Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)NC(C)(C)c1ccc(I)nc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)(C)c1ccc(-c2ccc(Br)cc2)nc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-(2-(6-iodopyridin-3-yl)propan-2-yl)acetamide, 33-d, (22 g, 72.4 mmol) in dioxane (100 ml) was added 4-bromophenylboronic acid (16 g, 79.6 mmol) and Pd(PPh3)4 (4.2 g, 3.62 mmol) and aq Na2CO3 (2N) (25.3 g, 238.8 mmol). The reaction mixture was then stirred at 95° C. for 3 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuo. The concentrate was extracted with ethyl acetate, washed with brine, and re-concentrated. Purification by silica gel (petroleum ether:ethyl acetate=1:1-ethyl acetate) gave the solid, 33-e, (18 g, 75%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:21]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1-c1ccccc1)c1ccccc1
Yield: 93.7 %

Procedure:
A 250 mL round bottom flask equipped with efficient magnetic stirring was charged with o-phenylphenol (17.0 g, 0.1 mol), toluene (100 mL) and triethylamine (11.1 g, 0.11mol, 10% excess). Benzoyl chloride (14.7 g, 0.105 mol, 5% excess) was added portionwise over 15 minutes while using an ice bath to help maintain the temperature below 30° C. The initially clear reaction mixture became a white slurry during the acid chloride addition. After stirring at room temperature for an additional 2.5 hours, the slurry was filtered and the clear organic layer was stripped on a rotary evaporator at 60° C./P=3.4 kPa. The light yellow oil crystallized upon cooling. The crude product was recrystallized from a mixture of hexane (100 mL)/toluene (20 mL) yielding 25.7 g (93.8%) white crystals. The structure was confined using 13C and 1H NMR, IR and GC/MS.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][C@H:12]([OH:11])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O[C@H]1CCNC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](O)C1
Yield: 96 %

Procedure:
Following Example 231, 5-Chloro-1-methyl-4-nitro-1H-pyrazole and (S)-(−)-3-hydroxypyrrolidine gave (S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol (250 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.64-4.59 (m, 1H), 3.78 (s, 3H), 3.71-3.59 (m, 2H), 3.39 (td, J=8.8, 3.4 Hz, 1H), 3.24 (dt, J=10.2, 1.6 Hz, 1H), 2.34-2.23 (m, 1H), 2.14-2.04 (m, 2H)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH2:10].[BH4-].[Na+]>CO>[CH3:9][NH:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of benzaldehyde (2.0 ml, 20.0 mmol) and methylamine (2.0M in THF) (20.0 ml, 40.0 mmol) and methanol (20 ml) was stirred at room temperature for 20 h under a nitrogen atmosphere. Sodium borohydride (2.27 g, 60.0 mmol) was added to the solution and it was stirred at room temperature for 2 h. The solvent was removed out under reduced pressure and the residue dissolved in chloroform. The chloroform was washed with brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure to yield a yellow oil (1.32 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:29]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:3][CH2:4]4)=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCCC1=O
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)ccc23)cc1Cl
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.37 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile and 339 mg (2.20 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 9:1 methylene chloride/methanol) gives 66 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 125-130° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].P(Br)(Br)[Br:17]>C(#N)C>[Br:17][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: BrP(Br)Br
Reactant: O=C1c2cccnc2C(=O)N1CCCO
Solvent: CC#N
Product: O=C1c2cccnc2C(=O)N1CCCBr
Yield: 83.8 %

