Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1[O:7][CH:6]([CH:8]([CH3:10])[CH3:9])[C:5]([CH3:12])([CH3:11])[CH2:4][O:3]1.[CH3:13][C:14]1([CH3:40])[CH2:19][CH:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:17][C:16]([CH3:39])([CH3:38])[NH:15]1>>[CH3:11][C:5]1([CH3:12])[CH2:4][O:3][P:2]([N:20]([CH:18]2[CH2:19][C:14]([CH3:40])([CH3:13])[NH:15][C:16]([CH3:39])([CH3:38])[CH2:17]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([P:2]2[O:7][CH:6]([CH:8]([CH3:9])[CH3:10])[C:5]([CH3:11])([CH3:12])[CH2:4][O:3]2)[CH:28]2[CH2:29][C:30]([CH3:37])([CH3:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH2:33]2)[O:7][CH:6]1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C1OP(Cl)OCC1(C)C
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Product: CC(C)C1OP(N(CCCCCCN(C2CC(C)(C)NC(C)(C)C2)P2OCC(C)(C)C(C(C)C)O2)C2CC(C)(C)NC(C)(C)C2)OCC1(C)C

Procedure:
If 2-chloro-5,5-dimethyl-4-isopropyl-1,3,2-dioxaphosphorinane is reacted with N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine in a procedure analogous to Example 1, N,N'-bis(5,5-dimethyl-4-isopropyl-1,3,2-dioxaphosphorinan-2-yl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine is obtained, which melts at 95°-97° (Compound No. 7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:25](=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:34][N:32]([CH3:33])[CH3:31])[CH2:21][CH2:20]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=Cc2nc(CC3CCNCC3)no2)cc1OC
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Product: COc1ccc(C=Cc2nc(CC3CCN(CCN(C)C)CC3)no2)cc1OC
Temperature: 25 °C

Procedure:
N,N-Dimethylethyl chloride (0.21 g, 1.45 mmol) was added slowly into a solution of 4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine (compound of Example 19; 0.4 g, 1.21 mmol) and anhydrous potassium carbonate (0.37 g, 1.82 mmol) in dry DMF (10 mL). The mixture was heated at 55° C. to 60° C. for 4 h. The reaction mixture was cooled to room temperature and ice water (5 mL) was added into it. The solid obtained was filtered and dried to afford the title compound.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[N:14]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13])=[N+:15]=[N-:16]
Reactant: CCOC(=O)N1CCC(Br)C(O)C1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (5.1 g) was dissolved in anhydrous DMF (20 mL) under an argon atmosphere, followed by the addition of 18-crown-6 (0.27 g) and sodium azide (2.89 g). The reaction was heated at 90° C. for twenty-three hours, then stirred overnight, slowly cooling to room temperature. The reaction was then added to deionised water (150 mL) to quench it, saturated with solid sodium chloride, and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo, yielding the title compound (4.3 g, 100%). MS (GC-EI)[(M-N2)+]: 186 for C8H14BrN4O3.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (89%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20](Br)[C:15]2=[N:14]1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:15]2=[N:14]1
Reactant: O=c1n(CCc2ccc3ncccc3n2)nc2c(Br)cccn12
Reactant: OB(O)c1ccncc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1n(CCc2ccc3ncccc3n2)nc2c(-c3ccncc3)cccn12
Temperature: 100 °C
Yield: 23 %

Procedure:
Triazolopyridinone 10-3 (22 mg, 0.059 mmol) and pyridin-4-ylboronic acid (11 mg, 0.089 mmol) were placed in a microwave vial and dissolved in dioxane (1 mL). To the mixture was added 1 M aq. Cs2CO3 solution (0.12 mL, 0.12 mmol). The mixture was then sparged with N2 gas for 3 min, and bis(tri-tert-butylphosphine)palladium (3.0 mg, 0.006 mmol) was added. The vial was capped and heated at 100° C. under microwave irradiation for 20 min. After cooling, the reaction mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (12 g cartridge), eluting with 0-15% MeOH/CH2Cl2. The fractions containing the desired product (10-4) were pooled, and after solvent removal in vacuo, 5.0 mg (23%) of a semisolid were obtained. 1H NMR (300 MHz, CHCl3-d): δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 2H), 8.37-8.31 (m, 2H), 7.84 (dd, J=6.9, 1.2 Hz, 1H), 7.71 (dd, J=4.8, 1.8 Hz, 2H), 7.63 (dd, J=8.7, 4.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.39 (dd, J=6.9, 1.2 Hz, 1H), 6.64 (t, J=6.9 Hz, 1H), 4.65 (t, J=6.9 Hz, 2H), 3.60 (t, J=6.9 Hz, 2H). HRMS (ES) 369.1443 found (M+H), 369.1461 required.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][C:5]([CH:7]([C:12]([O:14][CH3:15])=[O:13])C(OC)=O)=O.[CH3:16][O-:17].[Na+]>CO>[CH3:1][N:2]1[C:16]([OH:17])=[CH:4][C:5]([CH2:7][C:12]([O:14][CH3:15])=[O:13])=[N:3]1
Reactant: CNN
Reactant: COC(=O)C(C(C)=O)C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(O)n(C)n1
Reaction time: 2 h
Yield: 35.3 %

