Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3C)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 2-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (68 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1B(O)O.C(Cl)Cl>O1CCOCC1.O.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>[Cl:1][C:2]1[C:7]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[Cl:17])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1cc(Cl)c(I)cn1
Reactant: OB(O)c1ccncc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cc(Cl)c(-c2ccncc2Cl)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
4-Chloro-5-iodopyridin-2-amine (8.100 g, 31.8 mmol), sodium carbonate (5.00 g, 47.7 mmol), and 3-chloropyridin-4-ylboronic acid hydrate (11.2 g, 63.7 mmol) were combined in 100 mL of 1,4-Dioxane and 25 mL of water. Nitrogen was bubbled through the solution for ˜2 min before adding trans-dichlorobis(triphenyl-phosphine)palladium (II) (2.05 g, 2.92 mmol). The solution was heated to 60° C. overnight. Additional trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.2 g, 0.285 mmol), 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol), 15 mL of water (degassed) and sodium carbonate (1.75 g, 16.6 mmol) were added. The solution was heated to 100° C. for 5 hours. Additional 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol) was added and the reaction continued for 2 h at 100° C. The solution was concentrated under vacuum to ⅕th the volume and extracted between DCM and water. The aqueous layer was extracted with 10% isopropanol/DCM. The combined organics were dried over MgSO4 and then concentrated under vacuum to give an orange solid. The solid was slurried with DCM and then filtered through a fitted funnel. The solids were washed with additional DCM. The combined filtrate was purified on a 80 g Combiflash column (dry loaded), eluting with 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 8% methanol/0.4% NH4OH (˜28% in water)/DCM. The fractions containing the product were concentrated under vacuum to give a yellowish solid. The solids were triturated with DCM to give 4-chloro-5-(3-chloropyridin-4-yl)pyridin-2-amine (3.93 g, 51%) as an off white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73 (1 H, s), 8.58 (1 H, d, J=4.9 Hz), 7.87 (1 H, s), 7.44 (1 H, d, J=4.9 Hz), 6.64 (1 H, s), 6.55 (2 H, br. s.); LCMS-ESI (POS), M/Z, M+1: Found 239.9.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]6[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccncc4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 354. MS (ESI+) 500.1. 1H NMR (400 MHz, DMSO) δ 8.56 (dd, J=4.5, 1.6, 2H), 8.24 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=8.3, 1H), 7.93 (s, 1H), 7.32 (dd, J=8.3, 1.8, 1H), 7.26 (d, J=1.8, 1H), 7.23-7.19 (m, 2H), 6.12 (s, 2H), 4.71 (s, 1H), 4.35 (t, J=5.0, 2H), 4.03 (s, 2H), 3.43 (t, J=5.0, 2H), 1.09 (s, 6H)
Reaction SMILES: Cl.NO.[CH2:4]([O:6][C:7](=[O:23])[C:8]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[CH:9][N:10](C)C)[CH3:5].C([O-])(=O)C.[Na+].CCOCC>CO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[N:10][O:22][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:23])[CH3:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 43.8 %

Procedure:
Hydroxylamine hydrochloride (1.1 g.; 0.016 mol.) was added to a mixture of ethyl-2-(2',4'-dichlorobenzoyl)-3-dimethylaminopropenoate (4.74 g.; 0.015 mol.) and anhydrous sodium acetate (1.25 g.; 0.015 mol.) in 50 ml. of ether and 25 ml. of methanol at 25° C. An additional 25 ml. of methanol was added, and the resultant mixture was stirred for 30 minutes. The mixture was washed into a separatory funnel with 150 ml. of ether and the ether layer was washed free of salts with water. The ether layer was dried with magnesium sulfate, filtered, then concentrated to yield an oil which was crystallized from pentane to yield ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (1.88 g.; 44% yield) as tan crystals having a melting point of 82°-84° C. and the following analysis:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:32][CH2:33][CH2:34][OH:35])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:36]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([CH2:31][O:32][CH2:33][CH2:34][O:35][C:41]([C:38]3[CH:39]=[CH:40][S:36][CH:37]=3)=[O:42])[C:20]=2[O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Cl:30])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccsc1
Reactant: COc1ccc(Cl)c(Oc2c(COCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COc1ccc(Cl)c(Oc2c(COCCOC(=O)c3ccsc3)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By reacting 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidin-4-yl]-benzenesuiphonamide with 3-thiophencarboxylic acid there was obtained thiophene-3-carboxylic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]-ethyl ester. MS: M=631.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].Cl.[CH2:8]([O:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Cl:1][CH:2]([Cl:6])[C:3]([NH:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccccc1)C(Cl)Cl
Yield: 82 %

