Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 117.2 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidine carboxylate (Intermediate 5) (400 mg, 0.545 mmols), 3-fluorophenyl boronic acid (397 mg, 2.84 mmols), potassium carbonate (782 mg, 5.67 mmol), and Pd(PPh3)4 (218 mg, 0.189 mmol) in dioxane/water (7 mL/1 mL) were reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (280 mg, 68%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Reactant: C1CCNC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN1CCCC1
Yield: 50 %

Procedure:
Using a procedure similar to that described in Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g) was reacted with pyrrolidine (2.5 ml) to give the title product as a foam (0.151 g, 50%); 1H NMR Spectrum: (CDCl3) 1.68-1.75 (m, 4H), 1.90-2.01 (m, 1H), 2.04-2.14 (m, 2H), 2.15-2.23 (m, 1H), 2.51-2.61 (m, 2H), 2.66-2.74 (m, 2H), 3.15-3.21 (d, 1H), 3.38-3.48 (m, 2H), 3.55-3.62 (m, 1H), 4.00-4.08 (m, 4H), 4.52-4.55 (d, 1H), 4.68-4.74 (t, 1H), 7.06-7.27 (m, 3H), 7.90-7.96 (m, 1H), 8.43 (s, 1H), 8.60 (s, 1H), 8.69 (s, 1H); Mass Spectrum: (M−H)− 512.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH:31]=[CH:32]O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>CC#N>[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH:31]=[CH:32][Br:20])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(CC=CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cccc(CC=CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.8 %

Procedure:
To a suspension of Ph3P (1.0 g) in 40 mL of MeCN at 0° C. was added bromine (0.6 g) and the mixture was stirred at 0° C. for 15 minutes and then warmed to ambient temperature. To the suspension of Br2PPh3 was then added 3-cyano-1-(3-hydroxyprop-2-en-1yl)benzene (0.5 g) in 10 mL MeCN dropwise. The resulting solution was stirred at 60° C. for 30 minutes, cooled to ambient temperature and concentrated. The residue was triturated with 10% hexane in ethyl acetate. The mixture was filtered through a silica gel pad and the filtrate was concentrated to afford 0.71 g of 3-cyano-1-(3-bromoprop-2-en-1yl)benzene as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=O)[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][O:33][NH2:34].O.O.O.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=[N:34][O:33][CH3:32])[CH3:19])=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CON=C(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.4 %

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 460 (150 mg, 0.3 mmol) in H2O (10 mL) and dioxane (20 mL) was treated with methoxyamine hydrochloride (84 mg, 1 mmol) and sodium acetate trihydrate (138 mg, 1 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate and purified by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 20 mg, 15%). mp 143–145° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, 1H), 7.65 (q, J=10 Hz, 1H), 7.82 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.24 (s, 1H); MS (APCI+) m/z 464 (M+H)+; (APCI−) m/z 498 (M+Cl)−. Anal. calc. for C21H19F2N3OS: C, 54.42; H, 4.13; N, 9.06. Found: C, 54.33; H, 3.93; N, 8.92.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:13]>>[NH2:13][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: N
Reactant: Clc1nc2ccccc2nc1Cl
Product: Nc1nc2ccccc2nc1Cl

Procedure:
2.1 g (10.4 mmol) of 2,3-dichloroquinoxaline are stirred for 8 hours with 50 ml of 20% ethanolic ammonia in an autoclave at 80°–85° C. and autogenous pressure. The reaction solution is evaporated to dryness in a rotary evaporator, and the crude product is chromatographed over silica gel using toluene/ethyl acetate. The product-containing fractions are collected and evaporated in a rotary evaporator. Yield: 1.18 g (63%)
Reaction SMILES: Cl[O-].[Na+].[CH3:4][C:5]1[CH:10]([CH2:11][CH2:12][C:13]([CH3:15])=[O:14])[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][CH:6]=1.C(Cl)[Cl:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:19][CH:6]1[C:5](=[CH2:4])[CH:10]([CH2:11][CH2:12][C:13](=[O:14])[CH3:15])[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: ClCCl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=C1C(Cl)CCC(C)(C)C1CCC(C)=O
Reaction time: 1 h
Yield: 61 %

Procedure:
