Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1([F:18])[CH2:17][NH:16][CH2:15]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[O:20]1)[CH2:26]2.C(N(CC)CC)C>C(#N)C>[F:13][C:14]1([F:18])[CH2:17][N:16]([C:4]([C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][C:29]([C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[O:20]2)[CH2:26]3)=[O:30])=[O:6])[CH2:15]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)O1)C2
Reactant: FC1(F)CNC1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1NC(=O)C12CC3CC(CC(C3)O1)C2)N1CC(F)(F)C1

Procedure:
2-Amino-6-fluorobenzoic acid (0.25 g) and 3,3-difluoro-azetidine hydrochloride (0.25 g) were reacted according to the method of Example 332C. The resultant intermediate (0.15 g) was then reacted with 2-oxaadamantane 1-carbonylchloride (1.25 equiv) (prepared from 2-oxaadamantane 1-carboxylic acid and thionyl chloride as in Example 12) and triethylamine (2 equiv) in acetonitrile (10 mL). Evaporation of solvents and flash chromotography over silica gel (20% ethyl acetate/hexane) provided 80 mg of the title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.66-2.03 (m, 10H), 2.17 (br s, 2H), 4.36-4.53 (m, 4H), 7.09 (m, 1H), 7.49 (m, 1H), 7.63 (d, 1H), 9.85 (s, 1H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28]([OH:30])=O)=[CH:5][CH:4]=1.Cl.[CH3:32][NH2:33]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28](=[O:30])[NH:33][CH3:32])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Yield: 88.2 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and methylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 88.2%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:18]=[N:19][NH:20][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Brc1cccc(-c2nn[nH]n2)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of 3-bromobenzonitrile (30.00 g, 164.8 mmol) in toluene (300 mL) was treated with triethylamine hydrochloride (68.05 g, 494.4 mmol) and sodium azide (32.14 g, 494.4 mmol) and the reaction mixture heated to reflux over night. Cooled to room temperature, diluted with water (300 mL), the layers were separated, and the aqueous portion acidified to pH 1 using concentrated HCl. The precipitated solid was collected by filtration, washed with water, and dried to give 34.96 g of product (94.3% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)(=[O:3])[CH3:2].[Br:20]Br>O1CCOCC1>[Br:20][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)=[O:3]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)cn1-c1ncccc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)CBr)cn1-c1ncccc1Cl

Procedure:
427 mg (1.48 mmol) of methyl 4-acetyl-1-(3-chloropyridin-2-yl)-1H-pyrrole-2-carboxylate were initially charged in 12 ml of dioxane, and 284 mg (1.78 mmol) of bromine were added dropwise at RT. The mixture was then stirred under reflux for 7 h. The solvent was distilled off under reduced pressure, giving an oil which was directly, without purification, reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:12]=1[C:13]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14]>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:12]=1[C:13]([C:15](=[CH:21][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[Cl:1])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Reactant: Nc1ccc(F)cc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CNc1ccc(F)cc1Cl)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 ml of a chloroform solution containing 1.2 ml of 2-chloro-4-fluoroaniline was added dropwise to 13 ml of a chloroform solution containing 2.46 g of ethyl 2-(2,4,5-trifluorobenzoyl)-3-ethoxyacrylate and stirred overnight at room temperature. The solvent was distilled off then to the residue, ethanol was added. The resulting crystals were collected by filtration and washed with diethyl ether, to give ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2-chloro-4-fluorophenylamino)acrylate. To 15 ml of a N,N-dimethylformamide solution containing 3.00 g of ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2-chloro-4-fluorophenylamino)acrylate was added 1.03 g of potassium carbonate. The solution was stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, the precipitated solid was collected by filtration and washed with ethanol and diethyl ether, to give 2.74 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]=[CH:6]2)=[O:4].[CH:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]=[CH:13]2.C1(C)C=CC=CC=1.C(O)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]=[CH:6]2.[CH3:1][O:2][C:3]([CH:13]1[CH2:14][CH:15]2[CH2:18][CH:12]1[CH:17]=[CH:16]2)=[O:4]
Reactant: COC(=O)C12C=CC(CC1)C2
Agent: [Pd+2]
Agent: C1=CC2CCC1C2
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 127.9 %

Procedure:
A norbornene carboxylic acid methyl ester monomer (16.74 g), a norbornene monomer (4.44 g), and 37 Ml of toluene were added to a 250 Ml Schlenk flask. A solution of Pd(OAc)2 (4.79 mg) and [(Cy)3PH][B(C6F5)4] (40.4 mg) in dichloromethane (2 Ml) was added to the flask, and the reaction mixture was incubated at 90° C. for 10 hours while stirring. Then, the reaction solution was added to excess ethanol to obtain a white copolymer precipitate. The precipitate was filtered through a glass funnel and dried in a vacuum oven at 65° C. for 24 hours to give 14.86 g of a norbornene/5-norbornene-2-carboxylic acid methyl ester copolymer (yield: 70.2 wt % based on the total weight of the monomers). The Mw and Mw/Mn of the polymer were 184,000 and 2.12, respectively.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reaction time: 1 h
Yield: 83.3 %