Procedure:
Prepared in 82% yield (2.6 g, 11.1 mmol) from the reaction of 2,2-dichloroacetyl chloride (2.0 g, 13.6 mmol) with O-benzylhydroxylamine, hydrochloride (2.15 g, 13.6 mmol) via general procedure A. Rf=0.52 (3:1, hexanes:EtOAc); 1H NMR (400 MHz, CD3CN) δ 9.89 (br s, 1H), 7.63-7.17 (m, 4H), 6.02 (s, 1H), and 4.89 (s, 2H); 13C NMR (101 MHz, CD3CN) δ 162.2, 136.1, 130.4, 129.7, 129.4, 78.8, and 65.6; IR (film) 3135 (br), 2996, 2880, 2860, 1700, 1677 (st), 1531, 1468, 1454, 1367, 1341, 1214, 1200, 1046, 1027 cm-1; HR-APPIMS calculated for C9H9Cl2NO2 (M*)+233.0005, observed 232.9976.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]([CH3:14])([CH2:12][OH:13])[CH2:10]O)=O)(C)(C)C.N1C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl.C(OCC)C>[CH3:14][C:9]1([CH2:10][Cl:24])[CH2:12][O:13][C:6](=[O:5])[NH:8]1
Reactant: CC(CO)(CO)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(CCl)COC(=O)N1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-2-methyl-1,3-propanediol (2.28 g, 11.1 mmol) in CH2Cl2 (100 ml) and pyridine (2.0 ml, 25 mmol) was cooled to 0° C. and sulfuryl chloride (1.0 ml, 12 mmol) in CH2Cl2 (20 ml) was added dropwise over 15 min. The solution was warmed to RT over 4 h, diluted with diethyl ether (300 ml), washed with 3× 100 ml 5% NaHSO4, 3× 100 ml sat. NaHCO3, 1× 100 ml sat. NaCl, dried on MgSO4, and evaporated. The crude material was purified by flash chromatography (30-100% EtOAc in hexanes) to afford the title compound as a clear oil (470 mg, 3.14 mmol, 28.3%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (s, 2H), 4.12 (d, 1H, J=9.2 Hz), 4.33 (d, 1H, J=8.8 Hz), 5.9 (br s, 1H). APCI/ESI calculated for C5H8ClNO2: 149.02. Found: 150 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH:9]=[C:8]([C:21]([O:23]CC)=[O:22])[C:7]2=[O:26].Cl>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:13]([F:20])=[CH:14][C:15]([F:19])=[CH:16][C:17]=1[F:18])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2c(F)cc(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2c(F)cc(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Yield: 67 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(2,4,6-trifluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.2 g) was added to 5 ml of conc. hydrochloric acid and 1 ml of acetic acid. The solution was heated at reflux for 3 hours. The reaction solution was allowed to cool down whereupon the precipitated solid was collected by filtration and washed with ethanol and diethyl ether to give 750 mg of the title compound.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([N:2]3[CH2:3][CH2:4][CH2:5][S:1]3(=[O:7])=[O:6])=[CH:14][N:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 37.8 %

Procedure:
Using isothiazolidine 1,1-dioxide (52 mg) and (5-bromopyridin-2-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (160 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (67 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([C:25]1[S:26]C=N[N:29]=1)[CH:11]=2.C(N)(=S)C.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([C:25](=[S:26])[NH2:29])[CH:11]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4nncs4)ccc3n2Cc2cccc(F)c2)C1
Agent: CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1
Yield: 59.6 %

Procedure:
Heat (R)-N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 127) (4.00 g, 10.3 mmol) with thioacetamide (1.54 g, 20.5 mmol) at reflux in 4N HCl in dioxane (100 mL) for 16 h. Cool the reaction, pour onto water, and neutralize with NaHCO3. Extract with EtOAc and evaporate to 4.2 g of a red foam. Purify using silica gel chromatography, eluting with 25-100% EtOAc/hexanes gradient to give 2.6 g (60%) of a yellow solid. MS (ES): m/z 424 (M+1); HPLC: Rt=1.90 min (95%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:39][S:40]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.43 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. After 0.138 ml of triethylamine and 0.077 ml of methanesulfonyl chloride were added to the solution under ice cooling, the mixture was stirred for 3 days at room temperature. To the reaction solution were added 50 ml of ethyl acetate and 20 ml of 2N hydrochloride to fractionate the organic phase. The solvent was removed by distillation under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted by chloroform:methanol (9:1 v/v). The obtained crude crystals were recrystallized from chloroform-n-hexane to give 0.31 g of dimethyl 4-[2-[4-(methanesulfonylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: [F:1][C:2]([F:30])([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:1][C:2]([F:30])([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
23 g (53.4 mmol) of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}-phenyl)prop-2-enoate is dissolved in 400 ml of dioxane. 30 ml of NaOH (30%) diluted in 250 ml of water is added to the solution. The mixture is heated to 55° C. for 2 hours. The mixture is cooled to room temperature and is carefully acidified to pH=2 with a HCl solution (25%) and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 18 g of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}phenyl)-prop-2-enoic acid as a colourless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18](O)[CH:19]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)O1>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([C:29]2[CH:30]=[CH:31][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)[CH:17]=[C:11]([C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)C(=O)c1cc(OCc2ccccc2)cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 58 using 3-benzyloxy-5-hydroxy-N,N-dimethylbenzamide instead of 4-hydroxy-3-methoxybenzaldehyde and tert-butyl N-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane-2-yl)bezyl]carbamate instead of phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:6]([CH2:5][C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: BrCCCCCCBr
Reactant: COc1ccccc1CNCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 1 (0.3 g, 1.3 mmol) was dissolved in 10 mL CH3CN and 1,6-dibromohexane (4.85 g, 19 mmol), and potassium carbonate (0.37 g, 2.6 mmol) was added. The reaction mixture stirred overnight at room temperature. The solvent was evaporated to a minimum volume and purified by silica gel chromatography eluting with 100% CH2Cl2 twice and several times with 0.5% methanolic NH3 (7 M NH3 in methanol)/99.5% CH. The organic layers were combined and rotovaped (61.5%). 1H NMR (CDCl3) δ 8.480 (d, 1H, Ar), 7.612 (t, 1H, Ar), 7.553 (d, 1H, Ar), 7.474 (d, 1H, Ar), 7.192 (t, 1H, Ar), 7.097 (t, 1H, Ar), 6.923 (t, 1H, Ar), 6.824 (d, 1H, Ar), 3.776 (overlapped s, 5H, —CH2—, —OCH3), 3.671 (s, 2H, —CH2—), 3.328 (m, 2H, —CH2—), 2.488 (ddd, 2H, —CH2—), 1.783 (p, 2H, —CH2—), 1.531 (m, 2H, —CH2—), 1.331 (p, 2H, —CH2—), 1.271 (p, 2H, —CH2—). Mass Spect=391.14 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH:20]([CH3:22])[CH3:21])[CH3:2].[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36]Br)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:36][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH:20]([CH3:22])[CH3:21])[CH:5]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCC(=O)c1ccc(-c2cc(O)ccc2CC)c(C(C)C)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Product: CCC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2CC)c(C(C)C)c1

