Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:22][C:23]1([CH3:39])[O:28][CH:27]([C:29]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=[O:30])[C:26]([CH3:38])([CH3:37])[CH2:25][O:24]1>>[C:1]([NH:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:34](=[O:35])[CH2:33][CH2:32][NH:31][C:29]([CH:27]2[C:26]([CH3:37])([CH3:38])[CH2:25][O:24][C:23]([CH3:39])([CH3:22])[O:28]2)=[O:30])=[CH:17][CH:16]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(N)cc1
Product: CCCCCCCCCCCC(=O)Nc1ccc(NC(=O)CCNC(=O)C2OC(C)(C)OCC2(C)C)cc1
Yield: 83.3 %

Procedure:
4-Lauroylaminoaniline (250 mg) and 223 mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 381 mg of the title compound (yield: 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](Cl)=[O:30])[CH3:27]>CN(C)C=O>[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](=[O:30])[O:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1)[CH3:27]
Reactant: Cc1ccc(-c2cc3ccccc3c(O)n2)cc1
Reactant: CCN(CC)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1nc(-c2ccc(C)cc2)cc2ccccc12
Yield: 9 %

Procedure:
The procedure is as in Example 37, starting with 3-(4-methylphenyl)-1-isoquinolinol (4.7 g), triethylamine (8.1 g) and diethylcarbamoyl chloride (10.8 g) in dimethylformamide (50 cc). After chromatography on silica gel with a cyclohexane/ethyl acetate (4:1 by volume) mixture as eluant and recrystallization in ethyl ether, 3-(4-methylphenyl)-1-isoquinolyl diethylcarbamate (0.6 g), m.p. 98° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: ClCCCCBr
Product: COc1ccc(OCCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:27]5[CH2:28][CH2:29][CH2:30][S:26]5(=[O:32])=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nn2)CC1
Yield: 39.8 %

Procedure:
Using (6-chloropyridazin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (88 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31](O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Reactant: O=CO
Product: CN1CCCc2c1nnn2-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure M, 11 mg, 0.025 mmol), H2CO (37% in H2O, 3 mg, 0.037 mmol), and HCO2H (100 L). The vial was sealed and heated to 100° C. for 1 hour. The solvent was subsequently removed in vacuo and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 460.2, found 460.0.
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.COCCOC>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>[C:1]([C:3]1[C:4]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=2[Cl:29])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1I
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 99.7 %

Procedure:
A mixture of ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 0.000679 mol), 2,4-dichlorophenylboronic acid (262 mg, 0.00137 mol), tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.000044 mol) and sodium carbonate (220 mg, 0.0021 mol) in water (3 mL, 0.1 mol) and 1,2-dimethoxyethane (10 mL, 0.1 mol) was flushed with argon and then irradiated in microwave at 140° C. for 12 min. The reaction mixture was filtered and concentrated in vacuum to afford ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 99%). LCMS: (FA) ES+ 443.15.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[C:22](=[O:25])[CH:21]([CH3:26])[CH2:20][N:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:18]=3[N:33]=2)[CH3:13])=[C:8]([O:34][CH3:35])[CH:7]=1.O1CCCC1>CO>[CH:27]1([N:19]2[CH2:20][CH:21]([CH3:26])[C:22](=[O:25])[N:23]([CH3:24])[C:17]3[CH:16]=[N:15][C:14]([N:12]([CH3:13])[C:9]4[CH:10]=[CH:11][C:6]([C:5]([OH:36])=[O:4])=[CH:7][C:8]=4[O:34][CH3:35])=[N:33][C:18]2=3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc(N(C)c2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
An aqueous solution of sodium hydroxide (2N, 1.0 mL, 2 mmol) was added A mixture of 0.170 g (0.00036 mole) of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid methyl ester, 6 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of 2M sodium hydroxide was heated at 75 degrees for 4 hours. The mixture was concentrated under reduced pressure and then azeotroped with toluene and concentrated under reduced pressure, The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with 1M hydrochloric acid to pH=4. After stirring 30 minutes, the solid was collected, washed with water and dried to give 0.080 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid as white powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=S
Temperature: 25 °C

