Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:57]=[CH:56][CH:55]=[CH:54][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]([NH:15][NH:16][C:17]([C:19]1[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[C:22]3[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH3:53])[CH:48]=1)=O)=[O:14])[CH2:8][CH2:9]2.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[F:1][C:2]1[CH:57]=[CH:56][CH:55]=[CH:54][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]1[O:14][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:23]=[C:22]4[C:47]3[CH:52]=[CH:51][N:50]=[C:49]([CH3:53])[CH:48]=3)=[N:16][N:15]=1)[CH2:8][CH2:9]2
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NNC(=O)C4CCC5CCC4N5Cc4ccccc4F)cc23)ccn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(-c4nnc(C5CCC6CCC5N6Cc5ccccc5F)o4)cc23)ccn1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
To N′-(8-(2-fluorobenzyl)-8-azabicyclo[3.2.1]octane-2-carbonyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carbohydrazide (142 mg, 0.19 mmol) in acetonitrile (1.6 mL) was added pyridine (44 mg, 0.56 mmol), followed by phosphoryl trichloride (86 mg, 0.56 mmol). The reaction mixture was heated at 100° C. under microwave condition for 30 min. After quench with saturated NaHCO3, the mixture was extracted with EtOAc. The combined organic layer was dried and concentrated to give 40 mg crude product. The crude was brought to next step without further purification.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:1]([CH2:4][CH:5]2[C:9]3[C:10]([C:16]([NH:18][C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=4[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=3[O:7][CH2:6]2)=[O:3])=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1ccc(Cl)cc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccc(Cl)cc1
Yield: 58 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-chlorobenzylamine to give Compound 30 (0.15 g, 58%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>C(Cl)Cl>[Br:39][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(CO)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a cooled (0° C.) and stirred solution of DCM (100 mL) containing (2-fluoro-4-nitrophenyl)methanol (9 g, 52.6 mmol, 1 eq), triphenylphosphine (16.5 g, 63.1 mmol, 1.2 eq) was added followed by addition of NBS (11.24 g, 63.1 mmol, 1.2 eq), the mixture was allowed to warm to RT and stirred for 2 h. The DCM was evaporated under reduced pressure and the residue was purified by CC using PE/EtOAc (9:1) as eluent to get 1-(bromomethyl)-2-fluoro-4-nitrobenzene (10.50 g, 85%; TLC system: PE/EtOAc (7:3), Rf: 0.6).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(C1C=C([N+:18]([O-:20])=[O:19])C=CC=1SBr)=O.N>>[N+:18]([C:8]1[CH:7]=[CH:6][C:5]2[S:1][N:2]=[CH:3][C:4]=2[CH:9]=1)([O-:20])=[O:19]
Reactant: c1ccc2sncc2c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SBr
Agent: N
Product: O=[N+]([O-])c1ccc2sncc2c1

Procedure:
Angewandte Chemie, 36 (1923), 159, and Berichte der deutschen Chemischen Gesellschaft, 58 (1925), 2,095, disclose the reaction of thionaphthene-2,3-dione with ammonia and hydrogen peroxide to give 3-carbamyl-1,2-benzisothiazole and the conversion of the latter to 1,2-benzisothiazole by hydrolysis and decarboxylation. Berichte der deutschen Chemischen Gesellschaft, 56 (1923), 1,630, and Liebigs Annalen der Chemie, 454 (1927), 264, disclose the reaction of 2-formyl-4-nitrophenylsulfenyl bromide with ammonia to give 5-nitro-1,2-benzisothiazole. Benzisothiazoles can also be synthesized by cyclizing o-mercapto-phenyl-carbonyl compounds in the presence of polyphosphoric acid (Annali di Chimica, 53 (1963), No. 5, 577-587). German Laid-Open Application DOS No. 1,670,196 discloses the reaction of dihalomethylaryl compounds with ammonia and sulfur to give benzisothiazoles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.CB1OB(C)OB(C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:31])=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.7 %

