Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
Ethyl 6-chloro-8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.75 g, 2398 μmol) was dissolved in 1,4-dioxane (4797 μL) and N-ethyl-N-isopropylpropan-2-amine (1253 μL, 7195 μmol). tert-Butyl 2-aminoacetate hydrochloride (603 mg, 3597 μmol) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction was then diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (227 mg) as a white solid. MS (m/z)=420 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O>C(OCC)(=O)C>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=2[CH3:11])=[CH:22][CH:23]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1c(O)ccc(C=O)c1C
Reactant: CC(C)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C=O)ccc(OCc2ccc(CC(C)C)cc2)c1C
Yield: 88.2 %

Procedure:
A mixture of 4-hydroxy-2,3-dimethyl-benzaldehyde (220 mg), 4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) and ethyl methyl ketone (10 ml) was refluxed for 6 hrs. After cooling, the reaction mixture was diluted with ethyl acetate, the solution was washed with dil hydrochloric acid, water, successively, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane:EtOAc=10:1) to give the title compound (383 mg) having the following physical data:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]1[O:46][C@H:45]1[CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:47][C@H:45]4[CH2:44][O:46]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Reactant: OC[C@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4CO4)c(CC)c3)no2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (150 mg, 0.464 mmol) in THF (10 mL), PPh3 (146 mg, 0.557 mmol) and (S)-glycidol (52 mg, 0.696 mmol) is added. The mixture is cooled to 0° C. before DEAD (303 mg, 0.696 mmol, 320 μL of a 40% solution in toluene) is added. The mixture is warmed to rt and stirred for 1 h. The solvent is evaporated and the residue is purified by chromatography on prep. TLC plates with heptane:EA 1:1 to give (R)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (201 mg) as a white solid; LC-MS*: tR=1.10* min; [M+1]+=380.42.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:18]=[CH:17][C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=1.[C@@H:19]1([NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH2:25]>[Cu]I.O1CCOCC1>[CH3:15][N:14]([CH3:16])[C:13]1[CH:17]=[CH:18][C:10]([NH:25][C@@H:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]2[NH2:26])=[CH:11][CH:12]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(N[C@@H]2CCCC[C@H]2N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 59.3 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (190 mg, 0.998 mmol), K3PO4 (2.10 g, 9.89 mmol), 4-bromo-N,N-dimethylaniline (1.00 g, 5.00 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (0.60 L, 5.00 mmol) and dioxane (3.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 70 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 40:1; 20 mL fractions). Fractions 12-16 provided 692 mg (59% yield) of the product as a brown solid. 1H NMR (400 MHz, CDCl3): δ 6.75−6.63 (m, 4H), 3.00 (br s, 1H), 2.87−2.77 (m, 7H), 2.53−2.45 (m, 1H), 2.17−2.04 (m, 1H), 2.02−1.94 (m, 1H), 1.78−1.16 (m, 7H), 1.04−0.92 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 144.7, 140.9, 116.2, 116.1, 62.0, 56.5, 42.6, 35.7, 33.0, 25.8, 25.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O>[CH2:26]([O:25][C:23]([CH:22]([NH:1][C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:13]=2)[CH:7]=1)[CH3:28])=[O:24])[CH3:27]
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c(N)c2)c1=O
Solvent: O
Product: CCOC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)ccc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
A mixture of 0.12 g of 3-(5-amino-4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-19) and 0.23 g of ethyl 2-bromopropionate was stirred at 130° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 52 mg (yield, 32%) of 3-{5-[1-(ethoxycarbonyl)ethylamino]-4-fluorophenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-355; m.p., 78.2° C.).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:3])=[O:9]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of m-chlorobenzoic acid (8.26 g, 52.8 mmol) in 50 ml of ether. The mixture was concentrated and distilled under reduced pressure to give a colorless transparent oil of methyl m-chlorobenzoate (6.1 g, 35.8 mmol, yield 67.8%, b.p. 116°-121° C./21 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N(CC)CC)C.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH:39]([C:40]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)Nc2ccccc2)cc13
