Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:9]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
To a solution of vanilin (76.1 g) in N,N-dimethylformamide (500 mL) is added successively 4-(2-chloroethyl)morpholine hydrochloride (130 g), sodium iodide (7.5 g), and potassium carbonate (207 g). The mixture is stirred at 80° C. for 15 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. To the residue is added diisopropyl ether and the resultant crystals are collected by filtration to give 3-methoxy-4-(2-morpholinoethoxy)-benzaldehyde (112.6 g, yield; 85%) as orange crystals. MS (APCI) m/z: 266 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Yield: 75.3 %

Procedure:
A stirred solution of 5-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (752 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](N)[C:8]=2[CH3:13])[N:3]=1.Cl.N([O-])=O.[Na+].[C-]#N.[K+].[N:23]1C2C(=CC=CC=2)C=N[C:24]=1[N+]#N>O.C(=O)([O-])[O-].[K+].[K+].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]#[N:23])[C:8]=2[CH3:13])[N:3]=1
Reactant: Cc1c(N)ccc2nc(N)nc(N)c12
Reactant: N#[N+]c1ncc2ccccc2n1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1c(C#N)ccc2nc(N)nc(N)c12
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.5 grams (0.013 mole) of 2,4,6-triamino-5-methylquinazoline (prepared in Example 13) and 25 mL of 2N hydrochloric acid (0.050 mole) was cooled to 5° C., and a solution of 1.1 grams (0.016 mole) of sodium nitrite in 4 mL of water was added dropwise. Upon completion of addition, the reaction mixture was stirred at 5° C. during a 10 minute period. In a separate reaction vessel, a stirred solution of 14.7 grams (0.225 mole) of potassium cyanide in 70 mL of water was cooled to 5° C., and a solution of 1.4 grams (0.056 mole) of copper(II) sulfate pentahydrate in 100 mL of water was added dropwise. To this solution was added, portionwise, the reaction mixture containing the quinazoline diazonium salt prepared above. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred during a 2 hour period. After this time, the reaction mixture was diluted with 60 mL of aqueous 50% potassium carbonate and was extracted with four 700 mL portions of tetrahydrofuran. The combined extracts were acidified with 50 mL of acetic acid, and the mixture was concentrated under reduced pressure to a residual solid. The solid was subjected twice to column chromatography on silica gel. Elution was accomplished in each case with 20% N,N-dimethylformamide in ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of 2,4-diamino-6-cyano-5-methylquinazoline. The NMR spectrum was consistent with the proposed structure; however, it showed that the product was in the form of the acetate salt.
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].O.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13](Cl)=[CH:14][C:15]=1[Cl:16]>C(#N)C>[N+:18]([C:12]1[CH:11]=[C:10]([C:9]([F:8])([F:21])[F:22])[C:15]([Cl:16])=[CH:14][C:13]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: NCP(=O)(O)O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
) 3.3 g (30 mmol) of aminomethanephosphonic acid is introduced into 120 ml of water and 120 ml of acetonitrile together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene and refluxed for 4 hours at a bath temperature of 120° C. After the acetonitrile is drawn off in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is made acidic at pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid with a melting point of 207.3° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (183 mg, 0.54 mmol) [prepared according to the procedure of Example 167], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (298 mg, 0.64 mmol) in chloroform (5 mL). DIEA (470 μL, 2.69 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.36 mmol, 69%): LC-MS (ES) m/z=653 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[C:55]([F:60])[CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O.C(OCC)(=O)C>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[C:55]([F:60])[CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Pyridazinamine (0.42 g, 4.37 mmol), HATU (2.22 g, 5.83 mmol) and diisopropylethylamine (1.53 ml, 8.74 mmol) were added to a solution of 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 89; 1 g, 2.91 mmol) in N,N-dimethylformamide (25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), shaken and allowed to stand for 5 min. The precipitate was filtered, washed with water (25 ml) and ethyl acetate (50 ml), and dried under vacuum to yield the title compound as a white solid. No further purification was carried out. 900 mg.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:11].[N:12](OCCC(C)C)=[O:13]>C(O)C.C(OCC)C>[C:8](/[C:7](=[N:12]\[O-:13])/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:9].[Na+:11]
Reactant: CC(C)CCON=O
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: N#C/C(=N\[O-])c1ccccc1
Reaction time: 2 h
Yield: 56.6 %