Procedure:
23 g of monomethylhydrazine were added to 87 g (0.5 mole) of acetonedicarboxylic acid dimethyl ester in 200 ml of methanol, during which the reaction temperature rose to 65° C. After completion of the addition, the mixture was stirred for a further 2 hours and 0.5 mole of sodium methylate in methanol was then added. The reaction was slightly exothermic. The reaction mixture was stirred for a further 2 hours and evaporated, and the residue was dissolved in water. After acidification with glacial acetic acid, the precipitate was filtered off, dried and recrystallized from an ethyl acetate/acetonitrile mixture. 30 g (35% of theory) of 1-methyl-3-methoxycarbonylmethyl-5-hydroxypyrazole of melting point 148° C were obtained. ##SPC7##
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][O:8][C@H:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]1[CH:14]=[O:15])=[O:4].I[CH2:17][CH2:18][CH2:19][CH3:20].CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]([C@:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][O:8][C@H:7]([C:10]([CH3:11])([CH3:12])[CH3:13])[N:6]1[CH:14]=[O:15])=[O:4]
Reactant: CCCCI
Reactant: COC(=O)[C@@H]1CO[C@H](C(C)(C)C)N1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[C@@]1(C(=O)OC)CO[C@H](C(C)(C)C)N1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of (2R,4S)-2-tert-butyl-3-formyloxazolidine-4-carboxylic acid methyl ester (4.6 g, 21.4 mmol) [see D. Seebach, J. D. Aebi, M. Gander-Coquoz and R. Naef, Helv. Chim. Acta., 70, 1194 (1987)] in dry THF (120 mL) under N2 was added 1-iodobutane (12.2 mL, 106.8 mmol) and HMPA (12 mL). The mixture was cooled to −78° C. and a solution of sodium bis(trimethylsilyl)amide in THF (1 M, 32 mL, 32 mmol) was added dropwise over 15 minutes. After 2 h, the reaction mixture was warmed to 0° C. and quenched with saturated aqueous NH4Cl (200 mL). The quenched reaction mixture was diluted with ether (400 mL) and washed with water (3×200 mL) and brine (200 mL), then dried (Na2SO4) and filtered. Concentration of the filtrate and flash chromatography of the residue (20% ethyl acetate/hexanes) provided the title compound as a pale brown solid (4.0 g, 69%). MS(ES) m/e 272 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([OH:14])=[O:13]>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.COCCOC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
To a mixed solution of ethylene glycol dimethyl ether (400 ml)-2M aqueous sodium carbonate solution (80 ml), 4-bromobenzotrifluoride (5.0 g), 4-carboxyphenylboronic acid (3.9 g) and tetrakistriphenylphosphinepalladium (2.5 g) were added and stirred at 100° C. for a day and night. Concentrating the reaction liquid under reduced pressure, the residue was extracted with 1N aqueous sodium hydroxide solution, and the aqueous layer was neutralized by gradual addition of conc. sulfuric acid. The precipitated solid was recovered by filtration, washed with water and diethyl ether and dried under reduced pressure to provide the title compound (4.2 g) as white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccccc3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cccc(N3CCNCC3)n2)cc1

Procedure:
A solution of 0.7 g (2.06 mmol) of tert.butyl 4-(6-phenyl-pyridin-2-yl)-piperazine-1-carboxylate and 3 ml of trifluoroacetic acid in 30 ml of dichloromethane is stirred for three hours at ambient temperature. The solvent is then distilled off, the residue is combined with water and made basic with sodium hydroxide solution. It is then extracted with dichloromethane and the organic phase is separated off and dried over sodium sulphate.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1>>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]4)=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)Nc4ccccc4)cc3)cc2)CC1
Yield: 15.7 %

Procedure:
The title compound (7.4 mg, 16%) was prepared from {4-[(phenylamino)carbonyl]phenyl}boronic acid (24.1 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 495 (M+Na).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])/[C:18](=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)/[CH3:19])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Na+]>C1COCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21](/[CH:20]=[C:18](\[CH3:19])/[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]([CH3:8])[CH3:9])=[CH:11][CH:12]=2)=[O:30])=[CH:22][CH:23]=1
Reactant: C/C(=C\c1ccc([N+](=O)[O-])cc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(N)cc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A mixture of (±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-[(4-nitrophenyl)-methylene]propanamide (0.00742 mol) in THF (80 ml) and TiCl3 (30 ml) was stirred at 0° C. for 15 minutes. The mixture was poured into water, ice and NaOH 3N and extracted with CH2Cl2 (2×100 ml). The combined organic layers were dried, filtered and the solvent evaporated. The residue was taken up in CH2Cl2 and (C2H5)2O. The precipitate was filtered off and stirred K2CO3 10% and CH2Cl2, dried, filtered off and evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off, taken up in Na2CO3 10% and CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O, yielding 1.5 g (±)-(E)-2-[(4-aminophenyl)methylene]-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]propanamide (compound 61 1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[Cl:12][C:6]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: O=C(CBr)c1cccc(Cl)c1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 2-bromo-1-(2,3-dichlorophenyl)ethanone (4.25 g, 15.9 mmol) and potassium thiocyanate (1.54 g, 15.9 mmol) in ethanol (40 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.10 g (79.5%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[Sn](CCCC)(CCCC)CCCC>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.O1CCOCC1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-c2nccn2C)cc1
Temperature: 100 °C

