Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-(trifluoromethoxy)-benzylamine (93 mg, 0.49 mmol). The title compound was obtained as a solid (50 mg, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.42 (1H, m), 8.98 (2H, s), 8.47 (1H, s), 7.42 (2H, dd), 7.33 (2H, dd), 4.43 (2H, m). MS m/z: 521.98, 523.99 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:14][OH:15])[NH2:5]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C#N)c(Cl)c1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(N)=NO)c(Cl)c1

Procedure:
The nitrile from Step B was dissolved into 100 mL of 1:1 ethanol/50% aqueous hydroxylamine then heated to reflux for 12 h. After evaporation of the solvent, the residue was dissolved into 400 mL of ethyl acetate then washed with saturated aqueous brine (150 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound, which was used without further purification. LC/MS 449.05 (M+1), 451.03 (M+3).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[N:20]#[C:21][NH2:22].C(OCC)C>CO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:22][C:21]#[N:20])=[CH:14][CH:13]=1
Reactant: N#CN
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Solvent: CO
Solvent: CCOCC
Product: N#CN=Cc1ccc(N)nc1-c1csc(N=C(N)N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (4.0 g) and cyanamide (1.2 g) in methanol (80 ml) was stirred for 16 hours at ambient temperature. To the mixture was added a diethyl ether (80 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of ethyl acetate and water and adjusted to pH 9.5 with 20% aqueous potassium carbonate. The precipitate was collected by filtration and recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(cyanoimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (3.04 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([NH:42]C(=O)OC(C)(C)C)=[N:39][C:40]=2[CH3:41])OC1>>[CH3:41][C:40]1[N:39]=[C:38]([NH2:42])[CH:37]=[CH:36][C:35]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1B1OCC(C)(C)CO1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-ylcarbamate via General Procedure A. Purification on silica yielded 258. NMR (CDCl3): 2.60-2.63 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.22-3.24 (m, 4H, 2×CH2), 3.78-3.81 (m, 6H, 3×CH2), 3.91-3.94 (m, 4H, 2×CH2), 4.43 (s, 2H, NH2), 6.36 (d, H, ArH, J=8.38 Hz), 7.22 (s, H, ArH), 7.98 (d, H, ArH, J=8.41 Hz). MS: (ESI+): MH+504.22
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][NH:22][CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][N:22]([CH:27]2[CH2:28][O:25][CH2:26]2)[CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC1
Reactant: O=C(OCc1ccccc1)N1CCNCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCN(C2COC2)CC12CC2
Reaction time: 68 h

Procedure:
A mixture of 4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester oxalate (200 mg, 0.59 mmol), oxetan-3-one (50 mg, 0.69 mmol), NEt3 (82 μL, 0.59 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at r.t. for 2 h before the addition of sodium triacetoxyborohydride (164 mg, 0.78 mmol). The resulting mixture was stirred for 68 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound. LCMS (method H): RT 2.01 min, [M+H]+ 303.3
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)nc1

Procedure:
In an analogous manner to that described in J. Medicinal Chem. 33:2087–93 (1990), the reaction 4-fluorobenzylalcohol instead of benzylalcohol with 2-chloro-5-nitropyridine yields the 2-(4-fluoro-benzyloxy)-5-nitro-pyridine as a yellow solid.
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C:12]4=[O:25])[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.C(O)C.CCOC(C)=O>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4[OH:25])[CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
17β-Cyclopropyloxy-4-aza-androst-5-en-3,7-dione (1.000 g, 2.9115 mmol) prepared in Example 18B or otherwise obtained, dissolved in a mixture of THF (25 mL) and ethanol (25 mL) is added to a solution of sodium borohydride (NaBH4; 1.000 g, 26.43 mmol) in ethanol (50 mL). The reaction mixture is stirred 5 hours at ambient temperature. At the end of this time, the reaction solution is diluted with EtOAc (100 mL) and washed with brine (NaCl; 3×100 mL). The organic solution is dried over MgSO4, filtered, concentrated and purified by flash chromatography (1:1 EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:22][CH:23]([OH:26])[CH2:24]O)[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:26][CH:23]([CH2:22][O:21][C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[CH3:20])[CH2:24][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(Cl)cc1OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(Cl)cc1OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1

