Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3cccc([N+](=O)[O-])c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (106.9 mg, 0.327 mmol) and 3-nitrophenol were reacted as starting materials at 150° C. for 17 hours and post-treatment was then conducted, whereby the title compound was obtained as pale yellow prisms (140.4 mg, 99.9%). Melting point: 172.2-174.0° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 64.6 %

Procedure:
A solution of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.846 g, 1.83 mmol) in ethyl acetate (10 mL) was added to a suspension of platinum (IV) oxide (45 mg, 0.198 mmol) in absolute ethanol (30 mL) and the mixture hydrogenated at 10 psi of hydrogen for 100 minutes. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane afforded 0.548 g (64%) of [(2R)-8-(2.6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. HRMS: calcd for C23H20Cl2O4S+H+, 463.0532 1. found (ESI, [M+H]+), 463.0555.
Reaction SMILES: [CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([OH:10])=[N:3]1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cn1nc(O)c(=O)nc1S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(=O)nc1S

Procedure:
A solution of 2-methyl-3-mercapto-6-hydroxy-2,5-dihydro-1,2,4-triazin-5-one (0.8 g) in dry tetrahydrofuran (25 ml) was stirred for 30 min with triethylamine (0.835 ml) and tertbutyldiphenylsilylchloride (1.53 ml). The reaction mixture was partitioned between 1% aqueous NaHCO3 and ethyl acetate. Removal of the solvent from the dried organic layer left a residue which crystallized by trituration with light petrol affording 2-methyl-3-mercapto-6-tert-butyldiphenylsilyloxy-2,5-dihydro-1,2,4-triazin-5-one (1.34 g), m.p. 135° C. (decomp.);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][O:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: BrCCBr
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 3-fluoro-5-methylsulfonyl-phenol (4.2 g, 22.08 mmol), 1.2-dibromoethane (24 ml, 27.7 mmol) and potassium carbonate (6.1 g, 44.2 mmol) in acetonitrile (36 ml) was divided into 6 aliquots which were each heated under microwave radiation at 120° C. for 30 min. The reaction mixtures were cooled to room temperature, filtrated and pooled. The volatiles were evaporated, aqueous sodium carbonate (100 ml, 10%) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with brine (75 ml), dried (Na2SO4) and evaporated. Purification by flash column chromatography (ethyl acetate/isooctane, 0:1 to 1:0) gave the title compound (4.77 g, 73%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82 (15).
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][N:8]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc(OC)c1OC
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with N2 inlet, a 10-mL addition funnel and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (0.92 g, 3.92 mmol) in CH2Cl2 (5 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered, and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf =0.34) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 1.02 g (79.1%) of off-white solid (35); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2985, 2955, 2910, 2890, 2780 (C--H), 1620 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3H, CH3, J=6.5 Hz), 1.09 (d, 3H, CH3, J=6.7 Hz), 1.64-1.79 [m, 3H, H(5) and H(9)], 2.05 [bs, 1H, H(1)], 2.44 [bd, 1H, H(4)ax, J=10.6 Hz], 2.57 [bd, 1H, H(6)ax, J=10.8 Hz], 2.66 [heptet, 1H, CH(CH3)2, J=6.6 Hz], 2.71 [bd, 1H, H(6)eq, J=11.0 Hz], 3.02-3.07 [m, 2H, H(4)eq and H(2)ax ], 3.31 [bd, 1H, H(8)ax, J=13.2 Hz], 3.80-3.92 [m, 10H, H(8)eq and OCH3 ], 4.77 [bd, 1H, H(2)eq, J=13.5 Hz], 7.29 (s, 2H, Ar--H); 13C NMR (DCCl3) ppm 15.87, 19.42 (CH3), 29.02 [C(1)], 29.78 [C(5)], 32.35 [C(9)], 46.64 [C(2)], 51.73 [C(4)], 52.48 [C(8)], 54.39 [CH(CH3)2 ], 54.95 [C(6)], 56.13, 60.86 (OCH3), 103.83, 133.32, 133.21, 138.22, 153.21 (Ar--C), 169.66 (C=O). Anal. Calcd. for C20H30N 2 O4 : C, 66.27; H, 8.34. Found: C, 66.04; H, 8.32.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][C:18]=1[F:19].C(N(CC)CC)C>C(OC)(C)(C)C.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.[Cu]I>[F:12][C:13]1[CH:14]=[C:15]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: Fc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCOc1ccc(C#Cc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-ethoxyphenylacetylene, 0.02 m of 3,4-difluoroiodobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with 100 ml of methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4-difluoro-4'-ethoxytolan, K 67 I, Δε=11.18.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:17]([O:19][C:20](=[O:33])[CH:21]([N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]1=[O:32])[O:22][CH2:23][CH3:24])[CH3:18].CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:33])[CH:21]([O:22][CH2:23][CH3:24])[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]1=[O:32])[CH3:18]
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Reactant: OB(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Reaction time: 72 h
Yield: 47.6 %

