with vigorously stirring. Zinc (2051 mg, 31.4 mmol) was added slowly (exothermic reaction). The mixture was stirred at RT for 20 min, and filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated to give tert-butyl 5-aminopyridin-2-ylcarbamate: LC/MS: [(M+1-56)]+=154.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:37][CH:38]=2)=CC=1)([O-])=O>C(Cl)Cl>[CH:40]1([O:39][C:36]2[N:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: O=C(Nc1ccc(OC2CCCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC5CCCC5)nc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (12 mg, 0.044 mmol), prepared as described in Example 1d, (6-cyclopentyloxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (20 mg, 0.058 mmol), prepared as described in the previous step, and DCM (500 uL) was treated with TEA (6 uL, 0.043 mmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 2 h, diluted with DCM (2 mL), and washed with H2O (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4) and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound (6.0 mg, 29%). 1H-NMR (300 MHz, CDCl3): δ 9.10 (s, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 6.71 (d, 1H), 6.61 (bs, 1H), 5.30 (m, 1H), 4.32 (d, 2H), 4.08 (s, 6H), 3.62 (m, 1H), 3.20 (m, 2H), 2.16 (m, 2H), 1.98 (m, 4H), 1.79 (m, 4H), 1.62 (m, 2H). LC/MS (ESI) calcd for C26H31N5O4 477.56, found [M+1]+ 478.1.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.C([Sn](CCCC)(CCCC)C1[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=1)CCC>C1COCC1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([C:3]4[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=4)[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:25])([CH3:24])[CH3:26]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Solvent: C1CCOC1
Product: Cn1cnc(-c2[nH]c3cc(NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)c1
Temperature: 130 °C
Yield: 57.8 %

Procedure:
A mixture of intermediate 147(d) obtained from example 147 (184 mg, 0.5 mmol), 4-(tributylstannyl)-1-methyl-1H-imidazole (223 mg, 0.6 mmol) and Pd(PPh3)Cl2 (35 mg, 0.05 mmol) in THF (3 mL) was heated in a microwave oven (Personal Chemistry) for 2 hours at 130° C. The mixture was concentrated and the residue was purified by silica gel chromatography (5% MeOH/EtOAc) to give the title compound (110 mg, 0.289 mmol) in 59% yield as an orange powder.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH:11]([OH:28])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]1[O:8][CH2:7]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([OH:8])[CH2:5][O:9][CH2:10][CH:11]([OH:28])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCC(O)COCC1CO1
Reactant: NCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)COCC(O)CNCCO
Temperature: 80 °C
Yield: 75.2 %

Procedure:
A 300-ml flask equipped with a stirrer, reflux tube and dropping funnel was charged with 40.5 g (0.66 mol) of ethanolamine and 8.6 g of ethanol. While heating and stirring the mixture at 80° C., an ethanol solution of 4.08 g (11.8 mmol) of 2-hydroxyoctadecyl glycidyl ether was added dropwise over 3 hours. After the resultant mixture was heated and stirred further for 3 hours, it was poured into 500 ml of ice water to collect crystals formed by filtration. The thus-obtained crystals were recrystallized again from n-hexane, thereby obtaining 3.58 g (yield: 75%) of the title compound (Ia-12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C:7]1=[O:12].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([OH:18])=[C:8]2[C:7]1=[O:12]
Reactant: O=C1CNCCN1Cc1cccc(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1cccc(Cl)c1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-chlorobenzyl)piperazin-2-one (3.97 g, 17.67 mmol) and diethyl ethoxymethylenemalonate (4.01 g, 18.55 mmol) in toluene (60 mL) was heated in a sealed tube at 80° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (200 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 21.2 mL, 21.2 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[O:28][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(N(Cc2ccc(Oc3cccc(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: CCOC(=O)CCCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 120B and ethyl 4-bromobutyrate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[C:39]2[C:34]=1[C:35](=[O:58])[C:36]([C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)=[CH:37][N:38]2[CH2:47][C:48](O)=[O:49]>C(N(CC)CC)C.O.CN(C=O)C>[F:32][C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[C:39]2[C:34]=1[C:35](=[O:58])[C:36]([C:51]1[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=1)=[CH:37][N:38]2[CH2:47][C:48]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:49]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)O)c12
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 23 h
Yield: 24 %

Procedure:
4-(2-Aminoethyl)morpholine (184 mg, 1.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC, 295 mg, 1.54 mmol) and 1-hydroxybenzotriazole (HOBT, 215 mg, 1.41 mmol) were added to a DMF solution (7 ml) of [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (500 mg, 1.34 mmol) and then the mixture was stirred at room temperature for 23 hours. Water and triethylamine were added to the reaction mixture to make the reaction mixture basic, followed by extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (157 yield: 24%).
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:13][C:12]([O:16][CH3:17])([O:14][CH3:15])[CH2:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-:21].[K+].[K+].O>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:18]([NH2:19])=[O:21])[CH2:13][C:12]([O:14][CH3:15])([O:16][CH3:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC1(OC)CC(C#N)(c2ccc(Br)cc2)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC1(OC)CC(C(N)=O)(c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 488.5 %

