Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a stirred solution of 5.4 grams (0.017 mole) of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid in 25 mL of methylene chloride was added 2.4 grams (0.017 mole) of 4-nitrophenol. The reaction mixture was cooled to 0° C., and 3.5 grams (0.017 mole) of dicyclohexylcarbodiimide was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes, and then it was warmed to ambient temperature where it was stirred for an additional two hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was stirred with diethyl ether, and the resultant solid was collected by filtration to yield 5.4 grams of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate, m.p. 130°-132° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O=C1CCC(=O)N1[C:8](=[O:20])[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[NH2:21][C@H:22]([C@@H:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])[C:23]([OH:25])=[O:24].O>C1COCC1>[CH2:29]([O:28][C@@H:26]([CH3:27])[C@@H:22]([NH:21][C:8](=[O:20])[C:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])([CH3:11])[CH3:10])[C:23]([OH:25])=[O:24])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1C(=O)CCC1=O
Reactant: C[C@H](OCc1ccccc1)[C@@H](N)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](OCc1ccccc1)[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture comprising of tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylcarbamate (1 g, 3.33 mmol) (prepared according to the procedure described in EP1486498A1 page 20) and (2R,3S)-2-amino-3-(benzyloxy)butanoic acid (0.697 g, 3.33 mmol) in THF (40 ml)/water (10 ml) was treated with TEA (1.392 ml, 9.99 mmol) and stirred at 50° C. for 4 hours. The resulting mixture was concentrated in vacuo and EtOAc (20 ml) was added. The pH was adjusted to pH2 with 1M HCl. The organic portion was separated and the aqueous phase was back extracted with EtOAc (30 ml). The combined organic portions were washed with a saturated solution of brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:24][CH2:25][O:26][CH3:27])=[C:10]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:5])[CH3:2].[H][H]>[Pt].[C].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:24][CH2:25][O:26][CH3:27])=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCOC)c(-c2cccn2C(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCOC)c(C2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
8.2 g of 5% platinum-carbon catalyst was added to an ethanol (400 ml) solution of 28.4 g of t-butyl 2-(5-ethoxycarbonyl-2-methoxymethoxy-phenyl)-pyrrole-1-carboxylate, and the reaction liquid was stirred for 3 days in a hydrogen atmosphere. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/6.5 to 1/6) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]([OH:16])=O)[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.C[ClH]N.[CH2:32]([N:34](CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:32][NH:34][C:14]([C:4]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:2][N:7]=[N:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of methyl 3,5-diphenylpyridazine-4-carboxylic acid (compound 6) (200 mg, 0.72 mmol) in CH2Cl2 (10 mL), oxalyl chloride (230 mg, 1.81 mmol), catalytical DMF were added and stirred at 0° C. for 1 h. After the complete consumption of the acid shown by TLC, the volatiles were removed under reduced pressure and the crude acid chloride obtained was taken up in dry CH2Cl2 (5 mL). A solution of methyl amino hydrochloride (238 mg, 3.62 mmol) in CH2Cl2 (5 mL) cooled to 0° C., triethylamine (219 mg, 2.17 mmol) and acid chloride were added dropwise at 5° C. After the completion of the starting material, the reaction mixture was diluted with CH2Cl2 (20 mL), washed with aq NaHCO3 (5 mL×1), brine (5 mL×1) and dried over anhydrous Na2SO4. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 30% EtOAc in hexane) to furnish N-methyl-3,5-diphenylpyridazine-4-carboxamide (compound 1) (100 mg, 47%) as a light orange solid.