Procedure:
(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazole (29.5 g, 60.7 mmol) synthesized in Example (116c) was dissolved in tetrahydrofuran (400 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 66 mL, 66 mmol) was added, followed by stirring for 1 hour under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (400 mL) was added to the residue, and extraction was carried out twice with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (16.7 g, yield 83%) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([OH:29])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:29][C:26]1[CH:25]=[C:19]([CH:18]=[C:17]([O:16][CH2:14][CH3:15])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c(I)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Benzyl bromide (2.95 mL) was added to a DMF (200 mL) suspension of ethyl 3-ethoxy-5-hydroxy-4-iodobenzoate (7.59 g) and potassium carbonate (4.68 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.09 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[S:24][C:25]2[C:26]([N:31]=1)=[N:27][CH:28]=[CH:29][CH:30]=2.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:23]3[S:24][C:25]4[C:26]([N:31]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(O)ccc12
Reactant: Clc1nc2ncccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 6-hydroxy-benzofuran-3-carboxylic acid methyl ester (1.7 g, 8.8 mmol) in DMF (88 mL) was added Cs2CO3 (8.6 g, 1.8 mmol) followed by 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (1.8 g, 8.8 mmol) and the reaction mixture was stirred (rt, 3 h). The reaction mixture was treated with water (50 mL) to form a solid. The solid was filtered to provide the title compound as a white solid (2.5 g, 87%). MS (ESI): mass calcd. for C16H10N2O4S, 326.0; m/z found, 327.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.30 (s, 1H), 8.11 (d, J=8.6, 1H), 8.03 (dd, J=7.9, 1.6, 1H), 7.75 (d, J=2.1, 1H), 7.41 (dd, J=8.6, 2.1, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[OH:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.I[CH:27]([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[O:14][CH:27]([CH3:29])[CH3:28])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Yield: 53.9 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-5-nitro-4-oxoquinoline-3-carboxylate (393 mg, 1.11 mmol), 2-Iodopropane (0.167 mL, 1.67 mmol) and K2CO3 (231 mg, 1.67 mmol) in DMF (5 mL) was stirred at 80° C. for 5 h. After the reaction mixture was poured into ice-water, the crude product was extracted with CH2Cl2, washed with 1M HCl, saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product washed with hot EtOH and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-5-nitro-4-oxoquinoline-3-carboxylate (237 mg, 54%) as a pale yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Br:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][NH:38][C:37]5[CH:39]=[CH:40][CH:41]=[C:35]([Br:34])[CH:36]=5)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:22][CH:23]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C=O)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reactant: Nc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(CNc2cccc(Br)c2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
5′-Formyl-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (40 mg) and 3-bromo-aniline (18 mg) were stirred together in dry dichloromethane (10 ml) containing 3 A molecular sieves. The mixture was then heated to 40 C for 4 h. Sodium (triacetoxy)borohydride (50 mg) and glacial acetic acid (1 ml) were then added and stirring continued at 20 C for 18 h. The sieves were then removed by filtration and the mother liquor evaporated. The residue was purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave the title compound as a pale yellow solid (32 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[C:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1)N1CCCCC1
Yield: 95 %

Procedure:
Benzoyl chloride (500 mL, 606 g, 4.3 mol) was added dropwise to a rapidly stirring mixture of piperidine (426 mL, 367 g, 4.3 mol), sodium hydroxide (190 g, 4.7 mol, 1.1 equivalents), toluene (1 L), and water (1.7 L) over a period of 70 minutes. After the addition was complete, the mixture was stirred at 25° C. for one hour. The organic and aqueous phases were separated, and the organic phase was washed with 2N hydrochloric acid (2×100 mL), concentrated by rotary evaporation, and distilled under vacuum to yield benzoylpiperidine as a colorless liquid which crystallized on standing. (779 g, 95% yield, bp 169° C. to 171° C.).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:18][S:19][C:20]1[S:21][CH:22]=[C:23]([C:25](Cl)=[O:26])[N:24]=1>C1COCC1>[CH3:9][C:8]([NH:17][C:25]([C:23]1[N:24]=[C:20]([S:19][CH3:18])[S:21][CH:22]=1)=[O:26])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CSc1nc(C(=O)Cl)cs1
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(C(=O)NC(C)(C)c2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.24 ml) was added to a solution of cumylamine (3.2 ml) in anhydrous THF (30 ml). After stirring for 15 min, a solution of 2-(methylthio)-4 -thiazolecarbonyl chloride (Intermediate 12; 3.1 g) in anhydrous THF was added and the reaction mixture was concentrated in vacuo after 15 min. The residue was partitioned with EtOAc and water, dried with MgSO4, and concentrated to an orange oil. Flash purification on silica gel with isocratic elution of DCM yielded the product as a yellow oil (3.7 g). MS (ES) MH+: 293 for C14H16N2OS2; NMR: 1.68 (s, 6H), 2.76 (s, 3H), 7.20 (d, J=7.16 Hz, 1H), 7.29 (t, J=7.54 Hz, 2H), 7.36-7.41 (m, 2H), 8.04 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>>[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:10][C:7]3[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[C:15]([CH3:29])[O:14][N:13]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(N)nn1
Product: CCOc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Yield: 4 %

