Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 77.9 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.3 ml.), tetrahydrofuran (10 ml.) and methanol (30 ml.) was treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 67.1 %

Procedure:
Compound 139 (40 mg, 0.1 mmol) and HOBT (17 mg, 0.11 mmol) stirred in CH2Cl2 (2 mL) at r.t. EDC (29 ml, 0.15 mmol) and 1-methylpiperazine (45 mL, 0.4 mmol) were added, and the reaction stirred for 3 h. Organics were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by prep-HPLC gave 32 mg (67%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.87-7.95 (m, 2H), 7.80 (s, 1H), 7.40 (s, 1H), 3.39-3.62 (m, 4H), 3.31 (q, 2H, J=7.2 Hz), 3.16-3.30 (m, 4H), 2.95 (s, 3H), 2.38 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C26H28N4O3S, 477; found 477.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[N:29][CH:30]=1)[CH3:24]>C(#N)C>[F:31][C:28]1[N:29]=[CH:30][C:25]([CH:23]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH3:24])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Br)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 73 %

Procedure:
tert-Butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo.; 13.31 g, 71.5 mmol), potassium iodide (2.37 g, 14.29 mmol), and potassium carbonate (11.85 g, 86 mmol) were sequentially added to a solution of 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 71.5 mmol) in acetonitrile (300 mL) at 25° C., and the resulting mixture was heated at 80° C. for 1 h. The reaction mixture was then partially concentrated in vacuo (final volume: about 80 mL), diluted with EtOAc (600 mL), and sequentially washed with 4:1 water:brine (2×600 mL) and brine (600 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/Hexanes) furnished tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (16.9 g, 73% yield over (2 steps) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.8 Hz, 1H), 7.78 (td, J=8.1, 2.3 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.47 (q, J=6.7 Hz, 1H), 3.39 (t, J=4.8 Hz, 4H), 2.37-2.49 (m, 2H), 2.25-2.36 (m, 2H), 1.44 (s, 9H), 1.36 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −70.50 (dd, J=8.0, 2.3 Hz, 1F). m/z (ESI, +ve) 310.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([C:42]1[C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][C:45]([C:53]([F:56])([F:55])[F:54])=[CH:44][N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH2:1]([N:4]([C:42]1[C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]([C:53]([F:54])([F:55])[F:56])=[CH:44][N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1ncc(C(F)(F)F)cc1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ncc(C(F)(F)F)cc1C(=O)O

Procedure:
Ethyl 5-iodopyridin-2-one-3-carboxylate, prepared by the method of Taylor, J. Org. Chem. 54, 36 (1989), is treated with tert-butyldimethylsilyl chloride (TBSCl) in methylene chloride containing triethylamine to give the O-silylated pyridine. Treatment of ethyl 2-tert-butyldimethylsilyloxy-5-iodopyridine-3-carboxylate with bis(trifluoromethyl)cadmium in the presence of copper (I) bromide in dimethylformamide gives the ethyl 2-tert-butyldimethylsilyloxy-5-trifluoromethylpyridine-3-carboxylate compound. Treatment of the silyloxy compound with aqueous hydrochloric acid in tetrahydrofuran removes the silyl protecting group. Treatment of ethyl 2-hydroxy-5-trifluoromethylpyridine-3-carboxylate with phosphorus oxychloride affords the 2-chloro compound. Treatment of ethyl 2-chloro-5-trifluoromethylpyridine-3-carboxylate with N-triphenylmethyl-5-[2-(4'-propylaminomethyl-biphenyl)]tetrazole, prepared as described in Example 72B, in tetrahydrofuran containing triethylamine affords the tertiary amine. Treatment of ethyl 2-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-5-trifluoromethyl-pyridine-3-carboxylate with p-toluenesulfonic acid monohydrate in methanol to detritylate followed by sodium hydroxide in methanol hydrolysis gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH2:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(4-Chloro-2-fluorophenyl)-2-methylnicotinic acid (9 g, 33.9 mmol) (previous described in Example 16, Part E) was taken in DCM (50 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (14.83 mL, 169 mmol) followed by slow addition of DMF (1 mL). The mixture was heated at 40° C. for 3 h. After cooling, the volatiles were removed under reduced pressure. The residue taken up in DCM (25 mL) was cooled to 0° C., and TEA (22.08 mL, 158 mmol) and ammonium chloride (16.94 g, 317 mmol) were added slowly. After stirring at room temperature for 1 h, the reaction mixture was washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The organic layer was separated and dried with Na2SO4 to afford the 4-(4-chloro-2-fluorophenyl)-2-methylnicotinamide (3.5 g, 13.2 mmol, 42% crude yield) as a brown solid. The material was carried forward without further purification. LC/MS (ESI) m/e 264.4 [(M)+, calcd for C13H10ClFN2O 264.0] LC/MS retention time (method C): tR=1.58 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:16][OH:17]
Reactant: NO
Reactant: O=C1CCOc2c(Br)cc(F)c(F)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: ON=C1CCOc2c(Br)cc(F)c(F)c21
Yield: 94.9 %