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][CH:74]([CH3:76])[CH3:75])[CH:68]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[CH:68]=[C:69]([NH:73][CH:74]([CH3:76])[CH3:75])[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: CC(C)Nc1cc(Cl)ncn1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CC(C)Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 142 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloro-N-isopropylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J=1.89 Hz, 2H), 6.48 (d, J=1.89 Hz, 3H), 5.72 (s, 1H), 3.78-4.05 (m, 5H), 3.42-3.60 (m, 3H), 1.90-2.08 (m, 2H), 1.80 (td, J=3.59, 8.97 Hz, 3H), 1.65 (td, J=3.21, 8.03 Hz, 2H), 1.13-1.39 (m, 13H). EIMS (m/z): calcd. for C20H26O2N6O (M+1H) 437. found 437.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C[Si](C)(C)[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.O=[CH:25][CH2:26][CH2:27][NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>CC#N>[N:1]([CH:25]([O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:26][CH2:27][NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C)cc1
Reactant: O=CCCNC(=O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc(COC(CCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of azidotrimethylsilane (0.93 mL; 7.1 mmol) and methyl 4-[(trimethylsiloxy)methyl]benzoate (1.35 g; 5.7 mmol) in anhydrous MeCN (3 mL) was added dropwise to a solution of N-(3-oxopropyl)trifluoroacetamide (0.8 g; 4.7 mmol) containing a catalytic amount of anhydrous ferric chloride (38 mg; 0.2 mmol) in anhydrous MeCN (10 mL) cooled to −40° C. The mixture was stirred at −40° C. for 90 min and the reaction quenched with phosphate buffered saline (pH 7.4). The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried (MgSO4), filtrated and evaporated. The residue was purified by silica column chromatography (DCM:Hex:EtOAc, 6:3:1) and the methyl 4-[(3-amino-1-azidopropoxy)methyl]benzoate was obtained as a clear viscous liquid, which solidified upon prolonged standing in a yield of 0.95 g (56%). 1H-NMR (500 MHz, CDCl3): δ=2.04-2.14 ppm (m, 2H), 3.40-3.47 ppm (m, 1H), 3.56-3.64 ppm (m, 1H), 3.92 ppm (s, 3H), 4.63 ppm (d, J=12.0 Hz, 1H), 4.66 ppm (dd, J=6.0, 4.5 Hz, 1H), 4.90 ppm (d, J=12.0 Hz, 1H), 6.89 ppm (bs, 1H, NH), 7.41 ppm (d, J=8.5 Hz, 2H), 8.04 ppm (d, J=8.5 Hz, 2H); 13C-NMR (500 MHz, CDCl3): δ=33.94, 35.83, 52.29, 70.66, 90.46, 115.76 ppm (q, J=1146.5 Hz), 127.76, 130.02, 130.14, 141.30, 157.23 (q, J=148.0 Hz), 166.79 ppm. HRMS [+Scan]; calculated m/z for C12H19O3Si 239.1098; observed mass: 239.1095.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.C(=O)=O.[Br:24]Br>CC(C)=O.O>[Br:24][C:12]1[C:13]2[S:17][CH:16]=[CH:15][C:14]=2[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2cccc3sccc23)cc1
Reactant: BrBr
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2ccc(Br)c3sccc23)cc1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a 25 ml round bottom flask was added 4-(4-methoxyphenyl)-1-benzothiophene (500 mg, 2.08 mmol), CH2Cl2 (10 ml), and the solution was cooled to −20° C. (acetone-water, CO2). Bromine (8.33 ml of 0.25 M stock in CH2Cl2, 2.08 mmol) was slowly added dropwise over 0.5 h and the reaction was stirred for a additional 0.5 h. The reaction was then washed with water, dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 460 mg orange oil. Recrystallization from 3:97 EtOAc-hexanes afforded 350 mg (53%) of product as white crystals: 1H NMR (300 MHz, DMSO-d6): δ 3.83 (3H, s), 7.10 (2H, d, J=8.0 Hz), 7.31 (1H, d, J=7.9 Hz), 7.51 (2H, d, J=8.4 Hz), 7.56 (1H, d, J=5.6 Hz), 7.68 (1H, d, J=7.9 Hz), 7.92 (1H, d, J=5.6 Hz).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.[CH3:10][Mg]Cl>C1COCC1>[OH:1][CH:2]([CH3:10])[CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1
Reactant: C[Mg]Cl
Reactant: N#CCC1(CC=O)CC1
Solvent: C1CCOC1
Product: CC(O)CC1(CC#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a -5° C. solution of the aldehyde from Step 2 (3.00 g, 24.4 mmol) in 65 mL of THF was added methyl magnesium chloride (3.0M solution in THF, 9.5 mL, 29 mmol) and the reaction was stirred 2 h at 0° C. The reaction was quenched with 1M HCl and extracted with ethyl acetate. The organic extracts were washed with saturated NaHCO3 and brine and dried over MgSO4. Purification by flash chromatography (30% ethyl acetate/hexanes) provided 2.46 g of the title product.