Procedure:
The title compound (16 mg) was prepared from 6-ethoxypyridazin-3-amine (129 mg, 1.0 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (0.302 g, 1.0 mmol), following the procedure described for Intermediate 51. LCMS (2 min, formic) Rt 0.91 min, m/z (ES+) 405 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:5])#[N:2].CO/[CH:16]=[CH:17]/[C:18](=O)[CH3:19].N12CCN(CC1)CC2.C(OCC)(=O)C>COCCOCCO.O>[F:13][C:9]1[CH:8]=[C:7]([N:6]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1cccc(F)c1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1cccc(F)c1
Yield: 30.8 %

Procedure:
A solution (50 mL) of 2-cyano-N-(3-fluorophenyl)acetamide (6.60 g, 37.0 mmol), (3E)-4-methoxybut-3-en-2-one (5.60 g, 56.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (6.20 g, 56.0 mmol) in 2-(2-methoxyethoxy)ethanol was stirred at 120° C. for 12 hr. The reaction solution was divided into two layers with ethyl acetate and water and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (2.60 g, 31%) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CC[O-]
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2-Chloro-3-trifluoromethyl-pyridine (4.43 g, 24.4 mmol) was dissolved in 42 ml 21% (wt.) sodium ethoxide in ethanol. The mixture was stirred at ambient temperature for 1.5 days. After this period of time, the solvent was evaporated and the residue was taken into water and extracted with dichloromethane three times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethyl-pyridine as a light liquid (3.42 g, 73% yield). The crude product was used directly for the next step. 1H-NMR (400 MHz, CDCl3): δ 1.42 (t, 3H, J=7.07), 4.49 (q, 2H, J=7.07), 6.94 (dd, 1H, J=7.45, J=5.05), 7.85 (dd, 1H, J=1.26, J=7.45), 8.30 (dd, 1H, J=1.26, J=5.06).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=O.[CH:17]([SH:20])(S)[CH3:18].C1(C)C=CC([S:27](O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[S:20]1[CH2:17][CH2:18][S:27][CH:1]1[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cc(C=O)cnc1C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)S
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C2SCCS2)cnc1C(=O)OC
Yield: 67 %

Procedure:
A solution of dimethyl 5-formylpyridine-2,3-dicarboxylate (0.73 g, 0.00327 mol), ethanedithiol (0.357 mL, 0.00425 mol) and a catalytic amount of para-toluenesulfonic acid in chloroform (20 mL) is heated at reflux for 5.5 hours. During this time, water is removed by placement of an addition funnel containing 3 angstrom molecular sieves in between the reaction flask and the reflux condensor. After cooling, the reaction is diluted with methylene chloride (20 mL) and is washed with 10% aqueous sodium carbonate and saturated sodium chloride solutions. The organic solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and 33% ethyl acetate in hexanes as eluant to yield the title compound as a clear oil (0.66 g, 67%), identified by IR and NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:32][CH:33]([CH3:37])[CH2:34][CH2:35]O>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:23])([F:24])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:8][CH2:35][CH2:34][CH:33]([CH3:37])[CH3:32])=[O:7]
Reactant: CC(Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl)C(=O)O
Reactant: CC(C)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)CCOC(=O)C(C)Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Yield: 95 %

Procedure:
To a solution of 1.9 g (5.0 mmole) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl) -1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid in 50 mL methylene chloride was added 1.3 mL (15.0 mmole) oxalyl chloride over 5 minutes, causing the evolution of gas. When this evolution ceased, one drop of DMF was added and the solution stirred until the gas evolution ceased. The solution was stripped to dryness in vacuo. The acid chloride was dissolved in 40 mL of 3-methyl-1-butanol and heated to reflux for one hour. The reaction mixture was cooled, diluted with 100 mL cold water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified chromatographically using 25% ethyl acetate in hexane as the eluent to give 2.17 g (95%) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid, 3-methylbutyl ester as a white solid; mp 128° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]1.[F-].[K+]>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#C[C@H]1CC[C@H](N)CC1
Reactant: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (50 mg, 0.168 mmol), Trans-4-aminocyclohexanecarbonitrile (53 mg, 0.22 mmol) and KF (42.2 mg, 0.73 mmol) in DMSO (0.5 mL) was heated at 130° C. overnight. LCMS showed the reaction was almost complete. The mixture was purified by prep. HPLC to give trans-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanecarbonitrile (20 mg, 30.8%) as an off-white solid.