Procedure:
Phenylacetonitrile (9.72 g, 82.97 mmol) was metered into a suspension of 3.31 g (82.97 mmol) of NaOH in 60 ml of ethanol. Following the complete addition, 11.66 g (99.56 mmol) of isopentyl nitrite were metered in dropwise at temperatures of 15° C. The mixture was then stirred for a further 2 hours at this temperature. The reaction mixture was diluted with 300 ml of diethyl ether, and the precipitated solid was filtered off and washed twice with in each case 50 ml of diethyl ether. The white salt sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide (7.89 g, 56% yield) can be dried in vacuo or be further used directly. 1.49 g (6.24 mmol) of but-3-yn-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate and 103 mg (0.624 mmol) of potassium iodide were added to a solution of 1.05 g (6.24 mmol) of sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide in 25 ml of acetonitrile and 10 ml of DMF. The reaction mixture was stirred for 7 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed with water and dried over MgSO4. After removing the solvent, 2.21 g (99% yield, only 1 oxime isomer) of but-3-yn-1-yl{6-[({[(Z)-cyano(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate were isolated as a colourless solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=[O:15]>>[N:14]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15]
Reactant: O=N[O-]
Reactant: c1ccc(Nc2ccccc2)cc1
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
diphenylamine method, where diphenylamine as raw material is nitrosated using a nitrite in an organic solvent to produce N-nitrosodiphenylamine, which is rearranged to 4-nitrosodiphenylamine hydrochloride under the action of anhydrous hydrogen chloride, and then, 4-nitrosodiphenylamine hydrochloride is neutralized with a base to give 4-nitrosodiphenylamine which is finally reduced to 4-aminodiphenylamine by sodium sulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:24]=1[Cl:23])=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NC(=O)COc2cc(Cl)cc(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1

Procedure:
A DMF solution (0.5 mL) of 29 mg (0.081 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetyl chloride (5-4), 33 mg (0.163 mmol) of 2-chloro-4-methylsulfonylaniline (5-5) and 21 mg (0.163 mmol) of DIEA were stirred at 25° C. until the reaction would not proceed any further. This solution was loaded directly onto a CombiFlash silica gel column eluted with EtOAc:hexanes (3:97 to 100:0). Clean fractions were combined and concentrated in vacuo to give the desired product 5-6 as a white solid. Rf=0.8 (DCM:MeOH:NH4OH 98:2:0.2). HRMS (M+Na): measured 542.0066; theoretical 542.0105. 1H NMR(CDCl3): 3.07 (s, 3H), 4.69 (s, 2H), 6.61 (m, 1H), 6.74 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 7.25 (m, 1H), 7.42 (m, 1H), 6.94 (dd, 1H), 8.02 (m, 1H), 8.74 (d, 1H), 9.11 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([NH:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1)=[O:16]
Reactant: Nc1ncc(Cl)s1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-amino-5-chlorothiazole hydrochloric acid (1.0 g, 5.9 mmol), 5-chloro-2-methoxybenzoic acid (1.3 g, 7.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (Chem-Impex International, 2.2 g, 12 mmol), 1-hydroxbenzotriazole (0.95 g, 7.0 mmol) and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) in 6 mL of pyridine was allowed to stir at ambient temperature for 72 hours. The reaction mixture was concentrated under reduced pressure and 10 mL of H2O was added. The resulting solids were isolated by filtration, washed with 5 mL of H2O and twice with 5 mL of ethyl acetate, and dried to afford the title compound. MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: Nc1ccc(COC2CCCCO2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=S)c1cnc(C)nc1Nc1ccc(COC2CCCCO2)cc1
Yield: 94.4 %

