Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]1([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]1)[C:17](=[O:28])[N:18]2[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]2([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]2)[C:17](=[O:28])[N:18]3[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
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: [Na+]
Solvent: C1COCCO1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccc(N(C)C)nc3)cccc21
Temperature: 25 °C

Procedure:
To an oven-dried flask was charged with [6-(dimethylamino)pyridin-3-yl]boronic acid (37.0 mg, 0.17 mmol), Pd(PPh3)4 (13.5 mg, 0.012 mmol) followed by flashing with nitrogen. To the flask was added a solution of 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (50.0 mg, 0.12 mmol) in anhydrous dioxane (2.00 mL) followed by the addition of 2.0 M Na2CO3 (0.24 mL). The reaction mixture was heated at reflux for 48 h. After cooling down to ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (2.00 mL), washed with saturated ammonium chloride (2.00 mL), and concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compounds: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H), 7.32 (t, 1H), 6.87 (dd, 2H), 6.71 (dd, 1H), 6.23 (d, 1H), 6.20 (s, 1H), 5.88 (d, 2H), 4.56 (ABq, 2H), 3.89-3.80 (m, 1H), 3.69-3.59 (m, 1H), 3.05 (s, 6H), 1.78-1.69 (m, 2H), 1.39-1.35 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 158.3, 156.1, 148.8, 147.3, 142.9, 142.0, 137.8, 137.2, 129.9, 128.9, 125.6, 122.0, 121.0, 107.6, 104.3, 102.5, 101.5, 93.6, 77.8, 58.5, 40.5, 38.2, 29.1, 27.2, 22.4, 14.0; MS (ES+, m/z) 472.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[C:28]([CH3:41])=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:29]2[C:28]([CH3:41])=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Cc1c(F)ccc(N)c1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccn3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.52 g, 8.1 mmol) in DCM (15 mL) was added triethyloxonium tetrafluoroborate (1.63 g, 8.6 mmol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (15 mL). 4-fluoro-3-methyl-N2-pyridin-2-yl-benzene-1,2-diamine (1.0 g, 5.1 mmol) was added and the reaction heated at 75° C. for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (1.29 g, 76%). LCMS (Method C): RT=3.22 min, [M+H]+=371.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.CC(O)C>CS(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[C:21]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Nc2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)no1
Temperature: 120 °C

Procedure:
To a slurry of (5-t-butyl-isoxazol-3-yl)-(2-chloro-pyrimidin-4-yl)-amine (Example 2, Step A) (0.120 mg, 0.47 mmol) in DMSO (0.120 mL) was added 3-aminobenzenesulfonamide (0.082 g, 0.47 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 1 h at which time TLC indicated the disappearance of starting material. IPA (5 mL) was added and the mixture was filtered and washed with IPA (2×1 mL) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(F)c(F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(F)c(F)cc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 38.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.256 mmol), 2,4,5-trifluoroaniline (0.056 g, 0.383 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.15 (s, 2H), 7.34 (m, 2H), 7.41 (m, 1H), 7.51 (br s, 1H), 7.73 (q, J=10.8 Hz, 10.8 Hz, 1H), 8.54 (m, 1H), 10.13 (s, 1H), 11.27 (br s, 2H); MS [M+H]+: 505.08.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[N:7][N:6]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5](=[O:19])[C:4]=1[CH:20]=O.[NH2:23]N.O>CCO>[CH3:18][C:11]1([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14][CH:9]([N:6]2[C:5](=[O:19])[C:4]3[CH:20]=[N:23][NH:2][C:3]=3[CH:8]=[N:7]2)[CH2:10]1
Reactant: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1C=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1(C)CC(n2ncc3[nH]ncc3c2=O)CC(C)(C)C1
Yield: 46.3 %

