Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.[Br:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(Br)cc4)cc3)cc2)cc1
Temperature: 95 °C
Yield: 69.9 %

Procedure:
A mixture of compound 8 (3.0 g, 6.3 mmol), 1-bromo-4-iodobenzene (3.57 g, 12.6 mmol), Pd(PPh3)4 and potassium carbonate (1.74 g, 12.6 mmol) in dioxane/water (40 ml/8 ml) was degassed and heated at 95° C. for 24 hours. After being cooled to RT, a yellow solid precipitated and was collected by filtration. The solid was recrystallized in dichloromethane/methanol to give a pale yellow solid (2.22 g). The filtrate was loaded on silica gel and purified by flash column to give additional amount of yellow solid 9 (0.42 g). The total amount of solid was 2.64 g, in 83% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([OH:16])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 4 g (18.24 mmol) of 1-Benzyl-4-(2-oxoethyl)piperidine in 40 mL of THF at 0° C. was added 20 mL (36.5 mmol) of benzyl magnesium chloride (2M in THF, Aldrich). THe reaction mixture was warmed to rt and stirred for 30 min. The reaction mixture was poured into 100 mL of sat'd NH4Cl solution and extracted with EtOAc. The combined organic fractions were washed with sat'd Nacl solution, and dried over MgSO4 and filtered. The filtrate was concentrated and purified by chromatography (silica, hexanes:ehtyl acetate, 4:1) to give 5.32 g of the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH2:40]([O:47][C:48]1[CH:49]=[CH:50][C:51]([Br:55])=[C:52](O)[CH:53]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:24][O:25][C:50]1[CH:49]=[C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:53]=[CH:52][C:51]=1[Br:55])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
Diisopropylazodicarboxylate (0.10 ml, 0.603 mmol) was added to (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (161 mg, 0.469 mmol), 5-benzyloxy-2-bromophenol (131 mg, 0.469 mmol) and triphenylphosphine (160 mg, 0.610 mmol) in tetrahydrofuran (3 ml) under a nitrogen stream, followed by stirring for 5 hours at room temperature. Diisopropylazodicarboxylate (0.05 ml, 0.302 mmol) was added to the reaction mixture followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4, v/v) to give (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1(4-benzyloxyphenyl)ethylamine (214 mg, Yield 75%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A stirred solution of 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) and 4-fluoro-benzenesulfonyl chloride (190 mg) in acetone (8 ml) was treated with triethylamine (258 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (157 mg) as a yellow solid. Mass spectrum: 534 [M+H]+, retention time: 3.7 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([N:14]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH3:31])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)C(F)(F)F)c2c(c(C)c1OC)COC2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1N(C)C(=O)C(F)(F)F)C(=O)OC2
Reaction time: 24 h

Procedure:
To a solution of 0.35 g (0.82 mmol) of methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(trifluoroacetylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 4 ml of dimethylformamide was added 0.47 g (3.40 mmol) of potassium carbonate and 0.23 ml (3.69 mmol) of iodomethane. The mixture was stirred for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(N-trifluoroacetyl-N-methylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, an oil. NMR: δ 5.22-5.17 (multiplet ("m"), 2H); 5.10-5.04 (broad triplet, 1H); 3.81 (singlet ("s"), 3H); 3.62 (s, 3H); 3.42-3.27 (m, 5H); 2.45-2.25 (m, 5H); 1.75 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (358 mg).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.[H-].[Na+]>>[CH:15]1([O:14][C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [H-]
Agent: [Na+]
Product: c1ccc2c(c1)oc1c(OC3CCCC3)cccc12
Yield: 91.2 %

Procedure:
Reaction of dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) with cyclopentyl bromide (1.60 g, 10.86 mmol) in the presence of 60% sodium hydride (326 mg, 8.12 mmol), gave 1.25 g (92%) of the product as viscous liquid, IR (neat) 2957, 2870, 1449, 1269, 1193 cm−1. 1H NMR (300 MHz, CDCl3) δ 1.57-1.72 (m, 2H), 1.84-1.89 (m, 2H), 1.93-2.04 (m, 4H), 5.01 (quint., 1H), 6.97 (d, J=8.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[C:12]([C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:20])[C:15]([O:17]CC)=O)#[N:13]>CN(C=O)C.O1CCOCC1>[C:12]([C:14]1([CH3:20])[C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:15]1=[O:17])#[N:13]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1ccccc1C(C)(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.37 mL, 3.7 mmol) in dry DMF (4 mL) was added to a stirred suspension of NaH (0.16 mL, 3.7 mmol) in dry dioxane (50 mL) in a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (1.12 g, 3.7 mmol) was added in dry DMF (5 mL), and the solution was stirred overnight. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water, dried with MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with 0-30% EtOAc/hexane. MS (m/z)=272 (M+H)+.
Reaction SMILES: CN(C)C=O.Br[C:7]1[C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)CCC>[Cu]=O.O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:16]1[C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: O=[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 4-(2-bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (35 mg), tetrakistriphenylphosphine palladium (9.8 mg), tri-n-butyl-(2-pyridyl)-tin (63 mg), and copper(II) oxide (14 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone. The purification product was then dissolved in methanol, and the solution was added dropwise to water. The precipitate was collected by filtration to give the title compound (5.1 mg, yield 15%).
Reaction SMILES: C[N:2]([C:4]1[CH:9]=CC=CN=1)C.[CH3:10][CH2:11][S:12]([C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[C:16](C1NC=CC=1)=[O:17])=O>C1(C)C=CC=CC=1>[CH:4]1[N:2]2[C:11]([S:12][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]2=[O:17])=[CH:10][CH:9]=1
Reactant: CCS(=O)c1ccccc1C(=O)c1ccc[nH]1
Reactant: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2sc2cccn12
Reaction time: 29 h
Yield: 54.7 %