Procedure:
To a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one (7.2 mmol) in 40 mL of ethanol was added hydroxylamine hydrochloride (0.55 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol). This mixture heated at reflux for 20 hrs. The mixture was cooled, diluted with EtOAc, washed with water and brine, and then dried over Na2SO4. Concentration of the solvent provided the title compound as a white solid (1.9 g). 1H NMR (300 MHz, 10% CD3OD in CDCl3): δ 7.3 (t, 1H), 4.2 (t, 2H), 2.9 (t, 2H).
Reaction SMILES: [CH:1](=[N:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[Cl:10][CH:11]([Cl:15])[C:12](Cl)=[O:13].C(OCC)C>C(N(CC)CC)C>[C:6]([N:5]([CH:1]=[CH:2][CH2:3][CH3:4])[C:12](=[O:13])[CH:11]([Cl:15])[Cl:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCC=NC(C)(C)C
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC=CN(C(=O)C(Cl)Cl)C(C)(C)C

Procedure:
In a similar procedure as Example I, 6.6 g. (0.052 mole) N-butylidene-t-butylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 9.3 g. of the title compound, an oil, nD30 = 1.4858.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:30])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:30]
Reactant: Cc1cc2c(cc1C#N)C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 18.7 g (82.3 mmol) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 280 mL of dichloromethane, cooled at −78°, was added 123 mL (123 mmol) of diisobutyl aluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to gradually warm to room temperature. After 16 hours, the reaction mixture was treated with 30 mL of acetic acid added dropwise, followed by 150 mL of water. The organic layer was separated, diluted with 200 mL of hexane, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution 5-10% ethyl acetate/hexane) on silica gel to afford 11.8 g (63%) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C2CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Yield: 35.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (2.2 g, 11 mmol), 4-methylstyrene oxide (5.8 g, 44 mmol) and NaH (1.3 g, 32.5 mmol) were heated in DMF (70 mL) at 120° C. for 16 h (overnight). The contents were quenched by methanol and evaporated to dryness. The resulting crude product was purified by silica gel chromatography (230-400 mesh) using ethyl acetate-hexane gradient to obtain 1.3 g of racemic-2(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol. The free base was converted into its hydrochloride salt by treatment of ethanolic HCl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C@H:21]([NH:25]C(OC(C)(C)C)=O)[C:22](O)=O.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:54]>C(Cl)Cl.O>[ClH:54].[ClH:54].[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:20]([C@@H:21]([NH2:25])[CH3:22])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:19]
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 182.5 %

Procedure:
To a solution of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (1 g, 3.8 mmol), Boc-ala-OH (727 mg, 3.8 mmol) and HOAT (522 mg, 3.8 mmol) in DCM (20 mL) at 0° C. was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (810 mg, 4.2 mmol) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (20 mL, 4 M) and the reaction mixture heated at 75° C. for 45 min. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (1.48 g, 100%). LCMS (Method C): RT=1.95 min, [M+H]+=314.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=CC=1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: c1ccc2ncccc2c1
Reactant: Cc1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 300° C. in the presence of a HF·BF3 catalyst. After the reaction, the catalyst was recovered in a gas state, and a low boiling point component was removed to obtain a pitch. The optically anisotropic phase was 2 volume % as observed under a polarization microscope, the softening point was 176° C., the quinoline-insoluble content was 1.6% by weight, and the toluene-insoluble content was 34% by weight.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1.[CH2:18]([NH2:23])[CH:19]([NH2:22])[CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:22][CH:19]([CH2:20][CH3:21])[CH2:18][NH:23][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1
Reactant: CCC(N)CN
Reactant: Cc1cccc(Nc2cc(Cl)ncc2C#N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C#N)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.3) (38 mg, 0.16 mmol) in NMP (1 mL) was added butane-1,2-diamine (107 mg, 1.21 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.932 mmol). The reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was allowed to cool to room temperature, filtered, and purified directly via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[N:30]=[N:31][CH:32]=[N:28]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.3 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H -tetrazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]([F:34])=[C:31]([F:33])[F:32].Cl>O>[Cl:1][C:2]1[C:7]([O:8][C:31]([F:33])([F:32])[CH:30]([Cl:29])[F:34])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: FC(F)=C(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(F)(F)C(F)Cl)c(Cl)cc2F)c1=O
Reaction time: 0.17 h

