Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][OH:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C(=O)C>[S:34](=[O:36])(=[O:35])([O:32][CH2:31][CH2:30][C:28]1[CH:27]=[CH:26][C:25]2[C:18]3[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)=[C:2]([Cl:1])[CH:3]=4)=[N:22][CH:21]=[N:20][C:19]=3[S:23][C:24]=2[CH:29]=1)[NH2:37]
Reactant: OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To a solution of 2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}[1]benzothieno[2,3-d]pyrimidin-7-yl)ethanol (35 mg, 0.08 mmol, 1 equiv) in N,N-Dimethylacetamide (2 mL) was added chlorosulfonamide (87 mg, 0.76 mmol, 10 equiv) under nitrogen. The reaction mixture was stirred at rt for 15 h. The solvent was concentrated in vacuo. The crude material was separated by pre-HPLC to give a white solid (18.6 mg, 43%) as product. 1H-NMR (DMSO-d6) δ 9.0 (broad s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.54 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.03 (s, 1H), 7.88 (t, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.37 (t, 1H), 7.26 (d, J=8.7 Hz, 1H), 5.32 (s, 2H), 4.36 (t, 2H), 3.19 (t, 2H); LCMS RT=3.08 min, [M+H]+=542.10
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:26][C:27]([NH2:29])=[S:28])[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:22]([NH:26][C:27]1[S:28][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:29]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CCCCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2- (4-methylsulfonylphenyl) ethanone (Example 26, Step 2) (0.384 g, 1.03 mmol) in ethanol (15 mL) in a 25 mL round bottom flask was added N-butylthiourea (0.144 g, 1.09 mmol). The solution was heated to reflux for 14 hours and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 2-butylamino-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.319 g, 77%) as an off-white fluffy solid: mp 134°-135° C., 1HNMR (DMSO d6) 7.94 (t, J=5.37 Hz, 1 H), 7.78 (d, J=8.79, 2 H), 7.45-7.36 (m, 4 H), 7.15 (t, J=8.79 Hz, 2H), 3.25 (q, J=5.37 Hz, 2 H), 3.18 (s, 3 H), 1.58-1.50 (m, 2 H), 1.41-1.32 (m, 2H), 0.90 (t, J=7.33 Hz, 3 H); MS (EI) m/z 404 (M+). HRMS Δ=1.1 mmu.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CO.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(c2ccc(Cl)cc2)c2nccs2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(C(c2ccc(Cl)cc2)c2nccs2)cc1

Procedure:
A solution of 2-((4-chlorophenyl)(4-nitrophenyl)methyl)thiazole (550 mg, 1.663 mmol, 1 equip) and tin(II) chloride dihydrate (2.321 g, 9.976 mmol, 6 equip) in MeOH (11 mL) and concentrated HCl (1 ml) was heated at reflux temperature until analytical HPLC showed conversion to the desired product. The reaction mixture was made basic with excess triethylamine. The resulting thick precipitate was filtered through CELITE and the filter pad washed thoroughly with methanol. The filtrate was concentrated and the residue was purified by MPLC using ethyl acetate-heptane as the eluent to yield 4-((4-chlorophenyl)(thiazol-2-yl)methyl)aniline as a white solid (250 mg, 50%). (ES, m/z) 301, 303 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:35][CH:36]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[N:38]=[C:34]([CH3:33])[O:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1nc(C2(N)CC2)co1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5coc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine (0.047 g, 0.34 mmol, 1 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 14 h. The reaction was diluted with water and the product was extracted with dichloromethane and purified by preparative HPLC yielding the desired product. Yield: 47 mg (25%) 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.15 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.34 (s, 3H), 2.81-2.82 (d, 3H, J=4.60 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.31-7.32 (m, 1H), 7.34-7.40 (t, 2H, J=3.21 Hz), 7.56 (s, 1H), 7.61 (s, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.97-8.01 (m, 2H), 8.46-8.48 (m, 1H), 8.67 (s, 1H). LCMS: (ES+) m/z=554.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(CCl)NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
The reactant N-chloroacetyl 4-chlorobenzene sulfonamide was prepared by mixing 30.0 g of 4-chlorobenzene sulfonamide and 60.0 ml of chloroacetylchloride. The mixture was refluxed for 6 hours, allowed to cool, and stand at room temperature overnight. The crystalline product was removed by filtration, washed repeatedly with hexane, and dried. The product consisted of 32.5 g of reactant (m.p. 122°-124° C.). Structure was confirmed by IR and NMR.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]2[C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:4]2=[C:3]1[C:16]#[N:17].S(=O)(=O)(O)[OH:19]>O>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]2[C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:4]2=[C:3]1[C:16]([NH2:17])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c2c(c[nH]c1=O)C(=O)c1ccccc1-2
Solvent: O
Product: NC(=O)c1c2c(c[nH]c1=O)C(=O)c1ccccc1-2

