Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:13]([O:15]C)=[O:14])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:21](=[O:32])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:26][CH:27]=2)[C:13]([OH:15])=[O:14])=[O:8])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(NC(=O)c2ccc(OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a solution of methyl 3-[(4-methoxybenzoyl)amino]-4-[(4-tert-butylbenzoyl)amino]benzoate (0.487 g, 1.00 mmol) in tetrahydrofuran (32 mL) and methanol (8 mL) was added 5 N aqueous sodium hydroxide (0.6 mL). The resulting mixture was stirred for 16 h, a second portion of 5 N aqueous sodium hydroxide (0.6 mL) added, and the mixture stirred for an additional 16 h. The solvent was concentrated in vacuo and the crude product acidified with dilute aqueous hydrochloric acid and diluted with ethyl acetate. The mixture was extracted with saturated aqueous potassium carbonate solution. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from methylene chloride/-hexane provided 376 mg (100%) of the title product.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=2[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:27]1([C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=[C:31]2[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=23)=[O:39])[CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=3[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (125 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 mg, 0.67 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (257 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[Cl:15][C:16]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>N1C=CC=CC=1>[Cl:15][C:16]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (2.71 g, 12 mmol) and 2-(2,4-dichloro-phenoxy)aniline HCl (2.9 g, 10 mmol) were dissolved in pyridine (10 mL) at room temperature. After 1 hr the mixture was heated at 60° C. for 2 hour. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc and washed sequentially with 1M aq. HCl and sat. aq. NaHCO3 and the organic extract dried over MgSO4, and the solvent removed in vacuo to afford the title compound as a solid. LCMS (ES MS, M+H+found: 439) and proton NMR (400 MHz, CDCl3) δ 6.54-6.62 (m, 2H), 7.02-7.18 (m, 4H), 7.43 (d, J=2.5 Hz, 1H), 7.73 (dd, J=8.1 and 1.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 2H), 8.21 (d, J=8.6 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:14][CH:15]=1
Reactant: CNCC(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CNCC(C)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LCMS (PS-A3) Rt 6.94 min [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.86 (3H, s), 2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 7.37-7.40 (2H, m), 7.68 (2H, d), 8.35 (2H, s).
Reaction SMILES: [C:1]1([C@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl [((1S,2R)-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (39.2 g, 92 mmol), accessed via the method of 11A, and methyl iodide (39.2 g, 276 mmol, 3 eq) in 300 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (138 mL, 138 mmol, 1.5 eq). The reaction mixture was stirred 2 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM/hexanes (1:1), DCM, and EtOAc/hexanes (1:4)) to give the title compound (22.25 g, 58 mmol, 63%) as a pale yellow oil. ES-LCMS m/z 404.30(M+Na).
Reaction SMILES: [CH3:1][N:2]([C@@H:9]([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=1)[CH:10]=[CH2:11])[S@:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4].[OH-:31].[Na+].OO>C1COCC1>[OH:31][C:14]1[CH:13]=[C:12]([C@H:9]([N:2]([CH3:1])[S@:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4])[CH:10]=[CH2:11])[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: C=C[C@H](c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H](c1cc(O)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of (S)-N,2-dimethyl-N-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)allyl)propane-2-sulfinamide (800 mg, 1.8 mmol) and NaOH (144 mg, 3.6 mmol) in THF (10 mL), was added H2O2 (122 mg, 3.6 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After quenched with water, the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4. and then concentrated to give the title compound (500 mg, yield: 83%); m/z (ES+): 336 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH2:1]([C:5]1[N:9]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[C:8]([C:10]#[N:11])=[C:7]([C:12]#[N:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCCCc1nc(C#N)c(C#N)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-n-Butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole was prepared from 2-n-butyl-4,5-dicyanoimidazole by the procedure in Example 1, Part A using 4-nitrobenzyl bromide as the alkylating agent. The product was obtained as an oil. NMR (200 MHz, CDCl3) δ 8.29 (d, 2H, J=10 Hz); 7.29 (d, 2H, J=10 Hz); 5.36 (s, 2H); 2.67 (t, 2H, J=7 Hz); 1.70 (t of t, 2H, J=7,7 Hz); 1.36 (t of q, 2H, J=7,7 Hz); 0.86 (t, 3H, J=7 Hz); Mass Calcd. for C16H15N5O2 : 309.1225. Found: 309.1211.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1SC2C=CC=C(Cl)C=2N=1.[CH3:23][OH:24]>O>[CH3:23][O:24][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: CO
Reactant: Clc1cccc2sc(Br)nc12
Agent: Clc1nc2c(Cl)cccc2s1
Solvent: O
Product: COc1nc2c(Cl)cccc2s1
Yield: 92.5 %

