Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:28])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:29](Br)[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:10][C:11](=[O:28])[CH:12]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1

Procedure:
A mixture of N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine phenacyl ester prepared as above (3.56 g.), phenacyl bromide (1.84 g.) and potassium carbonate (1.28 g.) in an anhydrous acetone (71 ml.) was heated to reflux for 7 hours. The insoluble substances were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residual oil was dissolved in chloroform, washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was triturated with diisopropyl ether to give crystalline N-tert-butoxycarbonyl-2-(4-phenacyloxyphenyl)glycine phenacyl ester (4.12 g.), which was recrystallized from ethanol to give the pure material, mp 125° to 126.5° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(C#N)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1cc(C#N)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
The nitrile 25F (2.3 g, 13.8 mmol), 4-trifluoromethylphenylboronic acid (2.61 g, 1.1 mol eq), palladium acetate (62 mg, 0.02 mol eq), cesium carbonate (8.97 g, 2 mol eq), and XPhos (260 mg, 0.04 mol eq) were mixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added. The mixture was heated at 100° C. for 4 h. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×30 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (9:1 petroleum ether:EtOAc) to afford 26I as a pale yellow solid (840 mg, 25% Yield). 1HNMR (DMSO, 200 MHz) δ 4.03 (s, 3H), 7.46 (s, 1H), 7.90 (d, 2H, J=7.8), 8.17 (s, 1H), 8.40 (d, 2H, J=8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31](OC)=[O:32])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CCOC(C)=O.O>C1COCC1.CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[C:16]([CH2:31][OH:32])=[N:17]2)=[CH:23][C:24]=1[F:30])#[N:29]
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (27.2 mg, 0.1 mmol) in THF/MeOH (1:1) (3 mL) at room temperature under argon was added NaBH4 (18.9 mg, 0.5 mmol) at 0° C. in an ice bath under argon carefully. The reaction mixture was allowed to warm to room temperature gradually and stirred overnight. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 37 mg (82%) of tert-butyl 4-(1-(4-cyano-3-fluorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.39-1.53 (m, 9H) 1.68-1.88 (m, 2H) 1.88-2.09 (m, 2H) 2.51 (t, J=5.93 Hz, 1H) 3.20-3.49 (m, 2H) 3.54-3.76 (m, 2H) 4.43-4.63 (m, 1H) 4.69 (d, J=5.71 Hz, 2H) 6.23 (s, 1H) 7.53-7.85 (m, 3H). MS (ESI) 389 (M+H-tBu).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a methanol (3.0 mL) solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.086 g), 10% palladium-carbon (43 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 10 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.058 g of methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[OH:32][C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH:36]3[NH:43][CH3:44])[CH2:34]1)[CH2:40]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([N:43]([CH:36]2[CH:37]3[CH2:38][CH:39]4[CH2:40][C:33]([OH:32])([CH2:34][CH:35]2[CH2:41]4)[CH2:42]3)[CH3:44])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C(=O)c1cccc(OCC2CCCCC2)c1)C1C2CC3CC1CC(O)(C3)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
3-Cyclohexylmethoxy-benzoic acid (300 mg, 1.3 mmol), HOBT (294 mg, 1.9 mmol), EDC (245 mg, 1.3 mmol), and 1-hydroxy-4-methylaminoadamantane (232 mg, 1.28 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.6 mmol) was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was purified directly by Preparative HPLC to give 199 mg of the title compound as a mixture of two isomers.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:17]1([CH2:16][CH2:15][N:14]2[C:8]3[C:9](=[CH:10][C:11]4[C:2]([NH:36][C:35]5[CH:34]=[CH:33][C:32]([O:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:38][CH:37]=5)=[C:3]([C:23]#[N:24])[CH:4]=[N:5][C:6]=4[CH:7]=3)[N:12]=[CH:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Oc2ccccc2)cc1)ncn3CCN1CCOCC1
Yield: 69 %