Procedure:
A mixture of 5 parts of 3,9-dihydro-3,9-dioxo-2H-indeno-[2,1-c]pyridine-4-carbonitrile, 46 parts of concentrated sulfuric acid, and 1 part of water is heated at 60°-65° for 41/2 hours, then slowly diluted with 200 parts of water. The copious precipitate which forms is filtered off, washed with water, and crystallized from acetic acid to give 3,9-dihydro-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carboxamide melting above 300°. The product has the formula ##STR16##
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14])=[O:8])(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Yield: 76.7 %

Procedure:
Ethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]benzoate (6.37 g) is dissolved in methanol (100 ml), and thereto is added 1N aqueous sodium hydroxide solution (49.5 ml) under ice cooling, and the mixture is stirred for hours under nitrogen. After stirring further at room temperature overnight, the reaction mixture is acidified with saturated aqueous citric acid solution, and methanol is distilled off under reduced pressure. To the residue is added water (50 ml), and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].O>C(Cl)Cl>[C:30]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:19][CH:18]=1)(=[O:33])[CH2:31][CH3:32]
Reactant: CCC(=O)Cl
Reactant: CCCn1nc(-c2ccc(O)cc2)c2cccc(Cl)c21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCn1nc(-c2ccc(OC(=O)CC)cc2)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazol-3-yl)phenol (0.100 g, 0.35 mmol) and N,N-diisopropylethyl amine (0.5 g, 0.38 mmol) in CH2Cl2 (5 mL) was added dropwise propionyl chloride (0.035 g, 0.38 mmol). The solution was allowed to stir overnight at room temperature. Water was added and the solution was extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). The product was purified by flash chromatography (5/1 hexane/ethyl acetate) to yield a white solid (0.106 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:41](C([SnH3])=C(CCCC)CCCC)[CH2:42]CC>[Br-].C([N+](CC)(CC)CC)C.C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH:41]=[CH2:42])=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Br)cn4c3-c3ccccc3)cc2)CCC1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 120 °C

Procedure:
A mixture of {1-[4-(6-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (70 mg, 60% purity by UPLC-MS), potassium carbonate (11.2 mg), tetraethylammonium bromide (22.1 mg), tributylvinyl stannane (38.5 mg) and trans-dichlorobis(triphenylphosphine) palladium (II) (1.7 mg) in THF (0.66 mL) under argon was heated at 120° C. for 45 min. On cooling the reaction was partitioned between DCM and water, the organic extract dried and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].B>O1CCCC1>[OH:20][CH2:19][C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:9]=1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (2.66 g, 8.89 mmol) in dry tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added 1 M of borane solution in tetrahydrofuran (20 mL, 20 mmol). The reaction was stirred at 0° C. for 30 minutes after the addition was complete, and then the cooling bath was removed. After being stirred for 2 hours at room temperature, the reaction mixture was cooled at 0° C. and quenched by addition of 2 M aq. HCl (30 mL). The mixture was stirred for 1 hour at room temperature, and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:15]=1.CCN(CC)CC.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:7]1[C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN1C(=O)CNC(=O)c2cc(F)ccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(Cl)c2cc(F)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
As illustrated in the scheme above, 7-fluoro-3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione (0.495 g, 2.38 mmol) was suspended in POCl3 (10.6 mL) and heated at 100° C. for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCl3 were removed by adding toluene and concentrating the mixture in vacuo (2×). The residue was dissolved in CH2Cl2, the solution was cooled to 0° C., and Et3N (0.75 mL, 5.4 mmol) was added dropwise. The mixture was stirred for 0.5 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (9:1 CH2Cl2:EtOAc+0.5% Et3N) to provide the title compound as a light tan solid (0.422 g, 78%). 1H-NMR (CDCl3): δ 7.53-7.48 (m, 1H), 7.34-7.24 (m, 2H), 4.66 (br s, 1H), 3.72 (br s, 1H), 3.39 (s, 3H). MS (ESI) (M+H)+=227.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(Cl)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 77.4 %