Procedure:
In a manner similar to that of Example 1(o), by reacting 660 mg (2.2 mmol) of 1-(2′-ethyl-5′-hydroxy-2-isopropylbiphenyl-4-yl)propan-1-one with 1 g (2.3 mmol) of 3,4-bis-(benzoyloxymethyl)benzyl bromide, an oil is obtained, which is used without purification.
Reaction SMILES: CS(O)(=O)=O.[CH3:6][CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]1.[N-:14]=[N+]=[N-].[Na+]>COCCOC>[CH3:6][CH:7]1[NH:14][C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1COCCC1=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: COCCOC
Product: CC1COCCC(=O)N1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Methanesulfonic acid (20 mL) was added to a solution of 3-methyltetrahydro-4H-pyran-4-one (4-1, prepared by the method of Smith, A. B. et al. J. Am. Chem. Soc. 1991, 113, 2071, 3.00 g, 26.3 mmol, 1 equiv) in DME (30 mL) at −40° C. Sodium azide (5.13 g, 79.0 mmol, 3.00 equiv) was added in four equal portions over 30 min as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and a solution of 10% n-propanol in ethyl actetate (2×400 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-1,4-oxazepan-5-one (4-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.73 (br s, 1H), 3.97 (ddd, 1H,J=12.4, 5.6, 2.8 Hz), 3.83 (d, 1H,J=12.2 Hz), 3.76 (m, 1H), 3.66 (dd, 1H,J=12.4, 10.8 Hz), 3.35 (dd, 1H, J=12.2, 8.2 Hz), 2.89 (ddd, 1H,J=15.8, 10.8, 2.8 Hz), 2.54 (dd, 1H,J=15.8, 5.6 Hz), 1.15 (d, 3H,J=7.1 Hz).
Reaction SMILES: [C:1]([C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:12](COC)[C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[C:1]([C:9]1[N:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCn1c(-c2ccc(Cl)cc2)nc(C(=O)c2ccccc2)c1-c1ccncc1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1)c1nc(-c2ccc(Cl)cc2)[nH]c1-c1ccncc1
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A solution of 4-benzoyl-2-(4-chlorophenyl)-1-methoxymethyl-5-(4-pyridyl)imidazole (10 mg, 0.025 mmol) in methanol (0.8 mL) containing 6 N hydrochloric acid (21 μL) at 40° C. was stirred overnight. The reaction was quenched by the addition of 5% sodium bicarbonate solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-3% methanol in methylene chloride to yield the title compound as a orange glass (4 mg, 40% yield), mass spectrum (CI) m/e=360 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:12][N:11]=[N:10][C:9]=2[NH:21][NH2:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[C:31](O)=[O:32])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[N:11][N:10]3[C:31](=[O:32])[C:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[N:22][N:21]=[C:9]3[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Product: O=c1c(-c2ccc(F)cc2)nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12

Procedure:
The title compound was prepared using the method described in Example 1E, reacting 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine with 2-(4-fluorophenyl)-2-oxoacetic acid to give 8,9-bis(4-chlorophenyl)-3-(4-fluorophenyl)-4H -pyridazino[6,1-c][1,2,4]triazin-4-one. HPLC retention time=3.84 min; MS observed=463 (M+H); 1H NMR (CDCl3, 500 MHz) δ 8.76 (s, 1H), 8.58–8.53 (m, 2H), 7.39–7.34 (m, 4H), 7.31–7.25 (m, 2H), 7.22–7.13 (m, 4H).