Procedure:
Following the procedure of Example 7, a mixture of 82.2 mg (0.24 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 53.3 mg (0.29 mmol) of 4-phenoxyaniline and 33.5 mg (0.29 mmol) of pyridine hydrochloride in 3.5 mL of 2-ethoxyethanol is heated at 130–135° C. for 1 hour to yield 81.2 mg (69%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>CN(C)C=O>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13])(=[O:16])[CH3:15]
Reactant: COc1ccc(CCl)c(F)c1OC
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(C)=O)c(F)c1OC
Temperature: 0 °C

Procedure:
5.5 g of α-chloro-2-fluoro-3,4-dimethoxytoluene and 4.05 g of potassium acetate are stirred at 80° for 25 hours in 50 ml of dimethylformamide. The reaction mixture is subsequently poured into 150 ml of ice-water and extracted with ether. The ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. 2-fluoro-3,4-dimethoxybenzyl acetate is obtained as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:16])=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[CH:7]=[C:3]3[CH2:2][N:17]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[C:15](=[O:16])[C:4]3=[N:5]2)=[CH:9][CH:10]=1
Reactant: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CCl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2Cc3cn(-c4ccc(Cl)cc4)nc3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 4-(chloromethyl)-1-(4-chlorophenyl)-N-(4-hydroxy-3-methoxyphenyl)-1H-pyrazole-3-carboxamide (29.9 mg, 0.076 mmol) and potassium carbonate (42 mg, 0.304 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (4.5 mL). The pH of the resulting mixture was adjusted to 8 by adding 1N aq. HCl. The solid was collected via filtration to give a product as pink color solid (15 mg, 56% yield). The product was used for next step without further purification. LCMS (ES): m/z 356.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:17][C@H:15]([C:12]2[N:6]3[CH2:7][CH2:8][C:9]4[CH2:10][CH2:11][C:2]([F:1])=[CH:3][C:4]([C:5]=43)=[CH:14][N:13]=2)[CH3:16])[N:22]=[CH:21][N:20]=1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (46.4 mg, 0.30 mmol), and DIPEA (102 μL, 0.60 mmol) in isopropanol (1.5 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 2-7% 2M NH3/MeOH in DCM). Crystallisation from MeOH (5 mL) afforded 406 as a white solid (43.2 mg, 41%). LCMS (Method K): RT 2.91 min [M+H]+ 352.1. 1H NMR ((CD3)2SO, 400 MHz): 8.07 (1H, s), 7.69 (1H, d, J=7.5 Hz), 7.45 (1H, dd, J=8.8, 4.8 Hz), 7.31 (2H, bs), 7.00 (1H, dd, J=10.8, 8.7 Hz), 5.67 (1H, quintet, J=6.9 Hz), 4.25-4.14 (2H, m), 3.05-3.01 (2H, m), 2.08-1.93 (4H, m), 1.58 (3H, d, J=6.7 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=1)#[CH:34]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: C#Cc1ccc(CO)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].N1CCCCC1.CC(=O)[CH2:24][C:25](=[O:27])[CH3:26]>N1C=CC=CC=1.CCOCC>[C:25]([CH:26]1[C:13](=[O:15])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[C:7]1=[O:9])(=[O:27])[CH3:24]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reaction time: 6 h
Yield: 76.1 %

Procedure:
To a solution of 100 g of 3-nitrophthalic acid in 100 mL of pyridine was added 0.8 mL of piperdine followed by 500 g of 2,4-pentanedione at room temperature. The mixture was stirred at 35°-40° C. for 6 hours and then diluted with 100 mL ether. The pyridine salt was filtered oft, washed with 100 ml of ether, dried, suspended in waer, and acidified with 400 mL of 6N HCl. The title compound was filtered off, dried,and recrystallized from ethanol to yield 84 g of yellow crystals, m.p. 148°-150°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24].[CH2:26](I)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:27][CH3:28])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]
Reactant: CCCI
Reactant: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone (compound 176) (75 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Propyl iodide (113 mg) and potassium carbonate (153 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (22 mg, yield 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:24][CH:21]1[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(cyclopropylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=O)[CH:6]=[C:7]([O-])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[Na].Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>>[CH2:8]([C:7]1[N:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:22]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH:6]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)NN
Reactant: CCCCC([O-])=CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Product: CCCCc1cc(C(=O)OCC)nn1C(C)(C)C

