Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:32]2[CH2:33][CH2:34][CH:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[N:21]=4)[CH2:23][CH2:24]3)[CH2:30][CH2:31]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1nccc(N2CCN(CC3CCNCC3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(CC3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
A solution of 4-chlorophenylsulphonyl chloride (1.78 g) in methylene chloride (10 ml) was added dropwise over 15 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)piperazine-4-ylmethyl]piperidine trihydrochloride (2.78 g) and triethylamine (6.72 ml) in dichloromethane (40 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4ylmethyl]piperidine (2.50 g), mp 191-193° C. (decomp.).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[C:8]([F:19])[C:7]=1[F:20])[CH3:4].[CH3:21]I.Cl>CCCCC.C1COCC1.O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][O:18][CH3:21])=[CH:14][CH:13]=2)=[C:8]([F:19])[C:7]=1[F:20])[CH3:4]
Reactant: CCOc1ccc(-c2ccc(CO)[se]2)c(F)c1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: CCOc1ccc(-c2ccc(COC)[se]2)c(F)c1F
Reaction time: 2 h

Procedure:
400 mg (10.0 mmol) of sodium hydride (60% suspension in paraffin oil) are washed with n-pentane and suspended in 5 ml of THF. A solution of 1.9 g (about 6.0 mmol) of crude [5-(4-ethoxy-2,3-difluorophenyl)selenophen-2-yl]methanol in 20 ml of THF is added dropwise, and the mixture is stirred for 2 h. 1.0 ml (16.1 mmol) of methyl iodide is metered in, and the batch is stirred at RT for 2 h. Water is carefully added to the reaction mixture, which is then acidified using 2 N hydrochloric acid. The mixture is extracted with MTBE, and the extract is washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and MTBE. 2-(4-Ethoxy-2,3-difluorophenyl)-5-methoxymethylselenophene is obtained as a solid having an m.p. of 84° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C@H:28]([O:34][CH2:35][CH3:36])[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=3)[CH:14]=[C:13]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C@H:28]([O:34][CH2:35][CH3:36])[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=3)[CH:14]=[C:13]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH3:44])([CH3:46])[CH3:45])=[CH:39][CH:38]=3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccc(C(C)(C)C)cc3)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cc(-c3ccc(C(C)(C)C)cc3)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1)C(=O)O
Yield: 85.8 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 121) (345 mg, 0.56 mmol) and sodium hydroxide (1M, 1.1 ml, 1.1 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (284 mg, 86%) as a colourless foam.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(O)C.[Cl-].[NH4+]>[Fe].O>[Br:1][C:2]1[C:3]([CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1c(N)cccc1Br
Temperature: 80 °C

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 114c (1.00 g, 2.89 mmol), ethanol (20 mL), iron powder (−325 mesh, 1.62 g, 28.9 mmol), ammonium chloride (3.09 g, 57.8 mmol) and water (4 mL), and the reaction mixture was heated at 80° C. for 1 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite 521. The filter cake was washed with ethanol (3×50 mL), and the combined filtrates were concentrated under reduced pressure. The resulting residue was triturated with water (10 mL) and then dried to a constant weight at 45° C. under vacuum to afford 114d in quantitative yield (949 mg) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 6.82 (m, 2H), 6.53 (m, 1H), 4.86 (s, 2H), 4.68 (br s, 2H), 0.79 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:29])[CH:35]=2)[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.0 g), (3-methylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.35 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[OH:25][CH2:26][CH2:27][CH:28]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:28][CH2:27][CH2:26][OH:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=CCCO
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CCCO)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:18][C:19]([F:26])([F:25])[CH2:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:21]([CH2:20][C:19]([F:26])([F:25])[F:18])(=[O:23])=[O:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(NCc1cccnc1)c1ccc(Br)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(c1ccc(Br)cc1)N(Cc1cccnc1)S(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(1-(4-bromophenyl)ethyl)pyrid-3-ylmethylamine (630 mg, 2.16 mmol) and 4-(dimethylamino)pyridine (263 mg, 2.16 mmol) in 18 ml of dichloromethane was treated with 2,2,2-trifluoroethylsulfonyl chloride (420 mg, 2.3 mmol) with stirring for 15 minutes at room temperature. The solution was concentrated to approximately 2 ml and directly purified by radial chromatography on a 1 micron silica plate, eluting with 3% methanol/dichloromethane. The fractions were concentrated to afford the title compound. 1H NMR: 8.52 (bs,1H), 8.42 (bs,1H), (d,1H,J=8 Hz), 7.45 (d,2H,J=8 Hz), 7.22 (d,2H,J=8 Hz), 5.25 (q,1H,J=8 Hz), 4.38 (q,2H,ABX), 3.6 (q,2H,J=12 Hz), 1.68 (d,3H,J=8 Hz). MS calcd. 437.3; MS (M+1),(M+2), 438.0,439.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH:7]=[C:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[CH:7]=[C:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH3:2]
Reactant: CCNc1cc(C=C2SC(=O)NC2=O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1cc(C=C2SC(=O)NC2=O)ccc1N