Procedure:
A mixture (5 g, 0.023 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) (3.8 g, 0.025 mole) were added to methanol (80 c.c.), and the mixture was heated under reflux for 4 hours. After cooling, water (150 c.c.) was added to the reaction solution, followed by ice-cooling. The deposited crystals were filtered and washed twice with water to obtain 4.23 g of 2-methoxy-4-chlorobenzothiazole. Yield 92.5%, purity 98.5%, m.p. 55°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([Li])(CC)C.C1CCCCC1.C[O:45][B:46]([O:48]C)F>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[B:46]([OH:48])[OH:45]
Reactant: Fc1ccc(OC(F)(F)F)cc1
Reactant: COB(F)OC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cc(OC(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the 4-fluoro(trifluoromethoxy)benzene (2.0 g, 11.1 mmol) in dry THF (30 ml) at −78° C., was added ethylenediaminetetraacetic acid (EDTA, 1.36 g, 11.7 mmol) followed by a 1.4 M solution of sec-butyllithium in cyclohexane (8.33 ml, 11.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at −78° C., was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The volume of the reaction mixture was reduced in vacuo, then the residue dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10% NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3×40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a single regioisomer (1.51 g).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1.CN(C=O)C>O>[Br:1][C:25]1[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12]
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OC(C)C
Yield: 166.6 %

Procedure:
Dibromoisocyanuric acid (2.19 g) was added to a mixture of methyl 2′,4′-difluoro-3-isopropoxybiphenyl-4-carboxylate (3.90 g) and DMF (40 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,6-dichloro-pyrimidine (20.93 g, 140 mmol) and sodium thiomethoxide (10.3 g, 147 mmol) in THF (100 mL) was stirred at room temperature for 16 h, then the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, then dried over sodium sulfate and concentrated. The crude product residue was purified by recrystallization from hexanes (60 mL) to afford the title compound. The mother liquor was concentrated and the residue was purified by silica gel flash chromatography (0% to 10% ethyl acetate in hexanes as eluant) to afford additional title compound containing a small amount of byproduct 4,6-bis methylthio-pyrimidine. 1H NMR 400 MHz (CDCl3) δ 8.72 (s, 1H), 7.21 (s, 1H), 2.58 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:31][CH2:32][CH2:33][NH2:34]>>[OH:31][CH2:32][CH2:33][NH:34][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NCCO
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 89 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-hydroxyethylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:18]
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CC(=O)Nc1nccc2c(C(=O)c3c(F)cccc3Cl)c[nH]c12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]acetamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 8).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(C)ccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent—hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent—hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[C:18]12(O)[CH2:27]C3C[CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[Br:13][C:9]1[C:10]([F:12])=[CH:11][C:6]([CH2:5][O:4][C:3]23[CH2:27][CH:18]4[CH2:19][CH:20]([CH2:26][CH:24]([CH2:25]4)[CH2:2]2)[CH2:21]3)=[C:7]([Cl:14])[CH:8]=1
Reactant: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Fc1cc(COC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 56 h
Yield: 44 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (3.95 g, 16.49 mmol) and 1-adamantanol (0.65 g, 4.26 mmol) in methylene chloride (15 mL) and cyclohexane (30 mL) was added trifluoromethanesulfonic acid (0.04 mL, 0.45 mmol) at 0° C. The reaction mixture was stirred for 56 h at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded 1-((4-bromo-2-chloro-5-fluorobenzyl)-oxy)adamantane as a colorless solid (0.70 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=6.3 Hz, 1H), 7.37 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 2.16 (br s, 3H), 1.82-1.80 (m, 6H), 1.70-1.55 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(Cl)Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.[O-]S([O-])(=O)=O.[Mg+2]>CCN(CC)CC>[C:18]([CH2:17][N:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Temperature: 20 °C

Procedure:
Alternatively, one may prepare compounds of the invention via the procedures of Scheme IV. In the first step, a benzaldehyde derivative is treated with ethyl glycinate hydrochloride in CH2Cl2, Et3N, and MgSO4 at room temperature to produce an imine ester of formula 24 (step 1). For example, 3,4-dimethoxybenzaldehyde is suspended in a CH2Cl2 solution of H2NCH2COOEt.HCl, Et3N and MgSO4 and stirred at 20° C. to produce 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), p-anisidine (616 mg, 5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [EDCI] (959 mg, 5 mmol) in 50% aqueous 1,4-dioxane (10 mL) was stirred at ambient temperature for 17 h. After concentrating in vacuo, the residue was taken up in 10% methanol in ethyl acetate, washed with 1.3M hydrochloric acid then with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded N-(4-Methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 1); mp 219°-220° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(OC(=O)C)(=O)C>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:1][C:2]2[N:3]=[N:4][C:5]([CH:8]=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C)nn1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)nn2)cc1
Yield: 44.4 %

Procedure:
First, 24 g of 3,6-dimethylpyridazine and 60 g of p-nitrobenzaldehyde were dissolved in 1 liter of acetic anhydride, then heated under reflux so as to obtain 33 g of 3,6-di(p-nitrostyryl)pyridazine.