To a mixture of commercial bleach (28.5 ml of a 5.25% solution of sodium hypochlorite) α-dihydro-ionone (3.88 g) and methylene chloride (110 ml) was added a solution of potassium phosphate (monobasic) (5.44 g) in water (40 ml) during a 15 minute period. The mixture was stirred for 1 hour at 25°. The methylene chloride solution was washed with sodium bicarbonate solution, the solvent evaporated, and the residue distilled to give 2.81 g (61% yield) of 4-(5-chloro-6-methylene-2,2-dimethylcyclohexyl)-2-butanone, bp 101°-106°, 0.2 mm. NMR (CDCl3) δ0.85 and 0.95 (6H,2s,>C(CH3)2), 0.9-2.6 (9H, m), 2.10 (3H, s, --COCH3), 4.36-4.55 (1H, t, J=6 Hz,>CHCl), 4.76 and 5.33 (2H,2s,>C=(CH2). IR (film) γmax 2950, 1720, 1675, 1650, 1455, 1360. MS m/e 193, 175, 159, 134, 119.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[C:39]3[CH2:41][O:42][C:43](=O)[C:38]3=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:43]1[C:38]2[C:39](=[N:40][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][OH:22])[CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[CH2:41][O:42]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (72 mg, 0.47 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred for 10 min at room temperature. A solution 2-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-7H-furo[3,4-b]pyridin-5-one (77 mg, 0.24 mmol) in THF (1.5 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is then treated with HCl (4M in dioxane, 5 mL) at 0° C. The reaction mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated and the residue is treated with saturated aqueous NaHCO3. The aqueous solution is extracted with EtOAc (2×). The combined organic extracts are dried (MgSO4) and concentrated. The residue is purified by chromatography (silica gel, gradient elution 20:1 chloroform:MeOH to 10:1 chloroform:MeOH). The product containing fractions are concentrated and the residue is triturated from EtOAc-hexane and collected by filtration to give the title compound as a yellow solid (22 mg, 20%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[H-].[Na+].Br[CH2:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.C(OCC)(=O)C>[S:27]1[C:26]2[C:21]([CH2:20][N:8]3[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:16])[C:7]3=[O:15])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]=[CH:28]1
Reactant: BrCc1cccc2ccsc12
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(O)CCn1c(=O)n(Cc2cccc3ccsc23)c2ccccc21
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (200 mg, 0.91 mmol) in DMA (5 ml) was added sodium hydride (60% oil dispersion, 55 mg, 1.4 mmol). The resulting mixture was stirred for 10 minutes at ambient temperature after which time 7-bromomethyl-benzo[b]thiophene (206 mg, 0.91 mmol) was added. The reaction was heated at 120° C. in a microwave for 20 minutes. Upon cooling to ambient temperature the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.) and brine. The aqueous phase was acidified using 1M HCl and extracted once with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 5% methanol/dichloromethane). The product-containing fractions were combined and concentrated to give 20 mg (6%) of the desired product. LCMS (ESMS): m/z 353.41 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([O:14][CH3:15])[CH:7]=[CH:6]2.[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1)[CH2:17][CH3:18].Cl>O1CCCC1>[CH3:15][O:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:22]3[CH2:23][CH2:24][CH:19]([CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]=3)[CH:4]=2)[CH:9]=1
Reactant: COC1C=Cc2cc(Br)ccc2C1=O
Reactant: CCCC1CC=CCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CC=C(c2ccc3cc(OC)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
5.7 g of magnesium was suspended in 12 ml of tetrahydrofuran. To the suspension was then added dropwise a solution of 50 g of 6-bromo-2-methoxynaphthalone in 200 ml of tetrahydrofuran at a rate such that tetrahydrofuran was gently refluxed. The reaction mixture was then further stirred for 1 hour. To the reaction solution was then added dropwise a solution of 30 g of 4-propylcyclohexanene in 120 ml of tetrahydrofuran at room temperature. The reaction mixture was then further stirred for 1 hour. To the reaction solution was then added 200 ml of a 10% hydrochloric acid. The reaction mixture was extracted with 300 ml of toluene, washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. To the residue were then added 280 ml of toluene and 4.0 g of p-toluenesulfonic acid monohydrate. The reaction mixture was then heated under reflux for 3 hours. The reaction solution was allowed to cool to room temperature, washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was then recrystallized from ethanol to obtain 44.8 g of 2-methoxy-6-(4-propylcyclohexa-1-ene-1-yl)naphthalene.