Procedure:
To a stirred solution of 5-(3-Ethylamino-4-nitro-benzylidene)-thiazolidine-2,4-dione in THF, a solution of sodium hydrosulfite (3 eq.) in water was slowly added followed by an aqueous solution of K2CO3. The reaction mixture was refluxed over night. THF was removed in vacuo and residue extracted with ethyl acetate The organic layer was dried on Na2SO4 and the solvent evaporated to give the corresponding aniline derivative, which was used without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([O-])=O>CCO.[C].[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1N
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A solution of t-butyl 2-nitrobenzoate (4.9 g, 22 mmol) in EtOH (160 mL) was stirred with 10% palladium-carbon (700 mg) under an atmosphere of H2 (60 psi) at 23° C. After 4 h, the mixture was filtered and evaporated in vacuo to give t-butyl 2-aminobenzoate (4.0 g, 20.7 mmol) as a yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[C:12]([F:21])[C:13]([F:20])=[C:14]([OH:19])[CH:15]=3)[O:10]2)[CH2:5][CH2:4]1)[CH3:2].I[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:23]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:21])[C:13]=1[F:20])[O:10][CH:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7]1)[CH2:18][CH2:17]2)[CH3:24]
Reactant: CCI
Reactant: CC[C@H]1CC[C@H](C2CCc3cc(O)c(F)c(F)c3O2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(c(F)c1F)OC([C@H]1CC[C@H](CC)CC1)CC2

Procedure:
The DMF (100 ml) suspension containing 2-(trans-4-ethylcyclohexyl)-7,8-difluoro-6-hydroxychroman (28 g), iodoethane (25 g), and anhydrous potassium carbonate (15 g) was heated to reflux for 2 hours. The reaction solution was poured into 5% hydrochloric acid, extracted with toluene, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 6-ethoxy-2-(trans-4-ethylcyclohexyl)-7,8-difluorochroman (30 g). Moreover, this was recrystallized using acetone to obtain 26 g of a pure substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:10]([OH:13])(=O)[CH3:11]>>[CH:9]1[C:4]([NH2:1])=[CH:5][CH:6]=[C:7]([O:13][C:10]2[CH:11]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(=O)O
Product: Nc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
Into a 100 ml four-necked flask provided with a stirrer, an inlet tube for the supply of an inert gas and an outlet pipe for the discharge of said inert gas 0.654 g of pyromellitic anhydride, 0.60 g of 4,4'-diaminodiphenyloxide, 0.45 ml of acetic acid and 10.0 ml of nitrobenzene. The reaction mixture is heated to 120° C with stirring and passing an inert gas and maintained at this temperature for 1 hour. On completion of the reaction and cooling the reaction mixture, the precipitated polymer is filtered off, repeatedly washed with acetone and ethanol and dried in vacuum at 120° C ηinh in sulfuric acid is 0.67 dl/g. (0.05 g of the polymer in 10 ml of the solvent).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[CH:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottom flask 6-bromo-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine (2.124 g), 4-trifluoromethoxyphenylboronic acid (2.466 g), and sodium carbonate (0.635 g) were suspended in a mixture of DMF (81 mL) and deionized water (9 mL) that was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0.462 g) was added and the reaction mixture stirred at 90° C. overnight, concentrated, the residue dissolved in ethyl acetate, and washed with water (2×) and concentrated NaHCO3. The combined organic phase dried over MgSO4 and concentrated, then subjected to gradient chromatography (ethyl acetate/hexane) to produce dark grey solid. The solid was recrystallized from ethyl acetate/hexanes mixture to produce off-white material.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[C:14](=O)([O-])[O-].[K+].[K+].IC.CN(C)C=O>O1CCCC1>[CH3:14][N:12]([CH3:13])[C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C)c1ccc(O)cc1
Reaction time: 18 h
Yield: 38.5 %

Procedure:
A mixture of 4-methylaminophenol sulfate (1.00 g) and potassium carbonate (0.88 g) in dry tetrahydrofuran (29 mL) was stirred for 45 minutes at room temperature before iodomethane (0.36 mL) was added. After the reaction was stirred for 18 h, TLC showed incomplete reaction. Dimethylformamide (5 mL) was added to make the reaction mixture homogeneous and stirring was continued. After a total of 42 h, the reaction was evaporated and the residue was suspended in ethyl acetate (75 mL). The suspension was washed (saturated sodium bicarbonate, brine), dried, evaporated and dried under vacuum to give the crude product as an oil. The oil was preadsorbed onto silica gel; and chromatography, eluting with hexane:ethyl acetate (2:1), gave 4-dimethylaminophenol as a white solid (0.26 g); TLC: Rf =0.35, hexane:ethyl acetate (2:1); MS: m/z=138(M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[CH:38][CH:39]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)c2ncccc2c1=O
Reactant: Brc1ccc(-c2cccnc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(-c2cccc(-c3ccc(-c4cccnc4)cc3)c2)c2ncccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of the boronate from Step 1, 3-(4-bromophenyl)pyridine from Step 2 (1.5 eq), [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (7 ml/mmol) was stirred at 85° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 7:3 mixture of ethyl acetate and methylene chloride to afford the N-Isopropyl-1-{3-[4-(pyridin-3-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:21]=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+].C1(OC2(OC)C=CC=C(C=O)C2)CCCC1>CO.C(O)(=O)C.CO.C(Cl)Cl>[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:21][NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: COC1(OC2CCCC2)C=CC=C(C=O)C1
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]nc1NCc1ccc(OC)c(OC2CCCC2)c1
Reaction time: 24 h

