Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1>C1COCC1.CCOC(C)=O>[Br:2][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: CC(C)(C)C(=O)COc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Add phosphorous tribromide (1.45 g, 5.34 mmol) slowly to a solution of 1-(4-hydroxymethyl-phenoxy)-3,3-dimethylbutan-2-one (1.08 g, 4.85 mmol) in anhydrous THF under nitrogen at 0° C. Stir at 0° C. for 1 h and then raise to ambient temperature. Stir overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:6) to provide the title compound (1.152 g, 83%). MS (ES+) m/z: 205 (M-Br)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[C:22](=[O:23])[N:21]4[CH:24]=[CH:25][S:26][C:20]4=[N:19][C:18]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:35][CH:36]([CH:40]([OH:44])[C:41]([OH:43])=[O:42])[C:37]([OH:39])=[O:38]>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[C:22](=[O:23])[N:21]4[CH:24]=[CH:25][S:26][C:20]4=[N:19][C:18]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1.[OH:35][CH:36]([CH:40]([OH:44])[C:41]([O-:43])=[O:42])[C:37]([O-:39])=[O:38]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cc1nc2sccn2c(=O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CC(C)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
A mixture of 4 parts of 6-[2-[4-[bis(4-fluorophenyl)-methylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]-pyrimidin-5-one, 1.3 parts of (+)-[R-(R*,R*)]-2,3-dihydroxybutanedioic acid and 96 parts of 2-propanol was stirred and heated till all solid entered solution. The whole was cooled while stirring. The product was filtered off and dried, yielding 5.1 parts (98%) of (+)-6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one [R-(R*,R*)]-2,3-dihydroxybutanedioate(1:1).; mp. 198.7° C. (compound 147).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanoate (305 mg) in THF (6.0 mL) and methanol (12 mL) was added 1N aqueous sodium hydroxide solution (5.9 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (282 mg) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][CH3:8].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:1][CH2:2][C:3]([CH3:10])([CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][CH3:8])#[N:18]
Reactant: CCC(=O)NCC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCC(=O)NCC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 68 %

Procedure:
Prepared as in Example 215c from N-(3-hydroxy-2,2-dimethylpropyl)propionamide (Example 226c) and 2,6-dinitrobenzonitrile in 68% yield. MS 306 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[CH3:9][O:8][C:7]1[C:2]([C:10]#[N:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: [C-]#N
Reactant: COc1cccnc1Br
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccnc1C#N

Procedure:
A solution of 2-bromo-3-methoxy-pyridine from Example 13a in DMSO is treated with NaCN at 120° C. for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), dried over MgSO4 and evaporated to give 3-methoxy-pyridine-2-carbonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][N:27]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][C:28]1=[O:36]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:30]3[CH:31]=[CH:32][N:27]([CH2:26][C:25]4[CH:37]=[CH:38][CH:39]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:28](=[O:36])[CH:29]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COc1cccc(Cn2ccc(C(=O)O)cc2=O)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COc1cccc(Cn2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cc2=O)c1

Procedure:
1-(3-Methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(3-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C30H25ClN3O4 [(M+H)+] 526.2, obsd. 526.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:44][C:45]1[CH:62]=[CH:61][C:48]([CH2:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53](=[O:60])[NH:52][N:51]=2)=[CH:47][C:46]=1[C:63]([N:65]1[CH2:70][CH2:69][CH:68](O)[CH2:67][CH2:66]1)=[O:64]>C(Cl)Cl>[F:44][C:45]1[CH:62]=[CH:61][C:48]([CH2:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53](=[O:60])[NH:52][N:51]=2)=[CH:47][C:46]=1[C:63]([N:65]1[CH2:66][CH2:67][CH:68]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:69][CH2:70]1)=[O:64]
Reactant: Cc1cccc(O)n1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(OC2CCN(C(=O)c3cc(Cc4n[nH]c(=O)c5ccccc45)ccc3F)CC2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 7.3 %