Reaction SMILES: N([O-])=O.[Na+].C[Si](C)(C)[Si](C)(C)C.[I:13]I.C(Cl)(Cl)(Cl)Cl.[C:20]([O:23][CH2:24][C@H:25]([N:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:38])[C:33]=2N)[C:28]1=[O:39])[CH3:26])(=[O:22])[CH3:21].C(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:20]([O:23][CH2:24][C@H:25]([N:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:38])[C:33]=2[I:13])[C:28]1=[O:39])[CH3:26])(=[O:22])[CH3:21]
Reactant: II
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: O=N[O-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC[C@@H](C)n1ccc2c(I)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of sodium nitrite (1 g, 0.02 mol), hexamethyldisilane (3 g, 0.02 mol), iodine (5 g, 0.02 mol) and benzyltriethylammonium chloride (0.3 g, 0.001 mol) in carbon tetrachloride (100 mL, 1 mol) was added a solution of (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (2.3 g, 0.0070 mol) in methylene chloride (3 mL, 0.05 mol) at 0° C. The mixture was stirred at the same temperature for 40 minutes and then warmed to room temperature overnight. The mixture was purified by flash chromatography to afford the desired product as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[N:9]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=2)=[CH:3][CH:2]=1.OS(O)(=O)=O.N([O-])=O.[Na+].[N-:45]=[N+:46]=[N-].[Na+]>O>[N:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:8]=[C:7]2[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a 1 L round bottom flask equipped with a magnetic stir bar was suspended 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (13.00 g, 28.7 mmol) in 400.00 ml of water and cooled to 0° C. 80 ml of cone. H2SO4 was added slowly over a period of 15 min at 0° C. A solution of NaNO2(2.48 g, 35.9 mmol) in 15 ml of water was added to the mixture and allowed to stir at 0° C. for 30 min. A solution of NaN3 (3.36 g, 51.7 mmol) in water was then added dropwise over a period of 15 min. The mixture was slowly warmed to room temperature and stirred overnight. Upon completion, the precipitate was filtered, washed with water and dried to give 5-azido-3-(pyridin-4-yl)-1-trityl-1H-indazole (12.62 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.Br[CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33].[I-].[Na+]>O1CCCC1.C(OCC)(=O)C.CCCCCC.C1C=CC=CC=1.C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]([O:2][CH3:1])=[C:8]([CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: CCCCC#CCCCBr
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Agent: [I-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCC#CCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3.0 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 500 ml of anhydrous tetrahydrofuran, this solution was cooled to -78° C. on a dry ice-acetone bath under an atmosphere of argon gas. To this solution was added dropwise 10.7 ml of secbutyllithium (1.3M cyclohexane solution), and stirred for 30 minutes. Then 3.54 g of 1-bromo-4-nonyne was added dropwise thereto, further 2.1 g of sodium iodide and 60 ml of hexamethylphosphoric triamide were added to the reaction mixture and stirred for 12 hours at room temperature. Tetrahydrofuran was removed under reduced pressure, then to the residue obtained was added 300 ml of mixed solvent of benzene-diethyl ether (1:1). The organic layer was washed four times with 100 ml of water, and washed four times with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate then the solvent was removed under reduced pressure. The residue obtained was treated by means of a silica gel column chromatography (diameter: 5.5 cm×length 15.5 cm, "Wakogel C-200", developing and eluting solvent: 20% ethyl acetate-n-hexane). There was obtained 1.4 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(4-nonynyl)benzene as in the form of colorless oily substance.