Procedure:
A mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.417 mmol) produced in Example (99a), cesium carbonate (408 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0417 mmol) and dimethylformamide (4 mL) was stirred at room temperature under a nitrogen atmosphere. Trimethylboroxine (0.06 mL, 0.417 mmol) was added to the mixture, and stirring was continued for 9 hours at an external temperature of 100° C. Ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 124 mg of the title compound as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[SH:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:44][C:45]5[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: Oc1ccc(S)cc1
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccc(O)cc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate (see ex. C1a) (300.0 mg, 0.45 mmol) was dissolved in 3 ml N,N-dimethylformamide, then 4-mercaptophenol (58.0 mg, 0.45 mmol), followed by triethylamine (62.7 ml, 0.45 mmol) was added. After 22 h the reaction mixture was poured on diethyl ether and the solid was collected by filtration. The brown solid material was suspended in water: acetonitrile (1:1) and chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (9:1, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:6])[CH3:3].S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>[OH-].[Na+]>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:22]([O-:24])=[O:23])=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
3-Ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g.) is added in small portions, at -20° C., whilst stirring, to concentrated sulphuric acid (d = 1.83; 325 cc.). After 10 minutes, a limpid solution is obtained. The mixture is cooled to -30° C., and concentrated nitric acid (d = 1.49; 10 cc.) is then added over the course of 15 minutes. The reaction mixture is left, whilst being stirred, at -40° C., for 30 minutes and is then poured onto ice (1 kg.) and rendered alkaline by adding sodium hydroxide solution (d = 1.33; 1,000 cc.) whilst maintaining the temperature at between 15° and 20° C. The batch is extracted with methylene chloride (3 × 500 cc.). The organic extracts are combined, dried over potassium carbonate, filtered and evaporated under reduced pressure (30 mm.Hg) at 40° C. A pinkish solid (34 g.) is obtained, which is recrystallised from diisopropyl ether (300 cc.). (S)-3-Ethoxycarbonyl-7-nitro-1,2,3,4-tetrahydroisoquinoline is thus obtained in the form of pale pink crystals (17.5 g.) melting at 94°-95° C. are thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:17]1([NH:16][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2ccc(Nc3ccccc3)cc2c1
Temperature: 100 °C

Procedure:
Methyl 6-bromoquinoline-3-carboxylate (Int-1, 0.25 g, 0.94 mmol), aniline (94 μL, 1.0 mmol), palladium(II) acetate (21 mg, 0.094 mmol), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (43 mg, 0.070 mmol), and cesium carbonate (431 mg, 1.32 mmol) were combined in a microwave vial fitted with a stirbar. N,N-Dimethylformamide (5.5 mL) was added, the vial was capped and the contents heated in a microwave at 100° C. for 1 h. The vial was cooled to room temperature, opened and the contents poured into water. The mixture was extracted three times with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes to 70/30 hexanes/ethyl acetate gradient) to afford pure Int-34. LC-MS: (FA) ES+ 279; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.02 (d, J=2.1 Hz, 1 H), 8.79-8.74 (m, 2H), 7.94 (d, J=9.0 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.62 (dd, J=9.1, 2.6 Hz, 1 H), 7.35-7.29 (m, 2H), 7.29-7.25 (m, 2H), 6.96 (tt, J=7.4, 7.4, 1.3, 1.3 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:25])=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=3[N:16]=2)[CH:10]=1)(=[O:4])=[O:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[OH:25][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)(=[O:4])=[O:3])=[CH:10][C:9]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: CN1CCNCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3O)nc12
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Yield: 97 %

Procedure:
A solution of 5-(5-chlorosulphonyl-2-hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.235 g, 0.0006 mol) and N-methylpiperazine (0.5 ml, 0.0045 mol) in ethanol (40 ml) was stirred at room temperature for 18 hours. The solution was evaporated under vacuum and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). The fine precipitate was filtered off, washed with water then ethyl acetate, and crystallised from ethyl acetate/DMF to give the title compound as an off-white powder (0.260 g, 49%), m.p. 283°-284° C. Found: C,53.53; H,5.89; N,18.40. C20H26N6O4S requires C,53.80; H,5.87; N,18.82%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][NH:35][CH3:36].[I-].[Na+]>COCCOC>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][N:35]([CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: CNCC1OCCO1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)CC1OCCO1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy- quinoline-3-carbonitrile, 515.5 mg (4.4 mmol) of 2-([1,3]-dioxolan-2-ylmethyl-methylamine and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 136.1 mg (65.2%) of the product as a yellow solid, m.p. 185-187° C., mass (electrospray, m/e): M+H 475.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[I:12]Cl>ClCCl>[I:12][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1
Reactant: COc1cnc2[nH]ccc2c1
Reactant: ClI
Solvent: ClCCl
Product: COc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (14, 300 mg, 2.0 mmol) in 30 mL of dichloromethane under nitrogen, iodine monochloride (3 mL, 1.0 M in dichloromethane, 3.0 mmol) was added at −40° C. The reaction was stirred to room temperature, then quenched with 10 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, then dried over sodium sulfate, decolored with activated carbon, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with 20% ethyl acetate in hexane to provide the desired compound (15, 371 mg). MS (ESI) [M+H+]+=275.03.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:17])#[N:14]>>[N:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)/[C:13]#[N:14])=[O:17])=[CH:21][CH:22]=1
Reactant: N#CCC(=O)NCc1ccncc1
Reactant: O=CC=Cc1ccc(O)c(O)c1
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1ccncc1

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) to 2-cyano-N-pyridin-4-ylmethylacetamide (33 mg, 0.2 mmol). After refluxing for 2 h and recrystallization from ethanol-water an orange solid was obtained (44 mg, 69%). The product gave the following analytical data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:14]N1C(=O)CCC1=O>ClCCl>[Cl:14][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1cc(Cl)cc(-c2cc[nH]n2)c1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reaction time: 96 h
Yield: 37.2 %