Procedure:
1-Ethoxy-1,2-dioxooct-3-en-4-olate, sodium salt (332.8 g, 1.50 mol) was treated with tert-butylhydrazine hydrochloride (186.6 g, 1.50 mol) according to the procedure described in Part B of Examples 37-39 to yield ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate as a brown oil.
Reaction SMILES: CCO.Cl.C([O:7][C:8]([C:10]1[NH:11][C:12]([CH3:19])=[CH:13][C:14]=1[NH:15][C:16](=[NH:18])[CH3:17])=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH3:17][C:16]1[NH:18][C:8](=[O:7])[C:10]2[NH:11][C:12]([CH3:19])=[CH:13][C:14]=2[N:15]=1
Reactant: CCOC(=O)c1[nH]c(C)cc1NC(C)=N
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2nc(C)[nH]c(=O)c2[nH]1
Temperature: 25 °C

Procedure:
A reaction flask equipped with a mechanical stirrer and a reflux condenser is charged with EtOH (900 mL), Ethyl-3-(ethanimidoylamino)-5-methyl-1H-pyrrole-2-carboxylate hydrochloride from example A5 (82.79 g; 0.34 mol) and 6M NaOH (226 mL; 1.36 mol). The well-stirred reaction mixture is heated to gentle reflux for 4 hours and is cooled to ambient temperature. The resulting solution is diluted with water (1000 mL) and the pH is adjusted to 6.5 by carefully addition of 2M citric acid. The precipitate is collected by suction filtration, washed with several portions of water and dried in vacuum at 50° C. to yield the title compound as off-white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17][C:18]2[C:26](CC)=[C:25](CC)[CH:24]=[CH:23][C:19]=2[C:20](N)=[O:21])[CH:14]=[CH:15][CH:16]=1.CO>CCCCCCC.C1COCC1.O1CCCC1>[CH3:9][O:10][C:11]1[C:12]2[C:20](=[O:21])[C:19]3[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(C(N)=O)c(Sc2cccc(OC)c2)c1CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCCC
Product: COc1cccc2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Finally, 1-methoxythioxanthen-9-one (S-12) was prepared. A stirred mixture of 2.05 mL of a 2.0 M solution in heptane/THF of lithium diisopropylamide (4.1 mmol) diluted with 15 mL of anhydrous tetrahydrofuran was cooled to 0° C. and treated dropwise with a solution of 2-[(3-methoxyphenyl)thio]diethylbenzamide (0.4 g, 1.4 mmol) in 3 mL of anhydrous tetrahydrofuran. The reaction mixture was warmed to ambient and stirred for 2 h. Methanol (1 mL) was added, and the resulting solution was washed twice with water, and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure to deposit a yellow solid. This crude product was recrystallized from methanol to provide 0.15 g (45% of theory) of a yellow solid. 1H NMR (CDCl3): δ 4.00 (s, 3H), 7.92 (d, 1H), 7.12 (d, 1H), 7.50 (m, 4H), 8.45 (d, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:39][C:40]([F:44])([F:43])[CH2:41]O.O>C1COCC1>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([O:26][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)O)cc1Cl
Reactant: OCC(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 38 (0.3 g, 0.79 mmol) was dissolved in THF (10 mL) to which carbonyldiimidazole (0.129 g, 0.79 mmol) was added. The solution was stirred at room temperature for one hour, at which time 2,2,2-trifluoroethanol (10 mL) was added and the solution stirred overnight at room temperature. The solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL). The organics were dried over MgSO4 and concentrated to a yellow-brown oil (0.19 g). Crude product was chromatographed using silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 petroleum ether/ethyl acetate as the mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(2,2,2-trifluoroethoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.09 g) as a green oil.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl>>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[CH:14][N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)CCCCl
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CN(C)CCCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 3-dimethylamino-1-propylchloride.