Reaction SMILES: N1C=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.C([Sn](CCCC)(CCCC)C1[N:39]=[CH:40][S:41]C=1)CCC.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:19]1[CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[N:39]=[CH:40][S:41][CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=[O:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCCC(c2ccccc2-c2cscn2)N1Cc1cccc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available 4-(tributylstannyl)thiazole (51 mg; 0.13 mmol), and PdCl2(PPh3)2 (8 mg; 0.011 mmol) in THF (1 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 446.14 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC=C[CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(O)cc1
Reaction time: 3 h

Procedure:
A mixed solution comprising 4-hydroxyphenylacetic acid (150.0 g), toluene (250 ml), ethanol (150 ml), and p-toluenesulfonic acid (50 g) was refluxed with stirring for 3 hours. The reaction mixture was washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate anhydride, and then concentrated under a vacuum to yield 164.3 g of oily ethyl 4-hydroxyphenylacetate. This material was subjected to a reaction identical to that of Reference Example 1, thereby yielding 138.2 g of oily ethyl 4-hydroxy-3-methallylphenylacetate. In a manner identical to Reference Examples 2 and 3, this material was successively subjected to catalytic reduction, benzylation, and hydrolysis reactions, thereby yielding 70.4 g of 4-benzyloxy-3-isobutylphenylacetic acid. As in the case of Example 3, this material (1.0 g) was subjected to a condensation reaction with 1-isobutylpiperazine (0.48 g), thereby yielding 1.3 g of the aimed compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH:7]([C@@H:9]1[C@@H:11]([C:12]([O:14][CH2:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([CH3:24])=[C:18]([F:25])[C:17]=2[F:26])=[O:13])[C:10]1([CH3:28])[CH3:27])=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:27][C:10]1([CH3:28])[C@H:9](/[CH:7]=[CH:1]\[CH3:2])[C@H:11]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([CH3:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]
Reactant: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C\[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
A mixture of 1.1 g of ethyltriphenylphosphonium bromide and 30 ml of terahydrofuran was cooled by ice and 0.23 g of potassium tert-butoxide was added to the mixture under stirring. After 15 minutes, a tetrahydrofuran (5 ml) solution containing 0.32 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-3-formyl-2,2-dimethylcyclopropanecarboxylate was added to the mixture. After 30 minutes, the reaction mixture was filtered with celite and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.22 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]2[C:6]1=[O:21].[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[NH2:26][C:23]1[CH:24]=[CH:25][C:2]([Cl:1])=[C:3]([CH:22]=1)[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]2[C:6]1=[O:21]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cc(N)ccc1Cl
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of Example 90 (20 mg, 0.05 mmol) in acetone (0.4 mL) and water (0.1 ml) was added zinc dust (33 mg, 0.5 mmol) followed by ammonium chloride (27 mg, 0.5 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was filtered through a pad of celite, extracted with DCM and the organic layers were collected. The organic layers were washed with brine, dried with Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to provide the desired compound (5 mg, 27%). MS (ESI): mass calcd. for C17H16ClN7O, 369.8; m/z found, 370.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.48 (d, J=1.2 Hz, 1H), 8.87-8.79 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J=8.4 Hz, 1H), 5.06 (d, J=16.3 Hz, 1H), 4.96 (d, J=11.9 Hz, 1H), 4.81-4.68 (m, 1H), 4.34 (d, J=16.1 Hz, 1H), 4.06 (s, 1H), 1.17 (d, J=6.7 Hz, 3H).