Procedure:
To a 100 ml flask was added in sequence molecular sieves 4Å(200 mg), phenylboronic acid (418 mg), CH2Cl2 (10 ml), triethylamine (0.48 ml), a solution of (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (412 mg, example 19.2) in CH2Cl2 (10 ml), cupric acetate (31 mg) and TEMPO (295 mg). A CaCl2 trap was placed over the flask. The reaction was then stirred under air for 3 days. The solids were filtered off and washed with CH2Cl2. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane/EtOAc) to give (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (258 mg) as green oil. MS 317.2 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-piperidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J14) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow foam (257 mg).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:15][C:4]1[CH:3]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-methylbenzoate (1 g, 4.8 mmol) in methylsulfinylmethane (45 mL) were added phenol (0.43 g, 4.6 mmol) and potassium carbonate (1.24 g, 9 mmol). Then the mixture was stirred at 130° C. for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give tert-butyl 2-methyl-4-phenoxybenzoate (1.1 g, 86%) as a yellow solid. LRMS (M+H+) m/z: calcd 284.14. found 284.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18](O)=[O:19].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18]([Cl:25])=[O:19]
Reactant: O=C(O)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Reaction time: 8 h

Procedure:
A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) was stirred at room temperature under an atmosphere of nitrogen. Oxalyl chloride (0.28 ml) was added followed by N,N-dimethylformamide (1 drop) and stirring continued overnight. The solvent was removed in vacuo to give 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].Cl.ON.C(N(CC)CC)C.C([OH:30])C>O>[NH2:2][C:1]1[N+:11]([O-:30])=[CH:10][N:9]=[C:8]2[N:7]([CH3:14])[C:6](=[O:15])[N:5]([CH3:16])[C:4](=[O:17])[C:3]=12
Reactant: CCO
Reactant: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(N)[n+]([O-])cnc2n(C)c1=O
Yield: 85 %

Procedure:
0.235 g (1 mmol) of the compound 15, 0.138 g (2 mmol) of hydroxyamine hydrochloride and 0.243 g (2.4 mmol) of triethylamine were added to 3 ml of ethanol, and then the reaction mixture was refluxed for 3 hours. After cooling, 5 ml of water was added thereto, and the crystalline precipitate was filtered off and recrystallized from ethanol to give 0.223 g of 5-amino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione-6-oxide in a 85% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1.C([O-])(=O)CC([O-])=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:27])([CH3:26])[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C(=O)Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.5 %