Procedure:
A mixture of 6 parts of 2-bromo-2', 4'-dichloroacetophenone, 6 parts of 3-(4-chloro-o-tolyloxy)-1,2-propanediol, 3 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanol. The produce is filtered off and crystallized from petroleumether, yielding A + B 2-(bromomethyl)-4-(4-chloro-2-tolyloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:22][CH:21]=1>>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][S:16][C:13]3[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:17])=[C:7]4[C:12]=3[O:11][CH2:10][CH2:9][CH2:8]4)=[CH:21][CH:22]=2)=[N:27][CH:28]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)nc1
Product: O=C(O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 18B. MS m/z 490 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:49]1[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:50]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:49]3[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:50]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Yield: 77.4 %

Procedure:
A solution of 3-(4-methoxyphenyl)-isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (5 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z: calcd for C19H24N2O4: 344.1736, found 344.1737.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.Cl.C(NN)[C:28]1[CH:33]=[CH:32]C=[CH:30][CH:29]=1>>[CH2:23]([N:14]1[C:4]2=[N:5][N:6]=[C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([Cl:1])=[C:3]2[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:15]1)[C:24]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1
Reactant: NNCc1ccccc1
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cl
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccccc1
Reaction time: 16 h

Procedure:
Compound 31 was synthesised following similar procedures outlined in Example 31 (Compound 18), using benzyl hydrazine dihydrochloride instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 50° C. for 16 h. The crude residue was purified by column chromatography (silica gel, gradient 5 to 10% ethyl acetate/isohexane), followed by preparative HPLC, yielding Compound 31 as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:47]=[CH:46][C:8]([N:9]([C:13](=[O:45])[C@H:14]([OH:44])[C@@H:15]([OH:43])[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:41]#[N:42])=[C:23]([CH2:25][N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=2)=[O:17])[CH2:10][CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C>CC(O)(C)C.CS(C)=O>[C:1]([NH:4][C:5]1[CH:47]=[CH:46][C:8]([N:9]2[CH2:10][CH2:11][O:44][C@H:14]([C@@H:15]([OH:43])[C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:41]#[N:42])=[C:23]([CH2:25][N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=3)=[O:17])[C:13]2=[O:45])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N(CCCl)C(=O)[C@H](O)[C@@H](O)C(=O)Nc2ccc(C#N)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)C2=O)cc1
Yield: 35.9 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 39-4 (4.3 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 39-5 (1.46 g) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=[O:25])[C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:8][O:9][C:10](=[O:25])[C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)CC1CC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure U and using cyclopropylacetic acid (Lancaster) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=128-131° C.). The reaction was monitored by tlc (Rf=0.14 in 1:1 EtOAc/hexanes).
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:102])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:69]=[C:68]([C:86]3[CH:94]=[CH:93][C:89]4[O:90][CH2:91][O:92][C:88]=4[CH:87]=3)[CH:67]=2)[C:54]=1[CH2:95][CH2:96][C:97]([O:99]CC)=[O:98])C.[OH-].[Na+]>C1COCC1.CCO>[O:90]1[C:89]2[CH:93]=[CH:94][C:86]([C:68]3[CH:67]=[C:66]([CH:71]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[O:81][CH:82]([F:83])[F:84])[CH:69]=3)[O:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][C:55]3[C:54]([CH2:95][CH2:96][C:97]([OH:99])=[O:98])=[C:53]([CH:58]=[CH:57][CH:56]=3)[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:102])=[O:47])=[CH:87][C:88]=2[O:92][CH2:91]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 86.9 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (167 mg, 0.2 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(2-difluoromethoxy-benzyl carbamoyl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (130 mg, 87%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:14](OC(C)(C)C)=O)N)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][C:22](=O)CC.[C:26]1(C)C=CC=CC=1>>[CH3:26][C:14]1[NH:12][C:9]2[C:8]([C:21]=1[CH3:22])=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2
Reactant: Cc1ccccc1
Reactant: CCC(C)=O
Reactant: CCOC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1
Product: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 1-(4-(ethoxycarbonyl)phenyl)hydrazinecarboxylate (5.27 g, 18.8 mmol), butan-2-one (2.53 mL, 28.2 mmol), and TsOH monohydrate (21.5 g, 112.8 mmol) in toluene (300 mL) was heated at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated and then purified by flash chromatography (AcOEt/Hexane 5%) to obtain the title compound. ESI-MS (m/z): 218 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:12]\[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Na].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([S:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Sc1ccccc1
Reactant: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a suspension of 0.8 g (3 mmol) of (E)-2-methyl-N-phenyl-3-(phenylthio)-2-propenamide in toluene (4 ml) was added 0.62 g (3 mmol) of phosphorus pentachloride and the mixture was stirred at room temperature for 4 hours. After concentration of the mixture under vacuum, the residue was dissolved in 35 ml of N,N-dimethylformamide [DMF] and then 793 mg (6 mmol) of a benzenethiol sodium salt was added portionwise under ice cooling. The mixture was stirred at room temperature for 2 hours. After dilution with tert-butyl methyl ether, the mixture was washed sequentially with water (three times) and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 0.4 g of phenyl 2-methyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Oc2ccc(F)cc2)cc1
Yield: 140.3 %