Procedure:
A solution of 4.25 g (18.26 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate, 4.73 g (22.85 mmol) of 4-(tetrahydropyran-2-yloxymethyl)aniline and 6.4 ml (45.7 mmol) of triethylamine in sieve-dried 1,4-dioxan was heated at 60° C. for 4 hours. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give a brown oil which was purified by flash chromatography on silica gel using1:4 ethyl acetate/hexane as eluent. Product containing fractions were combined and evaporated to give 6.68 g (90%) of ethyl 4-[4-(tetrahydropyran-2-yloxymethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate as a yellow oil. [Mass spectrum (ESI) MH+ =404].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:7][C:6]3[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:10]([F:13])([F:12])[F:11])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (34% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.82-7.92, 7.57-7.68, 7.00-7.09, 6.96, 3.79, 3.71, 3.50, 2.64, 1.64-1.78, 1.51, 0.94. MS (ES+) m/z 454 (M+1).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Cl[CH:6]([C:12]([C:14]([F:17])([F:16])[F:15])=O)[C:7]([O:9]CC)=[O:8].C(N(CC)CC)C.[OH-].[Na+].Cl>O.C(#N)C>[CH3:2][C:1]1[S:3][C:6]([C:7]([OH:9])=[O:8])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2.3 h
Yield: 75.4 %

Procedure:
To a 22 L flask fitted with a mechanical stirrer, thermocouple, and a reflux condenser, was charged thioacetamide (500.6 g, 6.66 mol) and acetonitrile (4 L). This resulted in an endothermic dissolution. To this solution was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1105 g, 5.06 mol) over a period of 40 minutes. A slight exotherm occurred which raised the temperature to 55.820 C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52° C. The contents were gently refluxed for one hour (internal temperature 75.8° C). After cooling to 46° C., a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6° C. was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]=1[C:22]([O:24]CC)=[O:23])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:22]([OH:24])=[O:23])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Diethyl 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylate (24.8 g, 68.8 mmol) was suspended in ethanol (200 ml) and treated with sodium hydroxide (8.3 g, 206.4 mmol) dissolved in 200 ml of water. A further 50 ml of ethanol added to aid stirring. Heated to reflux, 100° C. All in solution on heating. Refluxed for 8 hours. Cooled to room temperature and stood overnight. Solvent was evaporated to almost dryness. Water was added and stirred in an ice bath. Acidified with 2M HCl solution (˜150 ml). The white precipitate was filtered, washed with water and dried in a vacuum oven to give the title compound as a white solid (18.77 g, 61.7 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[N:5]([C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[C:15]=1[N+:22]([O-:24])=[O:23])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[CH:26]([B-](F)(F)F)=[CH2:27].[K+].C(Cl)Cl.C(N(CC)CC)C>CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:25])[N:5]([C:14]1[CH:19]=[C:18]([CH:26]=[CH2:27])[N:17]=[C:16]([NH2:21])[C:15]=1[N+:22]([O-:24])=[O:23])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C=Cc1cc(N(Cc2ccc(C)nc2)C(=O)OCC)c([N+](=O)[O-])c(N)n1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
(2-Amino-6-chloro-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (715 mgs/1.955 mmols), potassium vinyltrifluoroborate (415 mgs/3.098 mmols), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH2Cl2 (90 mgs/0.11 mmols) and triethylamine (0.28 mls/2.0 mmols) were combined in iPrOH (8.0 mls) and heated at 50° C. under N2 for 24 hrs. Preadsorbed directly onto silica and purified by column chromatography to give title compound (270 mgs) as a purple resin
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:19]([F:25])([F:24])C(OC)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:19]([F:25])[F:24]
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OC(F)F)c(Cl)c1)C1CCCC1
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one (15 g, 59.35 mmol, Example B(58), Step 2)), methyl 2-chloro-2,2-difluoroacetate (17.15 g, 118.7 mmol, 2 equiv) and K2CO3 (12.4 g, 124.6 mmol, 2.1 equiv) in dry DMF (150 mL) was stirred at 75-80° C. for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous 1 M NaOH and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to fractional distillation affording 15.3 g (72%) of material that was about 80% pure by 1H NMR (bp 70° C./2 Torr). 1H NMR (CDCl3) 1.63 (m, 9H), 2.84 (m, 5H), 6.49 (t, 1H, J=72), 7.11 (m, 2H), 7.27 (s, 1H). MS calcd for C15H17F2O2Cl, 302.744; found [M−19(−F)]: 283.7 m/z.