Procedure:
Ethyl 1-[(4-iodophenyl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (800 mg, 1.84 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath to 110° C. Lawesson's Reagent (409 mg, 1.01 mmol, 0.55 equiv) was added portionwise over 45 minutes and after an additional 30 minutes at 110° C., the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17](Cl)[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)cc2ncccc12
Product: c1ccc(CN(Cc2ccccc2)c2ccc(-c3cc4ncccc4c(N4CCOCC4)n3)cc2)cc1

Procedure:
A solution of dibenzyl-[4-(5-chloro-[1,6]naphthyridin-7-yl)-phenyl]amine 3 (350 mg, 0.81 mmol, 1 eq) in morpholine (5.0 mL, 56 mmol, 70 eq) was heated up at 100° C. overnight under Ar(g). Once cooled down, the solution was partitioned and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:1-1:3) to yield the product, B, as a pale yellow solid (242 mg, 62%).
Reaction SMILES: C([N:8]1[C:12]([C:13]([OH:37])([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][C:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)([OH:37])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2c[nH]cn2)cc1

Procedure:
12,95 g of 1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxy-1-(4-tert-butylaminocarbonylphenyl)butyl]-1-H-imidazole is dissolved into ethanol (400 ml) and water (130 ml). 8,17 g of ammonium formate and 1,3 g of 10% Pd/C is added to the solution and the mixture is refluxed for three hours. Then the reaction mixture is filtered through siliceous earth and the flitrate is evaporated to dryness. The residue is dissolved into ethyl acetate, washed with 2M aqueous sodium hydroxide and water, dried and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]=[S:12]1(=[O:33])[C:17]2[CH:18]=[C:19]([O:22]C3C=C(O)C=CC=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:30][CH2:31][CH2:32][C:14]2=[N:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]3[CH2:30][CH2:31][CH2:32][C:14]3=[N:13][S:12](=[O:33])(=[O:11])[C:17]=2[CH:18]=1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(O)c3)cc21
Reactant: OB(O)c1cccc(Br)c1
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21

Procedure:
The procedure is as in Step B of Example 1, using as starting materials (3-bromophenyl)boronic acid and the product obtained in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1>C(N(CC)CC)C.[Pd].CN(C)C=O>[CH3:16][C:14]1[CH:15]=[C:6]2[NH:5][C:4]3[CH:3]=[CH:2][N:11]=[CH:10][C:9]=3[C:8](=[O:12])[N:7]2[N:13]=1
Reactant: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c3ccncc3c(=O)n2n1

Procedure:
23.5 g. of 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 3 are hydrogenated at 80° in 200 ml. of dimethylformamide in the presence of 15 g. of triethylamine and 10% palladium on charcoal as catalyst. When the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered hot and the mother liquor evaporated in vacuo to dryness. The remaining 2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is recrystallized from dimethylformamide, yield: 18.5 g. (92%); m.p. >300°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[H-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=c1cc(O)c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A solution of 4,7-dihydroxycoumarin (1.78 g, 0.01 mole) in dry DMF (7.5 ml) was stirred during the addition of 100% sodium hydride (0.24 g, 0.01 mole) and the mixture stirred for 1 hour at 100°. A solution of benzyl chloride (1.27 g, 0.01 mole) in dry DMF (1 ml) was added dropwise and stirring continued at 100° for a further 4 hours. After removal of the solvent in vacuo water was added and the oily solid which precipitated was separated. Recrystallisation from ethanol gave 0.623 g (23%) of title compound of m.p. 234° νmax (mull) 3150, 3050, 1710, 1630 cm-1, τ(DMSO) 4.67 (2H, s); 4.19 (1H, s); 3.28 (1H near s); 3.20 (1H, d.d., J 2.0 Hz; 5.0 Hz) 2.66-2.26 (6H, m), 1 low field broad exchangeable proton. (Found, C, 71.51; H, 4.70; C16H12O4 requires; C, 71.64; H, 4.51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 79.9 %