Procedure:
A solution of 5-dimethylamino-3-oxo-2-(3,3,5,5-tetramethyl-cyclohexyl)-2,3-dihydro-pyridazine-4-carbaldehyde (1.19 g, 3.903 mmol) in EtOH (30 mL) was treated with H2NNH2.H2O (1.2 mL, 39.03 mmol). After stirring at reflux for 20 h, the volatiles were removed in vacuo and the solid residue was extracted with EtOAc. The organics were then washed with brine, dried (Na2SO4). After evaporation of volatiles, the residue was purified by flash chromatography (50 g (solute SiO2 cartridge, continuous gradient 100% hexanes→hexanes/EtOAc, 1:1) to provide 5-(3,3,5,5-tetramethyl-cyclohexyl)-1,5-dihydro-pyrazolo[3,4-d]pyridazin-4-one (495.3 mg, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s), 8.31 (1H, s), 5.45 (1H, app heptet, J=4.6 Hz), 1.71-1.57 (4H, m), 1.40-1.22 (2H, m), 1.19 (6H, s), 1.00 (6H, s).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20])([CH3:13])([CH3:12])[CH3:11].O>C(O)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19](=[N:8][OH:9])[NH2:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: NO
Reactant: COc1ccc(C(C)(C)C)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1C(N)=NO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
Sodium carbonate (57 g.) was added with stirring to a mixture of hydroxylamine hydrochloride (75 g.), 5-tert-butyl-2-methoxybenzonitrile (50 g.) and water (400 ml.) Ethanol (400 ml.) was added, and the mixture was stirred at room temperature for 45 minutes and then heated under reflux for 18 hours. The ethanol was evaporated in vacuo, and the cooled aqueous suspension was extracted three times with diethyl ether. The combined extracts were dried over magnesium sulphate, filtered, and evaporated. The residual glass was triturated with warm diethyl ether, and the solid obtained was filtered off, washed with diethyl ether, and recrystallised from benzene to give 5-tert-butyl-2-methoxybenzamidoxime (48 g.), m.p. 132°-133° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:24][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(C(F)(F)F)cc1
Yield: 42 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was suspended in EtOH (4 mL) and alpha,alpha,alpha-Trifluoro-p-tolualdehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A15 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (71 mg, 42% yield).
Reaction SMILES: [OH-].[Na+].Cl.[F:4][C:5]([F:16])([F:15])[O:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1.[C:17]([C:19](=[C:23](SC)[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21])#[N:18]>C(O)C>[NH2:18][C:17]1[N:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]([F:15])([F:16])[F:4])[CH:8]=2)[N:14]=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nn(-c3cccc(OC(F)(F)F)c3)c(N)c2C(N)=O)cc1
Yield: 42.5 %

Procedure:
Powdered sodium hydroxide (88 mg, 2.2 mmol) was added to a solution of 3-trifluoromethoxyphenyl hydrazine hydrochloride (503 mg, 2.2 mmol) and 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol) in ethanol (20 ml) and the mixture heated at reflux for 18 h. On cooling, the solvent was removed under reduced pressure and the residue partitioned between water (80 ml) and ethyl acetate (100 ml). The aqueous layer was further extracted with ethyl acetate (2×80 ml) and the combined organic layers washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was recrystallised from isopropyl ether-heptane to give the title compound as white needles (320 mg) m.p. 177-179°. δH (CDCl3) 7.70 (1H, m), 7.51 (1H, d, J 8.0 Hz), 7.38 (1H, d, J 8.0 Hz), 7.40 (1H, m), 7.09 (1H, d, J 7.9 Hz), 5.74 (2H, br s), 5.35 (2H, br s) and 2.42 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[CH2:16][O:17]C2CCCCO2)[N:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:3]=1[C:37]([NH2:39])=[O:38].Cl>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[CH2:16][OH:17])[N:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:3]=1[C:37]([NH2:39])=[O:38]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2COC2CCCCO2)c1N
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2CO)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of 5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (690 mg, 1.3 mmol) in 10 mL of CH3CN was added hydrochloric acid (3 mL). After stirring at RT for 15 min, the mixture was concentrated to afford 550 mg (95%) of 5-amino-1-(2-(hydroxyl methyl)-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 62.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (200 mg, 0.380 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (185 mg, 0.58 mmol) in sodium carbonate (121 mg, 1.14 mmol), Pd(PPh3)2Cl2 (26.6 mg, 0.038 mmol), toluene/ethanol/water (20/7/3 mL). This afforded 153 mg (62.4% yield) after purification by column (Silica gel 6/120) using 3% methanol in chloroform as eluent. MS: m/z=645.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Br)[CH2:26][OH:27]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][OH:27])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2ccc(F)cc2)CC1
Yield: 79 %