Reaction SMILES: [S:1](=[O:3])=[O:2].[Ca:4].[S:5](=[O:8])([OH:7])[OH:6]>>[S:5](=[O:6])([OH:8])[O-:7].[Ca+2:4].[S:1](=[O:6])([OH:3])[O-:2]
Reactant: O=S=O
Reactant: [Ca]
Reactant: O=S(O)O
Product: O=S([O-])O
Product: [Ca+2]

Procedure:
Fifty grams of the above material was suspended in one liter of sulfurous acid solution containing 62.5 grams of sulfur dioxide. The molar ratio of sulfur dioxide to calcium in the original mixture was 3.00 or 50 percent in excess of that required to form calcium bisulfite. The mixture was held in a flask stoppered with a water trap tube at 20° C for 2 hours using intermittent agitation. At the end of the period the solution contained 54.4 grams of total sulfur dioxide or 87 percent of that originally present. The chitin was collected on a filter, washed and analyzed for residual calcium carbonate. It contained 0.81 grams or 2.5 percent of that originally present in the deproteinized shell. Demineralization was thus 97.5 percent complete and sulfur dioxide evolved with carbon dioxide through the trap tube was 13 percent of that originally present or 39 percent of the excess employed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1CCCC1=O>[O:24]1[CH2:25][CH2:26][N:21]([C:11]2[C:10]([CH3:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]3[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 150 °C
Reaction time: 3 h
Yield: 2.2 %

Procedure:
6,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in N-methylpyrrolidone (5 ml) and thereto is added morpholine (1.82 g), and the mixture is stirred at 150° C. for 3 hours. After the reaction, the reaction mixture is concentrated, and the resulting residue is recrystallized from ethanol to give 7-morpholino-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.05 g), as pale yellow flakes, m.p. 227.5°-228° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:28].[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:10][C:8]1[C:7]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:18])([F:19])[F:17])[O:13][N:12]=2)=[CH:6][C:5]([CH3:28])=[C:4]([CH:9]=1)[C:3]([OH:29])=[O:2]
Reactant: COC(=O)c1cc(Br)c(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 5-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (Example I22) (290 mg) in tetrahydrofuran (3 ml) was added a solution of potassium hydroxide (1.53 g) in methanol (3 ml) and water (3 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was acidified by addition of aqueous hydrochloric acid (4N). The aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×10 ml) and brine, dried over sodium sulfate, and concentrated to afford 5-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (220 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1H), 7.30-7.50 (m, 4H), 4.20 (d, 1H), 3.80 (d, 1H), 2.50 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21](C(Cl)=O)=[CH:20][CH:19]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[C:27]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][CH:9]2[C:15]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:17])=[O:7])=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: COCCNC(=O)C1CC(=CCl)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tertbutoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-methoxyethylamine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=399.6.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([O:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)Oc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridin (500 mg, 1.93 mmol), and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF was added potassium t-butoxide. The resulting mixture was stirred at rt. overnight. The mixture was quenched with water, brine and extracted 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After silica gel column chromatography purification, the title compound was obtained as a light yellow crystal, mp 106-109° C. Anal. For C20H26N2O4 calc. C, 67.02; H, 7.31; N, 7.82; found, C, 67.34; H, 7.40; N, 7.42.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCNC1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing the product from Example 160A (0.050 g, 0.195 mmol) in dichloromethane (1.0 mL) was added trifluoracetic acid (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with ether to give a white solid, which was collected by filtration and used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:44](O)(=[O:46])[CH3:45]>O1CCCC1>[C:44]([O:27][CH2:26][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:28])(=[O:46])[CH3:45]
Reactant: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 55 %

Procedure:
0.1 g (0.26 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 0.164 g (0.8 mmol) of dicyclohexylcarbodiimide and 0.046 ml (0.8 mmol) of glacial acetic acid are reacted in 5 ml of anhydrous tetrahydrofuran as described for Example 7a. Yield: 55%, m.p.: 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[N:4][CH:3]=1.Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>>[Br:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])/[N:4]([CH2:20][C:21]2[N:22]=[CH:23][S:24][CH:25]=2)[CH:3]=1
Reactant: BrCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(Br)cn1Cc1cscn1
Yield: 52 %

Procedure:
A mixture of Example 17A (1001 mg, 3.33 mmol) and commercially available 4-(bromomethyl)thiazole were processed using the method described for Example 16B to afford the title compound (660 mg, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 5.54 (s, 2H), 7.12 (d, J=9.2 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.69 (dd, J=15.9, 2.4 Hz, 2H), 7.93 (s, 1H), 9.10 (d, J=2.0 Hz, 1H) MS (DCI) m/z 445 (M+H)+; Anal. Calculated for C15H11BrClN3O2S2: C, 40.51; H, 2.49; N, 9.45. Found: C, 40.85; H, 2.90; N, 9.62.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([Cl:20])[CH:13]=1)P(OCC)(=O)OCC.[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[C:22]1=O)[CH2:28]2.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:20][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:22]2[CH:23]3[CH2:29][CH:27]4[CH2:26][CH:25]([CH2:30][CH:21]2[CH2:28]4)[CH2:24]3)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(Cl)cc(OC)c1
Temperature: -68 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Phosphonate 8 (4.62 g, 14 mmol) and 2-adamantanone (2.58 g, 17 mmol) were dissolved in anhydrous THF (35 ml) under argon and cooled to -68° C. Dropwise addition of lithium diisopropylamide (18.6 mmol) in anhydrous THF (20 ml) at -68° C. generated the ylid, followed by subsequent olefination of the ketone. The reaction was slowly warmed to room temperature over 2 h and then stirred at 75° C. for 1 h. The solution was partitioned between EtOAc/NH4Cl, dried over Na2 SO4, evaporated and purified by silica gel chromatography (2% EtOAc/hexanes), yielding 2.5 g (55%) of enol ether 9 as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:11]=2[CH:10]=[CH:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol), prepared by the procedures of Step 1 and Step 2 in the Example 34, was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess 3-amino-1-propanol by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 522 mg of desired compound as solid in 81% of yield.