Procedure:
2.3 g (0.0152 mol) of 3-(3,5-dichlorophenyl)-1H-pyrazole are dissolved, at room temperature and with stirring, in 300 ml of dichloromethane. 2.07 g (0.016 mol) of N-chlorosuccinimide are then added and then stirring is continued for 4 days at room temperature. The reaction mixture is then concentrated and then chromatographed on a silica column (eluent 70/30 heptane/ethyl acetate). 1.4 g (yield: 57%, melting point: 192° C.) of 4-chloro-3-(3,5-dichlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[S:12]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:41])[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:15]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[S:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (400 mg, 0.96 mmol) in DCM (4 mL) was added triethylamine (130 mg, 1.3 mmol), followed by isobutyryl chloride (130 mg, 1.3 mmol). After stirring for 1 hour, the reaction was quenched by the addition of methanol (0.1 mL). The reaction mixture was concentrated and purified by flash column chromatography (15:1 Hexanes/EtOAc) to provide the product (350 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1COCC1.C(OC(=O)C)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[NH:28]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 50 h
Yield: 89 %

Procedure:
Part B: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (19.0 g, 0.057 mol) is dissolved in benzene (150 mL) and PCl5 (13.0 g, 1.1 molar equivalent) is added. The resulting mixture is heated at reflux temperature for two hours, allowed to attain room temperature and concentrated in vacuo to give a residue. The residue is dissolved in anhydrous THF, cooled to 0° C. and transferred into an autoclave. Excess NH3 is quickly added from a lecture bottle and the mixture is stirred at room temperature for 50 hours. A mixture of ethylacetate and aqueous NaHCO3 is added. The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/1 (v/v), silicagel) to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzene-carboxamidine (16.9 g, 89% yield). Melting point: 108-109° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH2:1]([C:4]1[C:13]([O:14][C:26]2[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Temperature: 100 °C
Yield: 77.4 %

Procedure:
A mixture of dimethyl 4-allyl-5-hydroxyisophthalate (2.0 g, 7.99 mmol), 4-fluorophenyl methyl sulfone (2.1 g, 12 mmol), Cs2CO3 (5.2 g, 16 mmol) and CuI (400 mg, 2.1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via silica gel gradient chromatography eluted with EtOAc in hexanes (10/90 to 30/90) to afford the title compound (2.5 g, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (dd, J=6.69, 1.60 Hz, 2 H) 3.03-3.16 (m, 3 H) 3.93 (d, 6 H) 6.14-6.34 (m, 1 H) 6.63 (dd, J=16.11, 1.60 Hz, 1 H) 6.88-6.98 (m, 1 H) 6.97-7.09 (m, 2 H) 7.79 (d, J=1.70 Hz, 1 H) 7.87-8.01 (m, 2 H) 8.29 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z=405.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=2O)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=3[O:19][N:18]=2)=[CH:6][CH:7]=1
Reactant: CCc1ccc(O)c(C(=NO)c2ccc(Cl)cc2)c1
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Yield: 7.3 %

Procedure:
4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime (22.0g) was dissolved in hot acetic anhydride (45ml) and immediately cooled, causing the oxime mono-acetate to crystallise. This was filtered and dried (19.7g) m.p. 105°C. The oxime mono-acetate (19.0g) and sodium carbonate (13.3g) were heated together in triglyme, under reflux, for 30 minutes. On cooling, the mixture was poured into water (1.0l.) this was extracted with ether (3×250ml). The combined ether extracts were washed with water (3×250ml) and evaporated to dryness to give a yellow oil which crystallised at room temperature (16.4G). A sample (3.0g) this solid was recrystallised from methanol/water to give a white solid (1.5g) m.p. 42°-45°C
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[CH:5]=[CH:4][C:3]=1[CH2:18][C:19]1[C:27]2[CH:26]=[N:25][CH:24]=[N:23][C:22]=2[NH:21][CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:18][C:19]1[C:27]2[CH:26]=[N:25][CH:24]=[N:23][C:22]=2[NH:21][CH:20]=1
Reactant: COc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Yield: 93 %

Procedure:
To [6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(4-methoxy-benzyl)-amine (P-0105, 4.5 g, 12.38 mmol) in 100 mL of dichloromethane, trifluoroacetic acid (95 mL, 1.238 mol) was added. The reaction was stirred at reflux for several hours, then concentrated under vacuum. The resulting material was taken up in ethyl acetate and poured into aqueous potassium carbonate. The resulting solid was filtered, washed with water, azeotroped from toluene and triturated with dichloromethane. The solid was isolated by filtration to provide the desired compound as a white solid (68, 2.8 g, 11.51 mmol, 93% yield).