Procedure:
A solution of ethyl 3-aminopyrazole 4-carboxylate (70 g, 0.45 mol) and 3-cyclopentyloxy-4-methoxybenzaldehyde (100 g, 0.45 mol) in methanol (400 mL) was treated with sodium cyanoborohydride (19.0 g, 0.30 mol) and sodium acetate (2.0 g, 0.024 mol) in a stirred reaction vessel equipped with pH stat attached to a syringe pump and a syringe filled with 3 N acetic acid in methanol. The pH stat was set to maintain pH 7. The acetic acid solution was added as the reaction proceeded. After 24 hours, 169 mL of acetic acid solution had been added and no aldehyde remained- in the reaction mixture by TLC (silica gel, 10% methanol/methylene chloride) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (19.0 g, 0.086 mol) was added to the reaction mixture. After 30 hours, a total of 216 mL of acetic acid solution had been added and 3-cyclopentyloxy-4-methoxybenzaldehyde (16 g, 0.072 mol) was added to the reaction mixture. After 48 hours, 263 mL of acetic acid solution had been added and additional 3-cyclopentyloxy-3-methoxybenzaldehyde (29 g, 0.13 mol) was added to the reaction mixture. After 76 hours, 320 mL of acetic acid solution had been consumed and the reaction mixture was evaporated under reduced pressure. The residue was partitioned between water (400 mL) and ethyl acetate (400 mL) and the ethyl acetate was evaporated under reduced pressure to give 240 g of crude product. The crude product was purified by flash chromatography over 900 g of flash chromatography silica gel and eluted with methanol-methylene chloride mixtures. Elution with pure methylene chloride afforded by-product 3-cyclopentyloxy-4-methoxybenzyl alcohol. Elution with 1-25% methanol-methylene chloride gave 91 g (42%) of nearly pure ethyl 3-(3-cyclopentyloxy-4-methoxybenzyl-amino)pyrazole-4-carboxylate. A portion of this ethyl 3-(3-cyclopentyloxy-4-methoxybenzylamino)pyrazole carboxylate (29 g) was recrystallized from methyl t-butyl ether to give 16.8 g of pure ethyl 3-(3-cyclopentyloxy-4-methoxybenzyl-amino) pyrazole-4-carboxylate, mp 102-104°.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COB(OC)OC.B.CSC.CO>C1COCC1>[C:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccnc1Nc1ccccc1
Agent: B
Agent: COB(OC)OC
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccnc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a refluxing solution of 6.5 g (30.4 mmole) of 2-phenylamino-3-pyridinecarboxylic acid and 7.5 mL (64.2 mmoles) of trimethylborate in 40 mL of THF under N2 was added dropwise, 65 mL (130 mmole) of 2M borane-methyl sulfide over a 30 min period. The reaction mixture was refluxed for 2 hrs, then cooled, and 50 mL of CH3OH was added dropwise with stirring over a period of 30 min. The mixture was refluxed for 5 min, and the solvents were evaporated to leave a gummy light yellow semi-solid which was partitioned between 250 mL of 2N HCl and 150 mL of CH2Cl2. The aqueous layer was separated and brought to pH 8 (NaHCO3), and the mixture was extracted with CH2Cl2 (700 mL). The CH2Cl2 was evaporated to leave 3.0 g of semi-solid which was purified by dry-column chromatography (glass column, 4×60 cm; 235 gm of silica; eluted with CH2Cl2). The fractions containing the product were extracted with CH2Cl2 then with CH3OH. The solvents were evaporated, and the oily residue was convened to the HCl salt in acetone-Et2O to give 1.4 g (40%) of cream-colored solid; mp 180°-182° C. (J. Med. Chem. 11, 894 (1968), mp 189°-190° C.). MS (EI) m/e (relative intensity): 200 (M+, 27), 199 (24), 182 (65), 181 (100).
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]2[CH2:26][CH2:25][C:16]3[N:17]([CH3:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:15]=3[C:14]2=[O:27])[N:8]=[CH:7]1)(=O)=O.C(N(CC)CC)C>O1CCOCC1.C(#N)C>[CH3:24][N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:15]2[C:14](=[O:27])[N:13]([CH2:12][C:9]3[N:8]=[CH:7][NH:6][C:10]=3[CH3:11])[CH2:26][CH2:25][C:16]1=2
Reactant: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Yield: 69 %

Procedure:
A solution of N,N,5-trimethyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido[4,3-b]indol-2-yl)methyl]-1H-imidazole-1-sulphonamide (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) was irradiated at room temperature with a medium pressure mercury lamp for 24 h. The reaction mixture was then concentrated in vacuo onto FCC silica and purified by FCC eluting with System A (100:8:1) to give the title compound (203 mg) as a solid. The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.