Procedure:
6-methylpyridin-2-ol (95 mg, 0.87 mmol) was added in one portion to polymer supported triphenylphosphine (1.89 mmol/g; 460 mg, 0.87 mmol) in DCM (5 ml). Di-tert-butyl azodicarboxylate (201 mg, 0.87 mmol) and 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (111 mg, 0.29 mmol) in DCM (1 ml) was added and the resulting mixture was stirred at 20° C. for 4 hours. The reaction mixture was diluted with DCM and washed with water (×2). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (10 mg, 7.3% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.70-1.80 (1H, m), 1.85-1.95 (2H, m), 2.02-2.08 (1H, m), 2.41 (3H, s), 3.22-3.28 (1H, m), 3.51-3.57 (1H, m), 3.74-3.83 (1H, m), 3.95-4.03 (1H, m), 4.28 (2H, s), 5.32-5.35 (1H, m), 6.50 (1H, d), 6.69 (1H, d), 7.02 (1H, t), 7.26-7.29 (1H, m), 7.33-7.35 (1H, m), 7.44 (1H, t), 7.71-7.79 (3H, m), 8.45-8.48 (1H, m), 10.33 (1H, s); m/z (LC-MS, ESI+), RT=2.26 (M+H 473.6).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]2[CH:18]=1)([O-])=O>CO>[N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:18][N:13]2[CH:14]=[CH:15][CH:16]=[N:17][C:12]=12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cccnc2n1
Solvent: CO
Product: Nc1ccccc1-c1cn2cccnc2n1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
2-(2-Nitro-phenyl)-imidazo[1,2-a]pyrimidine (2 g, 8.33 mmol) and NaHS (2.8 g, 6 eq) were refluxed in 25% aqueous methanol (40 ml) water overnight. The reaction mixture was cooled to room temperature, and concentrated to dryness. Methanol (10 ml) and water (30 ml) were added, and the product was extracted with CH2Cl2 (3×100 ml). The combined organic layers were concentrated to dryness, chased with 10% MeOH:CH2Cl2 and dried under high vacuum at 45° C. to obtain the product as an orange solid (1.34 g, 76% yield). (MS, M++H=211.1)
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared by coupling 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-3-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 201). HPLC Ret time=3.67 min. LCMS [M+H]+ 411.221.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].CC(=O)OCC>CO.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1nc(Cl)ccc1N
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution of 6-chloro-N-methyl-3-nitropyridin-2-amine (630 mg, 3.36 mmol) in MeOH (10 ml) and water (10 ml) was added Fe (940.8 mg, 16.8 mmol) and NH4Cl (898.8 mg, 168 mmol) at 20° C. The mixture was stirred for 3 hours under reflux temperature until TLC (PE: EA=3:1) showed that the reaction was complete. The mixture was filtered, the filtrate concentrated and residue treated with water (10 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (30 ml), dried over Na2SO4 and concentrated to give the desired product (316 mg, 59.7%) as a yellow solid which was used in next step without further purification. LCMS (m/z): 158.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2].O.C(=O)(O)O>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCN(OC(=O)OC(C)(C)C)CC5)c(C#N)cc34)ccc21
Agent: O=C(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCNCC5)c(C#N)cc34)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 373.3 %

Procedure:
After dissolving 6-cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (180 mg, 0.0753 mmol) in trifluoroacetic acid (1 ml), the solution was stirred at room temperature for 0.5 hour. Saturated bicarbonate water was added, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, after which ethanol was added to the obtained amorphous substance for crystallization. After dilution with hexane, the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (132 mg, 0.2811 mmol, 88.96%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]([CH3:15])[NH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][N:13]([CH3:15])[NH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)Nc1ccc([N+](=O)[O-])c(N)c1
Temperature: 125 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (20 g, 116 mmol), N,N-dimethyl-hydrazine (44 mL, 580 mmol) and anhydrous potassium carbonate (17.6 g, 128 mmol) in N,N-dimethylacetamide (50 ml) were stirred at 125° C. under nitrogen for 3 days Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water (400 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(N′,N′-Dimethyl-hydrazino)-2-nitro-phenylamine (10.7 g, 47% yield) as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: COC([C:5]1([CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=O.[Li+].[Cl-]>CN(P(N(C)C)(N(C)C)=O)C>[CH3:14][C:12](=[CH2:13])[CH2:11][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: C=C(C)CC1(C(=O)OC)CCCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)CC1CCCC1=O
Temperature: 73 °C

Procedure:
A mixture of methyl-1-(2-methyl-2-propenyl)-2-oxo-1-cyclopentanecarboxylate (78.4 g), HMPA (hexamethylphosphoramide, 250 ml) and LiCl (34 g) is heated to 73° C. for 36 hrs. Extraction (3 times, ether/water) of the reaction product provides a brown oil which, upon fractional distillation (63° C.-75° C./5.32×102Pa), yields 2-(2-methyl-2-propenyl)-1-cyclopentanone.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[O:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: OCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 72.4 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 2.0 g (6.5 m mol) of 4,5-dichloro-2-(4-trifluoromethylphenyl)-3(2H)-pyridazinone and 0.92 g (6.5 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.51 g of powdery potassium hydroxide. Then, the procedures in Synthesis Example 2 were repeated to give 1.94 g of the intended compound.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH3:35])[C:23](O)=O)(=[O:18])[CH3:17]>CO>[C:16]([NH:19][C:20]1[CH:21]=[C:22]([C:23]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH3:35])(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1N1CCCCC1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Solvent: CO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(NC(C)=O)c3)n2)cc1F