Procedure:
A solution of 2.0 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)pyrimidinedione is treated with 0.25 g of potassium carbonate and the suspension is saturated with chlorotrifluoroethylene while stirring during 10 minutes. The reaction mixture is subsequently heated to 50° C. for 10 minutes, during which a slow stream of chlorotrifluoroethylene is conducted in. Thereafter, the reaction mixture is poured into a solution of 3 ml of 2N hydrochloric acid in 250 ml of water, and the whole is extracted with 100 ml of ethyl acetate. The organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (1:3) as the eluent. There is obtained 3-[4-chloro-5-(2-chloro-1,1,2-trifluoroethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHz : 7.40 ppm (d,1H), 7.32 ppm (m,1H), 6.37 ppm (s,1H), 6.33 ppm (m,1H), 3.57 ppm (d,3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][C:3]=1[CH:19]1[CH2:22][CH2:21][CH2:20]1>C(O)C>[Cl:1][C:2]1[C:3]([CH:19]2[CH2:20][CH2:21][CH2:22]2)=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)=[N:9][N:8]=2)[N:7]=1
Reactant: Fc1cc(F)cc(C=NNc2cc(C3CCC3)c(Cl)nn2)c1
Solvent: CCO
Product: Fc1cc(F)cc(-c2nnc3cc(C4CCC4)c(Cl)nn23)c1
Temperature: 70 °C
Yield: 62.9 %

Procedure:
Ferric chloride (3.423 g, 12.66 mmol) in ethanol (15 ml) was added dropwise to a solution of N-(6-chloro-5-cyclobutylpyridazin-3-yl)-N′-(3,5-difluorobenzylidene)hydrazine (0.816 g, 2.53 mmol) in ethanol (35 ml) and heated at 70° C. After 3 hours the reaction mixture was partitioned between dichloromethane (250 ml) and brine (250 ml). The organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title pyridazine (0.51 g, 63%). 1H NMR (250 MHz, CDCl3) 1.84-2.08 (1H, m), 2.08-2.36 (3H, m), 2.42-2.68 (2H, m), 3.65-3.87 (1H, m), 6.88-7.06 (1H, m), 8.01 (1H, s), 8.04-8.21 (2H, m). MS (ES+) 321 [MH]+, 323 [MH]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc(Br)c1O
Product: O=c1cc(N2CCN(Cc3cccc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.60-3.70 (m, 4H), 3.75 (s, 2H), 5.40 (s, 1H), 6.67-6.70 (m, 1H), 6.92-6.94 (m, 1H), 7.43-7.45 (m, 1H), 7.84 (s, 1H), 11.95 (br s, 1H). Mass spectrum (ES) MH+=365.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[NH4+:13].[OH-]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Agent: [OH-]
Solvent: CC(C)O
Product: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5,6-dichloropyridine-3-sulfonyl chloride (32.16 g) in isopropyl alcohol (300 mL) at 0° C. was added a 30% aqueous solution of NH4OH (50.8 mL). After stirring overnight, the solvent was reduced to ⅓ of the original volume. It was then partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel. The material was then slurried in 1:9 ethyl acetate/hexanes, filtered and dried under vacuum to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:20]([CH3:19])[CH:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)[N:7]=[CH:6][N:5]=2)=[O:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNC1CCC(C)CC1
Product: Cc1cc(O)ccc1NC(=O)c1cc(N(C)C2CCC(C)CC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N,4-dimethylcyclohexanamine (Enamine), the title compound was obtained as a mixture of cis-trans stereoisomers, as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:17]([CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (Glaxo DE 3513885, 1985) (52 g) in DMF (300 ml) was treated with sodium azide (12.24 g) and the mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with ethyl acetate and washed with water and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (39.11 g). TSP+ve 248(MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[NH:17])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[N:12][CH:11]=2)=[N:6][CH:7]=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:17]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH3:16])[N:8]=2)[CH:7]=1
Reactant: Cc1ccncc1C(=N)Nc1ccc(F)cn1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccncc1-c1nc2ccc(F)cn2n1
Temperature: 150 °C

Procedure:
Lead tetra acetate (0.0693 g, 0.000156 mol) was added to a solution of N-(5-fluoro-pyridin-2-yl)-4-methyl-nicotinamidine (22-1; 0.360 g, crude 0.000156 mol) in toluene (10 mL) in a 40 mL microwave vial at RT. The reaction mixture heated to 150° C. for 1.5 h under microwave irradiation. The reaction mixture cooled to RT, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.40-9.38 (t, J=8 Hz, 1H), 9.12 (s, 1H), 8.51-8.50 (d, J=4 Hz, 1H), 8.00-7.97 (m, J=12 Hz, 1H), 7.75-7.80 (t, J=20 Hz, 1H), 7.40-7.39 (d, J=4 Hz, 1H), 2.68 (s, 3H). MS (M+1): 229.1.