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 3-hydroxy-N-(tert-butyloxycarbonyl)morphinan (9 mg, 0.026 mmol) and triethylamine (10 μL, 0.04 mmol) in dry dichloromethane (0.3 mL) was added phenyl isocyanate (4 μL, 0.045 mmol) and the mixture was stirred for 1 h. After starting material disappeared on TLC, solvent was removed and column chromatography gave 11 mg (90%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.4 (2H, d); 7.3 (2H, t); 7.1 (3H, m); 6.9 (2H, m); 4.3 (1H, m); 3.8 (1H, m); 3.1 (1H, d. d.); 2.4˜2.8 (2H, m); 2.3 (1H, m); 1.3 (9H, s); 1.0˜1.7 (10H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][NH2:6].[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:30])[CH2:15][CH2:16][C@@H:17]2[CH2:27][CH:28]=O)[CH2:9]1>[OH-].[Na+].O1CCOCC1>[NH2:2][CH2:3][CH2:4][O:5][N:6]=[CH:28][CH2:27][C@H:17]1[CH2:16][CH2:15][C@:14]2([OH:30])[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:26])[C@@H:10]([CH2:9][C@@H:8]([OH:7])[CH2:25][CH2:24]1)[CH2:11][CH2:12]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=O)CC[C@]12O
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=NOCCN)CC[C@]12O
Yield: 52.7 %

Procedure:
To a solution of 0.47 g of 2-aminoethoxyamine hydrochloride in 16 ml of 1N NaOH and 20 ml of dioxane a solution of 0.89 g of 3β,14β-dihydroxy-5β-androstane-17β-ylacetaldehyde (Prepn. 2) in 15 ml of dioxane was added at room temperature. After 20 hrs the solution was extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography (SiO2) using chloroform with increasing amounts of methanol (6 to 20%) as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 0.55 g of the title compound (I-bf), as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH2:35][O:36][CH2:37][C@@H:38]([NH:40][CH:41]([CH3:43])[CH3:42])[CH3:39]>>[CH3:48][O:47][C:45]1[CH:44]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[CH:46]=1)[CH2:35][O:36][CH2:37][C@@H:38]([N:40]([CH:41]([CH3:43])[CH3:42])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:39]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: COc1cc(COC[C@H](C)NC(C)C)cc(OC)c1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3cc(OC)cc(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and [(S)-2-(3,5-dimethoxy-benzyloxy)-1-methyl-ethyl]-isopropyl-amine as described for example 1.
Reaction SMILES: II.[Br-:3].COC(=O)[C@@H]1CCCN1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:3][C:13]1[CH:18]=[CH:17][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reactant: [Br-]
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of 12 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.) for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2 H), 1.76-1.88 (m, 1 H), 1.94-2.08 (m, 1 H), 2.40 (dd, J=16.6, 9.0 Hz, 1 H), 2.92-3.00 (m, 1 H), 3.10 (d, J=12.7 Hz, 1 H), 3.38 (d, J=12.5 Hz, 1 H), 4.06 (dd, J=9.3, 4.6 Hz, 1 H), 5.04 (s, 1 H), 7.04-7.60 (m, 14H), 7,68 (d, J=8.3 Hz, 2 H), 7.82 (d, J=8.3 Hz, 2 H).
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=CC1=C[C@H]2CC(=O)O[C@H]2C1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Purified lactol 7 (800 mg, 4.15 mmol), was dissolved in CH2Cl2 (52 ml) and stirred at r.t. 4-Methylmorpholine N-oxide (729 mg, 6.23 mmol) and 4 Å molecular sieve (2.8 g) were added as solids and the reaction mixture was stirred at r.t. for 10 min. Tetrapropylammonium perruthenate (146 mg, 0.415 mmol) was added as a solid and the reaction was stirred at r.t. for 14 hours. The reaction mixture was filtered over Celite® and the solids were washed with CH2Cl2 (3×10 ml). The organic phase was concentrated to give the crude material as a black oil. The material was purified by column chromatography eluting with CH2Cl2/EtOAc (9:1), to give the lactone 54, (439 mg, 70%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(O)cc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>C1COCC1.C(Cl)Cl>[Cl:26][C:5]1[CH:6]=[C:7]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])[C:2]([C:32]([C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:42])=[N:3][CH:4]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 ml (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of phthalic anhydride (148 mg, 1.0 mmol) in 1 ml of DCM. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (70% ethyl acetate in hexane) to afford 80 mg of title compound as an off white solid. MS: (M+H)/z=564.0, (M-32)/z=532.0.