Procedure:
To a solution of 0.813 g (3.94 mmol) 6-(3-hydroxypropyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione in 10 ml acetonitrile were added dropwise 0.854 g (3.15 mmol) PBr3 and the mixture was heated to reflux for 2 hours. The mixture was concentrated in vacuo and 6 ml of cold water were added to the residue. The precipitate was filtered, washed with cold water and dried in vacuo to get 0.71 g (71%) of the desired product as a light yellow powder. 1H-NMR (DMSO): 2.10-2.23 (m, 2H), 3.52-3.63 (m, 2H), 3.70-3.82 (m, 2H), 7.72-7.81 (m, 1H), 8.22-8.33 (m, 1H), 8.91-9.00 (m, 1H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:12]=2)[C:7]1=[O:25])[CH3:2].C1(C2[O:34]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:12]=2)[C:7]1=[O:25])=[O:34])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCSCCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Solvent: ClCCl
Product: CCS(=O)CCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
A mixture of 2-(2-ethylsulfanyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione (96 mg, 0.27 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (84 mg, 0.32 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for 72 h. Then the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2: 2N NH3/MeOH 97:3 to 9:1) to afford the title compound (34 mg, 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH4+:12].[OH-].O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:12])=[O:8]
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-dichloro-nicotinoyl chloride from step (a) above (1.73 g, 8.22 mmol)) in CH2Cl2 (50 mL) was added to a mixture of 28% aq. NH4OH (20 mL), water (20 mL) and CH2Cl2 (50 mL), and vigorously stirred at room temperature for 2 h. The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 191 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Sn](CCCC)(CCCC)CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OC1(C#Cc2ncc(-c3ccccn3)cc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 150 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol, 150 mg of (2-pyridyl)tributyltin, 86 mg of tetrakis(triphenylphosphine)palladium(0) and 3.5 ml of toluene was heated under stirring in an oil bath kept at 110° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 2.5% methanol/ethyl acetate, to give 100 mg of the target compound.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: CN(C)CCN
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)C(=NCCN(C)C)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In this example, 22.0 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate and 68.7 g of N,N-dimethylethylenediamine are dissolved in 700 ml of dried benzene. To the solution is dropwise added a solution of 17.2 ml of titanium tetrachloride in 40 ml of dried benzene and the mixture is stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution is added thereto. After removing an insoluble solid by filtration, the filtrate is extracted with 500 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel with ethylacetate/triethylamine (10/1) as an eluent to obtain 13.8 g of the desired product as a colorless oily matter.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28]C)=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([OH:28])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
186 mg (0.403 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 1 was mixed with 19.3 mg (0.484 mmol) of sodium hydroxide, 1 ml of water and 2 ml of ethanol and the mixture was stirred at room temperature for 24 hours. Then, the mixture was-concentrated under reduced pressure and the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated under reduced pressure to obtain 142 mg of 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid.
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 87.9 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[5-(cyclohexylcarbonyl)-2-ethylthiophen-3-yl]methyl}amino)benzoate (347 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heating under reflux overnight, and concentrated under reduced pressure. The residue was dissolved in water (30 mL), and 1N hydrochloric acid (5 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (296 mg, 88%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([NH2:62])[CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:30])[NH:62][CH:57]3[CH2:61][CH2:60][CH2:59][CH2:58]3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC1CCCC1)c1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1

Procedure:
From (S)-2-[5-(4-Carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5353, example 353, 0.03 g, 0.07 mmol), HATU (0.033 g, 0.086 mmol), and (0.03 mL, 0.26 mmol) of cyclopentylamine using General Procedure 3F. 1HNMR (DMSO-d6) δ(ppm)12.42 (m, 0.7H), 8.30-8.27 (d, 1H), 7.80-7.11 (m, 10H), 5.06-4.89 (m, 2 H), 4.50 (m, 1H), 3.51-3.48 (m, 1H), 2.26 (m, 1H), 1.89-1.52 (m, 9H), 1.14 (s, 1H); MS: 519.2 (M+H+).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(O)C>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(CO)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 3,4-dihexoxybenzaldehyde (15.3 g., 0.05M), sodium borohydride (1.85 g., 0.05M) and ethanol (350 ml.) is stirred at room temperature for one hour and then concentrated in vacuo. The residue is dissolved in chloroform (500 ml.), the solution washed with water (4×100 ml.), dried (Na2SO4) and evaporated under reduced pressure to give 3,4-dihexoxybenzyl alcohol (15.0 g.) as a pale yellow oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)C(C)C)cnc12
Yield: 55.4 %