Procedure:
Hydrogen peroxide (2.05 ml, 20.07 mmol) was added over 2 h to a stirred mixture of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile (3.18 g, 10.74 mmol) and Potassium carbonate (0.297 g, 2.15 mmol) in DMSO (11 ml) at 40 degree under a nitrogen atmosphere. After the addition, the reaction mixture was heated to 80 degree for 3 h. The reaction mixture was allowed to cool down to room temperature and water (30 ml) was added. The reaction mixture was extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with water (2×30 ml), brine (30 ml), concentrated to give light yellow oil (3.3 g). 1H NMR (500 MHz, CDCl3) 7.40 (d, 2H), 7.11 (d, 2H), 5.89 (br, 1H), 5.58 (br, 1H), 3.12 (s, 3H), 3.02 (s, 3H), 2.97 (d, 2H), 2.52 (d, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Reactant: OB(O)c1cccc(F)c1
Product: COc1cc(-c2cccc(F)c2)cc([N+](=O)[O-])c1
Yield: 81.7 %

Procedure:
A similar procedure as described in Example 12, step 3 was used, starting from 1-iodo-3-methoxy-5-nitro-benzene (1.03 g, 3.69 mmol) and 3-fluoro-phenylboronic acid (800 mg, 5.72 mmol) to afford 3′-fluoro-5-methoxy-3-nitro-biphenyl (745 mg, 82%) as an amorphous white solid: EI(+)-HRMS m/e calculated for C13H10FNO3 (M)+ 247.0645, found 247.0645.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[C:7]([CH:20]=[CH2:21])[C:6]=2[CH:22]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[C:7]([CH:20]=[CH2:21])[C:6]=2[CH:22]=1
Reactant: C=CC1=C(C(=O)OCC)C(C(F)(F)F)Oc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)C(C(F)(F)F)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
The ester from Step 5 (0.300 g, 0.902 mmol) was dissolved in a THF-EtOH-H2O mixture (10 mL, 7:2:1) and treated with sodium hydroxide (0.360 mL, 0.902 mmol of a 2.5 N solution). This solution was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 mL). Diethyl ether (10 mL ) was added and the mixture acidified by the addition of concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The ether extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo yielding a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.163 g, 59%): mp 143.0–145.0° C. 1H NMR (CDCl3/300 MHz 7.49 (d, 1H, J=2.6 Hz), 7.33–7.17 (m, 2H), 6.99 (d, 1H, J=8.5 Hz), 5.82–5.72 (m, 2H), 5.42 (d, 1H, J=17.9 Hz). ESHRMS m/z 303.00207 (M−H, Calc'd. 303.003582). Anal. Calc'd for C13H8ClF3O3 (1.10 wt % H2O): C, 50.69; H, 2.74; Cl, 11.51. Found: C, 50.57; H, 2.37; Cl, 11.75.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6](O)[C:7](=[CH2:14])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].S(Br)([Br:22])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][Br:22])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:27]([NH:29][CH3:30])=[O:28])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=[CH2:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:27]([NH:29][CH3:30])=[O:28])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: C=C(C)c1ccc(-n2nc3cc(NS(C)(=O)=O)c(C4CC4)cc3c2C(=O)NC)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of compound (ii) (10 mg, 0.024 mmol) in MeOH (1 mL) was added 10% palladium on carbon (7 mg). The reaction was stirred vigorously under an atmosphere of hydrogen at RT for 2 h. The reaction mixture was filtered to give 5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2-[4-(propan-2-yl)phenyl]-2H-indazole-3-carboxamide (iii) as a white solid (10 mg, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1)([O-])=O.CO>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)CCO2
Reaction time: 1.5 h
Yield: 64 %

Procedure:
Into a Hydrogenation flask containing 2-Nitro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one (0.2 g, 0.001 mol), was added Methanol (20 mL, 0.5 mol), followed by 10% Pd/C (0.02 g). The reaction mixture was shaken in a Parr apparatus under 20 psi of H2 for 90 min, was filtered through celite, washed with MeOH, and concentrated under reduced pressure to obtain 114 mg (70% yield) of title compound as a pale yellow solid. 97% purity, MP=158-160. LCMS: 179.19 (M+1), NMR (CDCl3) δ 7.94 (bs, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.40 (dd, J=2.2 Hz, 8.5 Hz, 1H), 6.28 (s, 1H), 4.43-4.40 (m, 2H), 3.58 (bs, 2H), 2.79-2.76 (m, 2H).