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:5]1[CH:4]=[N:3][C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)OCCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cnc2c(c1)OCCCN2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of bromine (960 mg, 6 mmol) in CH2Cl2 (50 mL) was added dropwise at 0° C. to a CH2Cl2 (50 mL) suspension of 6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (750 mg, 5 mmol) and solid K2CO3 (1 g). The mixture was stirred for 30 min at 20° C., then the excess bromine was quenched with a saturated solution of aqueous NaHSO3. The basic aqueous phase was separated, extracted with CH2Cl2, the combined organic layers were dried and evaporated to afford the title compound (1.10 g, 96%). 1H NMR (300 MHz, DMSO-d6, 8): 7.78 (d, J=1.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 6.35 (s, br, 1H), 4.10 (t, J=5.7 Hz, 2H), 3.24 (m, 2H), 1.92 (m, 2H). MS (ESI): m/e 229 and 231 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-butanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Cl)cc1Cl
Product: O=C(O)c1ccncc1NCc1ccc(Cl)cc1Cl
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from 2,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.04 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.38-7.42 (m, 2H), 4.63 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299. Found 297, 299.
Reaction SMILES: [CH3:1][SH:2].[Na].O.[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][S:2][CH3:1])=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]
Reactant: CS
Reactant: COc1cc(C(=O)CBr)ccc1OC(C)=O
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C(=O)CSC)ccc1OC(C)=O
Reaction time: 20 h
Yield: 83 %

Procedure:
As shown in the above-described reaction formula, the mixture of 600 ml of sodium methyl mercaptan (8.56 ml) and three drops of aliquat/5 ml of water solution was added to the solution containing 2.46 g of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (8.56 mM) dissolved in 10 ml of benzene. The mixture solution was stirred for 20 hours. The resulting product was extracted with ethylacetate, dried with anhydrous magnesium sulfate and the remaining solvent was removed. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 2-methoxy-4-[-2-(methylthio)acetyl]phenyl acetate (3; 2.18 g).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[CH3:35].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:34]([O:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:7]([NH:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=4[F:19])[N:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:10]=3[CH3:27])=[CH:6][C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:4][N:3]=2)=[CH:39][CH:38]=1)[CH3:35]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOc1ccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (32.7 mg, 0.07 mmol), 6-ethoxypyridin-3-ylboronic acid (14.1 mg, 0.084 mmol), tris(dibenzylideneacetone)dipalladium (0) (3.3 mg, 3.6 μmol), and tricyclohexylphosphine (2.1 mg, 7.5 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (0.5 mL) and aq. 1. 3M potassium phosphate tribasic (0.1 mL, 0.13 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-45% EtOAc in hexanes) to afford a light yellow solid as N-(6′-ethoxy-5-morpholino-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (1H, d, J=4.9 Hz), 8.66 (1H, d, J=2.4 Hz), 8.10 (2H, m), 7.94 (2H, d, J=3.9 Hz), 7.68 (1H, m), 7.46 (1H, m), 7.01 (2H, ddd, J=13.4, 8.6, 2.4 Hz), 6.93 (1H, d, J=8.8 Hz), 6.62 (1H, m), 4.45 (2H, q, J=7.1 Hz), 3.90 (4H, m), 3.28 (4H, m), 2.28 (3H, s), 1.45 (3H, t, J=7.1 Hz). Mass Spectrum (pos.) m/e: 555.2 (M+1).