Procedure:
To 4 ml of a DMF solution containing 97 mg (0.2513 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 363.7 μl (2.513 mmol) of hexyl bromide, there were added 41.6 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 10 g of WAKO-gel C-200, eluent: hexane and toluene/ethyl acetate of 100/1) to obtain 94.4 mg (0.2008 mmol, 80%) of 2-hexyloxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8](I)[C:9]=2[OH:11])[CH2:4][CH2:3]1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1([F:20])[C:10]2[C:5](=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCc1cc(I)c(O)c2c1CCC2(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)c2c1CCC2(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Into a 50-mL round-bottom flask was placed ethyl 3-(1,1-difluoro-7-hydroxy-6-iodo-2,3-dihydro-1H-inden-4-yl)propanoate (80 mg, 0.20 mmol, 1.00 equiv), ethyl acetate (3 mL), Palladium on carbon (80 mg) and hydrogen was introduced last. The resulting solution was stirred overnight at 25° C. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resultant residue was purified by TLC with ethyl acetate/petroleum ether (1:3) to give 40 mg (73%) of ethyl 3-(1,1-difluoro-7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C14H16F2O3, 269.1 (M−H). found 269.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](O)=O)#[N:12].N>>[F:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[C:11]#[N:12]
Reactant: NC(=NO)c1cccnc1
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: N
Product: N#Cc1cc(-c2nc(-c3cccnc3)no2)ccc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ ppm 7.62-7.71 (m, 2H), 8.54-8.63 (m, 2H), 8.69 (dd, J=5.9, 2.2 Hz, 1H), 8.75 (dd, J=4.9, 1.5 Hz, 1H), 9.30 (dd, J=2.0, 1.0 Hz, 1H); MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].[C:15](Cl)(=[O:25])[C:16]1[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: COc1cc(Br)c(CCN)cc1OC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c(CCN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-4,5-dimethoxylbenzeneethanamine (3.5 g 13.2 mmol) was dissolved and stirred in 50 mL dry acetonitrile. 2.14 mL (1.1 equiv) phthaloyl dichloride and 7 mL (3 equiv) Hünig's base were added. The mixture was stirred at room temperature overnight. Acetonitrile was then removed, and the remaining product was taken up in dichloromethane and washed with basic water (pH=11). The aqueous wash was extracted with dichloromethane 3×15 mL. The organic fractions were combined and dried over sodium sulfate. Solvent was removed to give the crude product, which was then purified by column chromatography. Calculated yield: 1.8 g (34%).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([C:13](=[O:24])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH3:15])[CH:3]=1.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Br:1])=[CH:3][C:4]=1[C:13](=[O:24])[N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15]
Reactant: C[Si](C)(C)CCO
Reactant: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of DCM (10 mL) containing 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid (427 mg, 1.0 mmol) and 2-trimethylsilylethanol (183 mg, 1.5 mmol), were added DMAP (18.9 mg, 0.15 mmol) and DCC (320 mg, 1.5 mmol). The mixture was stirred at rt for 24 hrs, concentrated, and then directly purified via silica gel column chromatography eluting with ethyl acetate in hexane (20%) to yield {4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid 2-trimethylsilanyl-ethyl ester (520 mg). MS: (M−CH2CH2)+487.9/486.0; tR=3.34 min (method 1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 529.1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 3 g (0.1 mole) of sodium hydride (80% in oil) and 50 ml of dimethylformamide (DMF), there are slowly added 15.4 g (0.1 mole) of 2,4-dihydroxybenzoic acid dissolved in 50 ml of DMF. The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 13.1 ml (0.1 mole) of benzyl bromide and the mixture is stirred at ambient temperature until solubilization of the reaction medium. The reaction mixture is poured into water, and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by eluting with dichloromethane. 19.7 g (81% yield) of the expected ester having a melting point of 94°-95° C. are recovered.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:27].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O-:46])=[O:45].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:45][C:44](=[O:46])[CH2:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:7])=[CH:4][C:3]=1[Br:27]
Reactant: CCN(Cc1cc(C(=O)OCCCCCl)cc(Br)c1N)C1CCCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCCC1

Procedure:
This compound was prepared from 4-[4-amino-3-bromo-5-(N-ethyl-cycloheptylaminomethyl)-benzoyloxy]-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.