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (70 mg; 0.33 mmol) and Intermediate 32 (91.17 mg; 0.33 mmol). Title compound was isolated after trituration with MeOH as an off-white powder. 1H NMR (DMSO-d6, 300 MHz) δ 9.10 (bs, 1H), 8.88, (bs, 1H), 8.11 (t, J=7.6 Hz, 1H), 8.03 (dd, J=8.1, 1.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.45 (d, 8.4 Hz, 1H), 3.90 (s, 3H), 3.19-3.12 (m, 1H), 2.96-2.89 (m, 1H), 2.65-2.57 (m, 1H), 2.19 (s, 3H), 1.87-1.66 (m, 4H), 1.53-1.44 (m, 2H), 0.84 (d, J=6 Hz, 3H). LC/MS (Method B): 453.3 (M+H)+. HPLC (Method A) Rt 5.16 min (purity: 97.5%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[OH-].[Na+].CO>>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:6]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1-c1cc([N+](=O)[O-])ccc1C(=O)O

Procedure:
4-Nitro-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 178A, was saponified using aqueous NaOH—CH3OH to give 4-nitro-2-(2-methylphenyl)benzoic acid; HRMS calcd for C14H11NO4 257.0688, obsd 257.0699.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:39](=[O:40])[CH2:38][C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=1)=[O:42]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CSc1ccc(NC(=O)CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(NC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 3-(4-(methylthio)-phenylamino)-3-oxopropanoic acid (32.2 mg, 0.143 mmol), DMAP (13.08 mg, 0.107 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(methylthio)-phenylamino)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide (20 mg, 44.6% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=1>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[N:6]=[C:2]2[CH3:1])[N:23]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: COc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=316.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloro-4-methoxypyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5]O.ClCCCS([NH:37]CC(OC)CSCCCCCCCCCCCCCCCC)(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH3:1][O:2][CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][NH2:37]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)COC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)COC

Procedure:
2-Methoxymethyl-3-octadecylcarbamoyloxypropanol Vk2 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound: m.p. 84°-85° C. The summary of the experimental condition and the physical data of the product are listed in Table 6.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23](=[S:25])[NH2:24]>>[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:24]=1
Reactant: Cc1ccncc1C(N)=S
Reactant: CCOC(=O)c1cccc(C(=O)CBr)c1
Product: CCOC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1
Yield: 37.6 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using ethyl 3-(bromoacetyl)benzoate (18.10 g) and 4-methylpyridine-3-thiocarboxamide (8.11 g), the title compound (6.50 g) was obtained as pale-yellow powder crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[O:9]C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[OH:9]
Reactant: COc1c(F)cccc1I
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1c(F)cccc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs, Ann. Chem., 746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane (35 ml) is added a 1M solution of boron tribromide in dichloromethane (18.2 ml). The mixture is kept under argon and stirred for 4 hours at room temperature. The mixture is poured into a saturated aqueous sodium bicarbonate solution and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 2-fluoro-6-iodophenol (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2.[O:34]=[C:35]1[O:41][C@H:40]([C@H:42]([CH2:44][OH:45])[OH:43])[C:38]([OH:39])=[C:36]1[OH:37]>CO>[O:34]=[C:35]1[O:41][C@H:40]([C@H:42]([CH2:44][OH:45])[OH:43])[C:38]([O-:39])=[C:36]1[OH:37].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a warm solution of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (1.0 g, 2.2 mmol) in methanol (30 mL) was added a solution of L-ascorbic acid (475 mg, 2.7 mmol) in methanol (20 mL) and the solution was allowed to cool to room temperature. About 25 mL of the solvent was evaporated in vacuo and the remaining solution (25 mL) was allowed to stand at room temperature for 2.5 h. The crystals were filtered and dried in vacuo to give 1.3 gram (92% yield) of the title compound as light grey crystals. mp 235-245° C. Anal. Calcd. for C27H36N4O2×C6H8O6×H2O: C, 61.7; H, 7.2; N, 8.7. Found: C, 61.9; H, 7.0; N, 8.9.