Procedure:
Diethyl malonate (3.72 mL, 24.6 mmol) in ACN (50 mL) was cooled to 0° C. MgCl2 (2.34 g, 24.6 mmol) was added, followed by addition of TEA (7.18 mL, 51.7 mmol) slowly via syringe. The mixture was stirred at 0° C. for 15 minutes before being brought to room temperature and stirred for 2.5 hours. 2-(3-Chlorophenyl)-2-methylpropanoyl chloride (5.69 g, 24.6 mmol) was dissolved in ACN (20 mL) and added to the malonate solution. The reaction mixture was then stirred at 50° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and partitioned between 1M HCl and EtOAc. The aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the desired compound as a brown oil (8.76 g). MS (m/e)=341.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br>C(C(C)=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: Clc1ccc(OCCCBr)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
10 g of potassium carbonate was added to 30 ml of a methyl ketone solution containing 15.9 g of p-chlorophenol, and the solution was then heated with stirring at 60° C. for 1 hour. Afterward, 30 ml of a methyl ethyl ketone solution containing 50 g of 1,3-dibromopropane was added dropwise; After the addition, the solution was heated under reflux for 3 hours. The reaction solution was then cooled and a precipitate was removed therefrom, and the solution was evaporated to dryness under reduced pressure to obtain 23.2 g of 4-chlorophenoxypropyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(Cl)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-chloro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3): tR=1.01 min.
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C(C)C.[OH:14][CH:15]([CH3:20])[CH2:16][C:17]([O-:19])=O.C(O)(=O)C1C=CC=CC=1.O>C(O)CCCC>[OH:14][CH:15]1[CH2:20][N:4]([CH2:8][C:7]([NH2:6])=[O:9])[C:17](=[O:19])[CH2:16]1
Reactant: CC(O)CC(=O)[O-]
Reactant: CC(C)CN1CC(=O)NC1C(C)C
Agent: O=C(O)c1ccccc1
Solvent: CCCCCO
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Yield: 62.1 %

Procedure:
A solution of 2-methylpropyl 2-(1-methylethyl)-4-oxoimidazolidine-β-hydroxybutanoate (15 g, 52.4 mmol), benzoic acid (6.4 g, 52.4 mmol) and water (3.75 ml, 208 mmol) in n-pentanol (90 ml) was refluxed under nitrogen for 6 hr. After cooling the mixture was extracted twice with water (35 ml). The aqueous extracts were evaporated to dryness and the residue was crystallized from methanol to give 5.15 g (62.1%) of the title compound, m.p. 167°-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])(O)[CH:13]([C:15](O)=[O:16])[CH3:14])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.N1C=CC=CC=1>[F:23][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:15](=[O:16])[C:13]([CH3:14])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=[N:10]1
Reactant: CC(C(=O)O)C(O)(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
3-Carboxy-2-trifluoromethyl-2-hydroxy-1-butanal-1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) (0.315 g) was dissolved in the mixture of acetic acid (1.0 ml) and pyridine (1.0 ml) under a nitrogen atmosphere, and stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was diluted with diethyl ether (100 ml). Then, the diluted solution was washed with 3N hydrochloric acid (each 20 ml) twice, and saturated sodium bicarbonate (30 ml) once, dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was subjected to column chromatography. Thus, 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-on (0.227 g) was obtained.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (84 mg, 76%), MS (ISP) m/z=383.4 [(M+H)+], mp 170° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and propionic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2].[O:28]=[C:29]1[NH:34][C:33]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:32]=2[S:31][CH2:30]1>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:39]([C:36]2[CH:37]=[CH:38][C:32]3[S:31][CH2:30][C:29](=[O:28])[NH:34][C:33]=3[CH:35]=2)=[O:40])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1N
Product: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1NC(=O)c1ccc2c(c1)NC(=O)CS2

Procedure:
The title compound is prepared as an orange semisolid (280 mg, 87% yield) following Scheme 3 and in analogy to Example 35 using (3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (216 mg, 0.50 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (113 mg, 0.50 mmol, 1.0 eq) as starting material.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.Br[CH:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:21]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CCOC(=O)C(Br)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Oc1ccccc1-n1cccc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Sodium hydride (90 mg, 3.9 mmol) was added to a solution of 1-(2-hydroxyphenyl)pyrrole (0.41 g, 2.5 mmol) in anhydrous THF (5 mL) at RT. The reaction mixture was stirred for 1 h at RT, and then a solution of ethyl α-bromo-p-tolylacetate (1.0 g, 3.9 mmol) in anhydrous THF (5 mL) was added dropwise. After 12 h at RT, the solvent was removed in vacuo, and the residue was taken up in dichloromethane. The organic layers were washed with brine, dried, and evaporated. The residue was purified by chromatography (toluene) to give 0.46 g of the title compound as a colorless oil; IR (neat): 1734 cm−1; 1H NMR(CDCl3) d 1.16 (t, 3 H, J=7.0 Hz), 2.33 (s, 3 H), 4.13 (q, 2 H, J=7.0 Hz), 5.48 (s, 1H), 6.31 (m, 2 H), 6.95-7.40 (m, 10 H).