Procedure:
In the same manner as in Example 259 and using 2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (140 μL, 1.6 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 78%) was obtained as a pale-green solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=[CH:12][C:8]1=2
Reactant: ClCCOc1ccc2sccc2c1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2cc(OCCN3CCOCC3)ccc2s1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-(2-Chloroethoxy)benzo[b]thiophene (0.25 g, 1.17 mmol) was dissolved in DMF (3 mL) and treated with morpholine (0.205 mL, 2.35 mmol) and sodium iodide (0.035 g, 0.235 mmol). The mixture was heated to 70° C. and stirred overnight. The reaction was cooled down to room temperature and poured into a saturated aqueous solution of sodium bicarbonate (20 mL), which was extracted several times with ethyl acetate. All the organic extracts were combined and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The ethyl acetate layer was then dried with sodium sulfate and purified by flash chromatography using a gradient of 0 to 8% methanol in dichloromethane to obtain a clear oil. Yield=0.237 g. MS (M+H)+ 264.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:11](=[N:26][O:27][CH3:28])[CH2:12][NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:29]I>O1CCCC1>[Cl:3][C:4]1[C:5]([C:11](=[N:26][O:27][CH3:28])[CH2:12][N:13]([CH3:29])[C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:24])[F:23])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CI
Reactant: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C(CN(C)C(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To 33 mg of 60% sodium hydride in oil in 5 ml of tetrahydrofuran, 300 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-(methoxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 16 in 3 ml of tetrahydrofuran was added dropwise with stirring and cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. Then, the reaction mixture was mixed with 157 mg of methyl iodide, warmed to room temperature and stirred for another 1 hour. After completion of the reaction, the reaction mixture was poured into 20 ml of ice-water and extracted with ethyl acetate (50 ml×1), the organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 2:8) as the eluent to obtain 203 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N+:9]([O-:10])=[C:8]2[CH2:11][O:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]2=[CH:6][CH:5]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CO>[OH:1][CH:2]([C:4]1[N+:9]([O-:10])=[C:8]2[CH2:11][O:12][CH:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:14][C:7]2=[CH:6][CH:5]=1)[CH2:3][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: [O-][n+]1c(C2CO2)ccc2c1COC(c1ccccc1)O2
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc2c([n+]1[O-])COC(c1ccccc1)O2

Procedure:
To 15.0 g. (0.055 mole) of 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide in 200 ml. of methanol was added 30 ml. tert-butylamine and the resulting reaction mixture was heated to the reflux temperature for 3 hours. Solvent and excess tertbutylamine were removed in vacuo to give 13.4 g. (73.6%) of 6-(1-hydroxy-2-tert-butylaminoethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide after recrystallization from ethyl acetate: m.p. 165°-168° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[CH2:25]([OH:27])[CH3:26].[O-]CC.[Na+]>O>[CH2:25]([O:27][C:17]1[C:16]([CH3:22])=[N:15][N:14]([CH3:23])[C:13](=[O:24])[C:12]=1[C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:26]
Reactant: CCO
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC
Temperature: 70 °C
Reaction time: 4 h
Yield: 177.5 %

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (52.2 mg), ethanol (674.3 mg), and sodium ethoxide (121.8 mg) were added under a nitrogen atmosphere at room temperature and stirred for 4 hours at 70° C. To the reaction mixture was added water (4 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 83.6 mg of 5-ethoxy-4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-6)-(1)-39).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[OH-].[K+].O.CO>C(OCC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: C=CCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 43.3 %

Procedure:
A mixture of 17 g of methyl 4-(9-decenyloxy)benzoate. 17 g of potassium hydroxide, 20 ml of water and 200 ml of methanol was heated to 75° C. on an oil bath for 4 hours. The cooled mixture was treated with 100 ml of ice-cold 3N hydrochloric acid and the liberated acid was taken up in 150 ml of diethyl ether. The separated aqueous phase was back-extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the crude product obtained from ethanol gave 7 g of 4-(9-decenyloxy)benzoic acid, m.p. (C-SC) 77° C., phase transition (SC -N) 116° C., cl.p. (N-I) 137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]#[N:12])=[CH:7][S:8][CH:9]=1.S(=O)(=O)(O)[OH:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]([NH2:12])=[O:19])=[CH:7][S:8][CH:9]=1
Reactant: N#CCc1cscc1Nc1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28.3 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenacetonitrile are introduced into 150 ml of concentrated sulfuric acid and stirred for one hour at room temperature. It is poured onto ice, and the precipitate which has formed is filtered off. Recrystallization from ethyl acetate yields 4-(2,6-dichloroanilino)-3-thiophenacetamide (m. 172° to 173°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[C:11]([OH:15])(=O)[CH2:12]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:9])[C:12]([CH2:11][OH:15])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CO
Reactant: CNc1ccc(Cl)cc1N
Product: Cn1c(CO)nc2cc(Cl)ccc21
Temperature: 150 °C
Yield: 45 %

Procedure:
4-chloro-N1-methylbenzene-1,2-diamine (15.0 g, 96 mmol) and glycolic acid (8.1 g, 106 mmol) were mixed together in a sealed tube. The mixture was heated at 150° C. for 5 hours before it was cooled down to room temperature. The residue was purified by flash column chromatography (0–5% MeOH in CH2Cl2) to give the product (8.5 g, 45% yield). 1H NMR (300 MHz, CDCl3) δ: 3.80 (s, 3 H), 4.86 (s, 2 H), 7.13–7.22 (m, 2 H), 7.62–7.64 (m, 1 H).