Procedure:
To a mixture of 1-(4-fluorophenyl)piperazine (7.24 g), potassium carbonate powder (13.9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (10.0 g) under stirring. The mixture was stirred at room temperature for 3 hours, diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (1:3)] to give 7.12 g (79.0%) of 4-(4-fluorophenyl)-1-piperazineethanol as an oil. IR(Neat): 3150 cm-1. NMR (CDCl3)δ: 2.47-2.80(6H, m), 2.97-3.20(4H, m), 3.10(1H, s), 3.65(2H, t, J=5.5), 6.71-7.13(4H, m).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:29]4[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=4[CH3:36])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: Cc1ccc(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(F)cc1-c1cccc(C2CN(S(=O)(=O)c3ccccc3)C(=O)N2C(C)C)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-fluoro-2-methylphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(5′-fluoro-2′-methyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 453.1 ([M+H]+)
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[C:8]([C:43]3[CH:48]=[C:47]([C:49](=[O:61])[NH:50][C@@H:51]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH2:54][CH2:53][CH2:52]4)[CH:46]=[CH:45][N:44]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[C:8]([C:43]3[CH:48]=[C:47]([C:49](=[O:61])[NH:50][C@@H:51]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH2:54][CH2:53][CH2:52]4)[CH:46]=[CH:45][N:44]=3)[CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To (S)-tert-butyl 16-(3-((4-cyclobutoxy-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oate Example 284 was added trifluoracetic acid (1 mL). The mixture was stirred for 5 minutes, concentrated and purified by prep. TLC to give a yellow syrup (7.2 mg, 64%). MS (ES, m/z): 780.5[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8](OCC)OCC)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]>FC(F)(F)C(O)=O>[C:15]([C:3]1[CH:4]=[N:5][N:6]2[CH:7]=[CH:8][NH:1][C:2]=12)([OH:17])=[O:16]
Reactant: CCOC(Cn1ncc(C(=O)O)c1N)OCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn2cc[nH]c12
Yield: 55.1 %

Procedure:
A solution of 5-amino-4-carboxy-1-(2,2-diethoxyethyl)pyrazole (50 g) in 80% trifluoroacetic acid aqueous solution (250 ml) was stirred at room temperature for two days. The reaction mixture was evaporated in vacuo. The resultant solid was washed with cold water, collected by filtration and dried over phosphorus pentoxide in vacuo to give 7-carboxy-1H-imidazo[1,2-b]-pyrazole (17.10 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12].S(=O)(=O)(O)O.C(C1C=CC=CC=1)C>>[C:9]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Product: O=Cc1cccc2ccccc12
Temperature: 100 °C
Yield: 89.3 %

Procedure:
A bottom-removable four-necked flask having an inner volume of 1 L and equipped with a Dimroth condenser, a thermometer and a stirring blade was charged with 64.1 g of naphthalene (0.5 mol, produced by Kanto Chemical Co., Inc.), 150 g of an aqueous 40% by mass formalin solution (2 mol as formaldehyde, produced by Mitsubishi Gas Chemical Company, Inc.) and 79.7 g of 98% by mass sulfuric acid (produced by Kanto Chemical Co., Inc.) in a nitrogen stream, and the content of the flask was reacted while stirring under reflux under ordinary pressure at 100° C. for 6 hours. Thereto was added 150 g of ethylbenzene (produced by Kanto Chemical Co., Inc.) as a dilution solvent and left to still stand, and then an aqueous phase as a lower phase was removed. Furthermore, the resultant was subjected to neutralization and washing with water, and ethylbenzene and unreacted naphthalene were distilled off under reduced pressure to thereby provide 69.7 g of a naphthalene formaldehyde resin as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)[CH:2]=[CH2:3].C(N(CC)CC)C.C(=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH3:3][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:1]=1
Reactant: C=CCNc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1c[nH]c2ccccc12
Reaction time: 64 h
Yield: 37 %

Procedure:
Di(1H,2H,2H-perfluorooctyl)phenylphosphine (80 mg, 0.1 mmol), palladium (II) acetate (11 mg, 0.05 mmol), N-allyl-2-iodoaniline (259 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi), the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with 20% ether in hexane to give a white crystalline solid (49 mg, 0.37 mmol, 37%); δH (250 MHz; CDCl3) 7.85 (1H, br, NH), 7.63 (1H, m, H7), 7.34 (1H, m, H4), 7.15-7.26 (2H, m, H5 and H6), 6.97 (1H, s, NHCH), 2.38 (3H, s, Me).
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1.[OH-].[Li+]>C(#N)C.O>[I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)O)cc2)c1I

Procedure:
A solution of methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (Intermediate 7, Step 3, 1.5 g, 3.58 mmol) and lithium hydroxide (0.257 g, 10.73 mmol) in acetonitrile (6 mL) and water (6 mL) was heated to 50° C. for 2 h. The mixture was concentrated and extracted with EtOAc. The organics were dried (MgSO4) and concentrated to afford 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoic acid. LCMS: m/z 406.0 (M+H)+.