Procedure:
Dimethylaminopyridine (0.123 g, 1 mmol, 0.1 eq), 2-(2-ethylsulfinyl)benzoyl pyrrole (2.5 g, 10.1 mmol) and toluene (115 mL) are combined and refluxed with stirring in a flask covered with foil (to exclude light) for 29 hours, at which time the solvent is removed, in vacuo. The resulting crude solid is chromatographed to give 110 mg of comprising pyrrolo(2,1-b)-(1,3)benzothiazin-9-one (20 percent), 514 mg of pyrrolo(1,2-b)-(1,2)benzo-thiazin-10-one (46 percent) and 1.11 g of unreacted starting material. A small amount of 1H, 9H-(1)benzothiopyrano(3,2-b)pyrrol-9-one is detected by thin-layer chromatography but was not isolated. The pyrrolo(1,2-b)-(1,2)benzothiazin-10-one is recrystallized with EtOAc and hexanes to give an analytically pure yellow-orange solid (mp 100-102° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([N:30]6[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]6)=[N:28][CH:29]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:29]=[N:28][C:27]([N:30]6[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]6)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)nn34)ccnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N6CCNCC6)nc5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 50 mL recovery flask was charged with tert-butyl 4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (0.250 g, 0.44 mmol), TFA (0.75 ml, 9.6 mmol), and DCM (1.50 ml, 23 mmol), then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, then quenched with sat. aq. NaHCO3. The mixture was diluted with DCM (60 mL), resulting in an emulsion. The emulsion was filtered to give a brown solid. The solid was triturated with a combination of DCM/MeOH/MeCN and filtered to give 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15].[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15]
Reactant: COC(=O)c1ccc(Cl)c(C(F)F)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1c(C(=O)O)ccc(Cl)c1C(F)F
Yield: 93 %

Procedure:
Methyl 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoate (9.1 g) and lithium hydroxide (2.2 g) were dissolved in methanol and water and the mixture stirred overnight at room temperature. The mixture was then evaporated and the residue dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 2 M HCl and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoic acid (8.02 g) as a beige solid NMR (CDCl3) 2.5(s,3H), 7.5(d,1H), 7.65(t,1H), 7.8(d,1H). By proceeding in a similar manner 4-chloro-3-(N,N-dimethylcarboxamido)-2-methylsulphenylbenzoic acid was prepared from the appropriately substituted starting material as a yellow solid, NMR (CDCl3) 2.5(s,3H), 2.8(s,3H), 3.2(s,3H), 7.4(d,1H), 7.9(d,1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 130.8 %

Procedure:
A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (1.5 g, 5.65 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.527 g, 7.34 mmol) in dioxane (20 mL) was sparged with Ar, treated with a solution of K2CO3 (1.171 g, 8.47 mmol) in water (5 mL) and Pd(PPh3)4 (0.326 g, 0.282 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, treated with water, extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.3 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.43-8.42 (m, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.34 (s, 3H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:32][C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[CH:12][CH:11]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)[C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCN[C@@H](C)C1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (3 mL) was added (3S)-1-acetyl-3-methylpiperazine (140 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (273 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (184 mg, yield 72%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 591 (MH+).
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1)[CH3:3].C(N(CC)CC)C.[O:17]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25](Cl)=[O:26])=[N:18]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[CH2:2]([N:4]1[C:8]([OH:9])=[C:7]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:22]([C:19]3[CH:20]=[CH:21][O:17][N:18]=3)[C:23]=2[CH3:35])[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-c3ccon3)c2C)c1O
Temperature: 25 °C

Procedure:
Separately 0.38 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 10 ml of chloroform, and 0.52 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 5 ml of a chloroform solution containing the previously obtained 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for an hour. To the reaction mixture were added 0.26 g of triethylamine and 0.05 g of acetone cyanohydrin to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the obtained residue. The produced crystals were separated by filtration to give 0.18 g of the title compound as white crystals. m.p. 85~88° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(P(=[CH:32][CH:33]=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](/[CH:6]=[CH:32]/[CH:33]=[O:34])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1cccc(C(F)(F)F)c1
Yield: 51.1 %

Procedure:
3-(Trifluoromethyl)benzaldehyde (0.70 g) was dissolved in toluene (16 mL), and (triphenylphosphoranylidene)acetoaldehyde (1.22 g) was added. The reaction mixture was heated under reflux for 40 hr and concentrated, and the residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.41 g) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][S:4][C:5]3[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=3)[CH2:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(SCCCl)cc1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(SCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
1.8 G. of 4'-[(2-chloroethyl)thio]acetanilide, 2.7 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 4.5 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform and washed with water. From the organic phase there is obtained crude 4'-{[2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethyl]thio}acetanilide which melts at 150°-152°C. after recrystallization from acetic acid ethyl ester.