Procedure:
To a solution of 6.0 g of 4-fluorophenol (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 60 ml of chloroform were added 6 ml of triethylamine and a solution of 4.0 g of 4-methoxybenzoyl chloride (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 40 ml of chloroform, and the mixture was stirred at 55° C for 1 hour. The reaction solution was separated by adding to it 100 ml of dichloromethane, 200 ml of water, and 25 ml of a 1N aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain 8.1 g of the title compound.
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][N:42]=1.C(N(CC)CC)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=1>ClCCCl>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:47][C:45]3[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=3)=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccnc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccnc(F)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(Br)cc(Cl)nn12
Temperature: 70 °C
Reaction time: 14 h
Yield: 103.5 %

Procedure:
A ˜1:1 mixture of 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (2.0 g, 8.62 mmol) was suspended in DCE (20 mL), and treated with neat oxalyl dichloride (4.37 g, 34.5 mmol) followed by N,N-Dimethylformamide (0.534 mL, 6.90 mmol). The reaction mixture was heated at 70° C. for 6 hours, concentrated and dried under high vacuum for 1 hr and taken to the next step without further purification. The crude mixture of acid chloride was suspended in DCM (10 mL) and treated with 2-fluoropyridin-4-amine (1.0 g, 8.92 mmol) and triethylamine (3.75 mL, 26.8 mmol) and stirred at room temperature for 14 hours. The reaction mixture was filtered through a Buchner funnel, and washed with water (2×25 mL) to isolate 1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (1.18 g, 8.92 mmol, 40.5% yield) as yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.47 (M+H=326.1 and M+H=372.04).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O-:5])=[O:4].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[C:21]1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N:12]1([CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:5][CH3:21])=[O:4])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C([O-])C(Br)c1ccccc1
Reactant: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(c1ccccc1)n1nnc2ccccc21

Procedure:
A mixture of methyl ?-bromophenylacetate (6.9 g) and benzotriazole (11 g) in 50 mL of toluene was heated to reflux for 22 h, cooled and diluted with 400 mL of CHCl3. The mixture was then washed with 100 mL of 10% aqueous NaOH and the organic layer was dried over Na2SO4 and concentrated. After swishing from 1:1 hexane/EtOAc, 5.7 g of the title compound was obtained as a white solid.