Procedure:
A solution of 3-isobutyryl-4-chloro-8-methoxyquinoline (1.32 g, 5 mmol) and 4-amino-3-methylphenol (0.62 g, 5 mmol) in dioxan (50 ml) was heated at reflux for 1 hour, then cooled and the solid filtered off. This was taken up in a hot mixture of ethanol and tributylamine, cooled, and the solid filtered off. Recrystallisation from ethanol gave 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (0.97 g, 55%), m.p. 243°-5°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1[C:20](=[O:42])[C:21]2[CH:26]=[N:25][C:24](S(C)(=O)=O)=[N:23][C:22]=2[N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[CH2:38][CH2:37][CH2:36]3)[CH:32]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[C:20](=[O:42])[C:21]2[CH:26]=[N:25][C:24]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)=[N:23][C:22]=2[N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[CH2:38][CH2:37][CH2:36]3)[CH:32]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2c1=O
Yield: 64.6 %

Procedure:
Using the procedure outlined in Example 1 (g) the title compound was prepared from 4-morpholin-4-yl-phenylamine (6.5 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol). 11.9 mg of 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.38 (br, 1H), 8.53 (s, 1H), 7.69 (br, 1H), 7.43 (d, 1H), 7.23 (m, 4H), 6.64 (br, 2H), 4.36 (q, 2H), 3.87 (m, 4H), 3.04 (m, 8H), 2.22 (m, 2H), 1.39 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N5O4: 512.24 (M+H), Found: 512.4.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:20]1(N)[CH2:22][CH2:21]1.O>ClCCCl>[Cl:1][C:2]1[CH:13]=[C:12]([NH:14][CH:20]2[CH2:22][CH2:21]2)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]
Reactant: NC1CC1
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Solvent: ClCCCl
Solvent: O
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(NC2CC2)cc1Cl

Procedure:
2.00 g (5.95 mmol) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide (see Synthesis Example 4, Stage 1) were initially charged in 150 ml of 1,2-dichloroethane, 0.85 g (14.88 mmol) of cyclopropylamine was added and the mixture was heated under reflux for three hours. After cooling, water was added and the 2-chloro-N-cyclopropyl-4-(cyclopropylamino)-5-nitrobenzamide was filtered off with suction and dried. Yield 1.16 g (66% of theory)
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[CH3:17][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:15])[CH3:17])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N2 and then cooled to 0° C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off-white. The mixture was stirred at 0° C. for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2×50 mL), dried (Na2SO4), and concentrated to yield a light yellow solid (15.04 g, 98%).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([OH:43])=O)=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]>>[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([NH2:7])=[O:43])=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 212-213° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br s, 2H), 7.18-7.07 (m, 3H), 4.57 (d, J=16.3 Hz, 1H), 4.39 (d, J=16.3 Hz, 1H), 4.22 (dd, J=10.0, 9.1 Hz, 1H), 3.87-3.79 (m, 1H), 3.58 (dd, J=10.0, 6.6 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 366.9 (M+1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[C:9]1([C:19]([OH:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][CH:6]([O:20][C:19]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:21])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: C=CC(=O)OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CC(=O)OC(C)OC(=O)c1cccc2ccccc12
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (1.01 g, 8.7 mmol) and 1-naphthoic acid (1.00 g, 5.8 mmol) in 10 ml of freshly distilled CH2Cl2 was added EDC (1.60 g, 8.7 mmol) and DMAP (cat. amount) at room temperature. The resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and the mixture was washed with water. After extraction with EtOAc (3×20 ml), the organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 1.29 g (82%) of naphthalene-1-carbonyloxy-2-ethyl acrylate as a colorless oil. 1H NMR (250 MHz) δ 8.91 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.57 (m, 3H), 6.49 (d, J=17.3 Hz, 1H), 6.19 (dd, J=17.3, 10.4 Hz, 1H), 5.71 (d, J=10.4 Hz, 1H), 4.66 (m, 2H), 4.58 (m, 2H). 13C NMR (63 MHz) δ 167.2, 165.9, 133.8, 133.6, 131.5, 131.3, 130.5, 128.6, 128.0, 127.8, 126.6, 126.2, 125.7, 124.5, 62.7, 62.3.