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.22 g), 1-methyl-2-tributylstannanyl-1H-imidazole (0.50 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and 1,4-dioxane (4.4 mL) was heated at 100° C. for 1 hour. The mixture was cooled to room temperature and used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][O:18][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
Compound 158 (2.27 g, 8.33 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. Tosyl chloride (1.91 g, 10.0 mmol) and catalytic DMAP were added, followed by dropwise addition of triethylamine (2.55 mL, 18.33 mmol). The reaction was then stirred at 0° C. for 18 hours. The solvent was rotovapped off (removed under reduced pressure), and the crude material washed with EtOAc and filtered. The solids were washed with EtOAc, and the filtrate washed with 0.5N HCl (20 mL), brine (30 mL), dried over MgSO4, filtered, and rotovapped. The oil was chromatographed on silica eluting with a 5% EtOAc/hexanes gradient to 10% EtOAc/hexanes to give 159 (3.399 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.99 (dd, J=9.65, 3.54 Hz, 1H), 3.89 (dd, J=9.52, 5.37 Hz, 1H), 2.42 (s, 3H), 2.28 (dd, J=14.7, 6.23 Hz, 1H), 2.19–2.14 (m, 1H), 2.10 (dd, J=14.9, 6.35 Hz, 1H), 1.38 (s, 9H), 1.31–1.17 (m, 3H), 1.08–0.81 (m, 2H), 0.79–0.76 (m, 6H); [α]D=−10.1 (c1 in CHCl3).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([NH:17][C:18](=[O:20])[CH3:19])=[CH:12][C:11]=1[CH3:21])=O.[NH2:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CCO>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([CH:1]2[N:30]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:28](=[O:29])[C:27]3[C:26](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:25]2)=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[C:11]([CH3:21])=[CH:12][C:13]([NH:17][C:18](=[O:20])[CH3:19])=[CH:14][C:15]=1[CH3:16]
Reactant: COc1ccc(C=O)cc1COc1c(C)cc(NC(C)=O)cc1C
Reactant: Nc1ccccc1C(=O)NCc1cccnc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COc1ccc(C2Nc3ccccc3C(=O)N2Cc2cccnc2)cc1COc1c(C)cc(NC(C)=O)cc1C
Yield: 41.6 %

Procedure:
N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (100 mg, 0.305 mmol), 2-amino-N-(pyridin-3-ylmethyl)benzamide (83 mg, 0.367 mmol), and 0.2 equiv of Yb(OTf)3 in 5 mL of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 2-40% Methanol in DCM to give the desired product N-(4-(2-methoxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinazolin-2-yl)benzyloxy)-3,5-dimethylphenyl)acetamide (68.2 mg, 0.127 mmol, 41.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H), 2.08 (s, 6 H), 3.74 (s, 3 H), 3.98 (d, J=15.7 Hz, 1 H), 4.61 (s, 2 H), 5.07 (d, J=15.3 Hz, 1 H), 5.82 (d, J=2.3 Hz, 1 H), 6.58-6.74 (m, 2 H), 6.97 (d, J=8.2 Hz, 1 H), 7.12-7.37 (m, 6 H), 7.46 (d, J=2.0 Hz, 1 H), 7.64 (t, J=6.8 Hz, 2 H), 8.35-8.47 (m, 2 H), 9.67 (s, 1 H); LC/MS (electrospray+ve), m/z 537.2 (MH)+, Retention time t=4.23 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C32H32N4O4 [M+H]+537.2511, found 537.2511.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:37])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (74 mg, 59%), MS (ISP) m/z=505.3 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccc(N)nc4)nc3s2)cc1
Yield: 22 %

Procedure:
The titled compound (yield=22%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 2F (Example 2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.17 (s, 2H) 3.49 (s, 1H) 7.03 (d, J=9.35 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.89 (br. s., 2H) 8.08 (dd, J=11.12, 8.59 Hz, 3H) 8.24 (d, J=8.59 Hz, 1H) 8.62 (dd, J=9.35, 2.27 Hz, 1H) 8.72 (d, J=1.77 Hz, 1H) 13.02 (s, 1H); ESI-MS: m/z 420.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])=[O:5]>CO>[Cl:22][C:19]1[CH:18]=[C:3]([CH:2]=[CH:21][CH:20]=1)[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])=[O:5]
Reactant: Cc1ccc(CNC(=O)c2cc(Cl)ccc2Cl)cc1C(=O)O
Solvent: CO
Product: Cc1ccc(CNC(=O)c2cccc(Cl)c2)cc1C(=O)O

Procedure:
5-(2,5-dichloro-benzamido-methyl)-2-methyl-benzoic acid, melting point 215° to 217° C. (from diluted methanol).