Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Trifluoromethyl)-benzoyl chloride (5 mL, 332 mmol), N,O-dimethyl-hydroxylamine hydrochloride (42 g, 431 mmol) and methylene chloride were combined under argon, then cooled in an ice bath. Triethylamine (108 mL, 775 mmol) was added dropwise with stirring over 0.5 h. The contents of the reaction flask were then warmed to room temperature slowly. After 18 h, the reaction suspension was washed successively with 5% potassium bisulfate, sat. sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate then concentrated in vacuo to give Compound 1 as an oil: 82 g, (332 mmol, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1)[O:16][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(COc2cc(F)cc(C3(OC)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (1.5 g, 6.6 mmol), methyl 4-(bromomethyl)benzoate (1.7 g, 7.4 mmol), K2CO3 (0.6 g, 4.3 mmol), 18-crown-6 (0.05 g) and KI (0.05 g) in dimethylacetamide (5.00 mL) was stirred at room temperature for 16 h, and at 80° C. for 2 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 20% EtOAc in hexane, to furnish 2.2 g (88%) of methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate as a white solid: m.p. 88–89° C. 1H NMR (CDCl3/300 Hz) δ 8.07 (d, 2H, J=7.8 Hz), 7.5 (d, 2H, J=7.8 Hz), 6.81 (s, 1H), 6.72 (d, 1H, J=9.9 Hz), 6.6 (d, 1H, J=9.9 Hz), 5.12 (s, 2H), 3.93 (s, 3H), 3.82 (m, 4H), 2.97 (s, 3H), 1.92 (m, 4H). FABMS m/z 375 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([S:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[Cl:14].C([O-])(=[O:17])C.[K+].CS(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:3]=1[CH2:2][OH:17]
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)Sc1ccc(Cl)c(CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCc1cc(SC(F)(F)F)ccc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
A mixture of 55.7 g of crude 2-chloromethyl-4-(trifluoromethylthio)chlorobenzene, 23 g of potassium acetate, 150 ml of dimethyl sulfoxide and 10 g of triethylbenzylammonium chloride is stirred for 5 hours at 60° C. It is decomposed by pouring into water, extracted with benzene and the benzene evaporated. The oily residue is dissolved in 200 ml of ethanol, 100 ml of water and 20 ml of hydrochloric acid are added and the mixture is stirred and refluxed for 7 hours. Ethanol is distilled off, the residue mixed with water and extracted with benzene. The oil obtained by evaporation of the dried extract, is distilled in vacuo. There are obtained 40.2 g crude 2-chloro-5-(trifluoromethylthio)benzyl alcohol boiling at 140°-150° C./2 kPa. According to the 1H-NMR spectrum the product contains approximately 80% of the named compound and the remainder is the position isomer. In this state the substance is suitable for further processing.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][N:21]1S(C1C=CC(C)=CC=1)(=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[NH4+].[Cl-].C(Cl)Cl>CO>[Si:1]([O:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][NH:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3CC2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](OCC1CC2CC2CN1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Yield: 75.2 %

Procedure:
To a solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-tosyl-3-azabicyclo[4.1.0]heptane (D12) (3.12 g, 6 mmol) in MeOH (430 ml), under a nitrogen atmosphere, magnesium turnings (previously flame dried) (8.46 g, 348 mmol) and NH4Cl (8.9 g, 168 mmol) were added sequentially and the mixture was stirred at 23° C. Two further additions of magnesium (4.3 g), each one after 2 hrs stirring, were done. DCM (210 ml) and NH4Cl sat. sol. (285 ml) were added to the reaction mixture. The formed emulsion was filtered through a celite pad. The organic layer was separated and washed with brine (2×55 ml). The combined organic layers were evaporated and the resulting residue was purified by SPE-SCX (20 g) cartridge. Collected ammonia fractions after solvent evaporation afforded the title compound (D13) (1.65 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:40]2[CH2:39][CH2:38][N:37]([C:31]3[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:42][CH2:41]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: COc1ccc(C)cc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C)cc1N1CCN(CC(O)COc2ccc(OCc3ccccc3)cc2)CC1
Yield: 89.5 %

Procedure:
Using 1.37 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane, 50 ml of dioxane, 1.49 g of 1-(2-methoxy-5-methylphenyl)piperazine dihydrochloride and 1.6 ml of triethylamine, reaction and workup were carried out as in Example 1-A. Purification by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) gave 2.21 g of pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[CH2:27][O:28][CH3:29])=[CH:22][C:21]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[CH2:27][O:28][CH3:29])=[CH:22][C:21]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 56.7 %

Procedure:
4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole (580 mg, 1.166 mmol) was reacted with phosgene (725 uL, 1.399 mmol, 20% solution in toluene) using the procedure as described in example 12 to give 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (370 mg, 57% yield) as white solids.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[N:49]>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:16])[N:15]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Reactant: N#CCCCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(-c2ccccc2)c1
Yield: 62.2 %

Procedure:
Following the procedure described for Example 5, Step A, the anion derived from 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (239.1 mg, 0.564 mmol) and NaHMDS (1M in THF, 0.67 mL, 0.67 mmol) was alkylated with 7-bromoheptanenitrile (118 mg, 0.620 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 7-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (187 mg). MS 533.3 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20](NC1SC=CN=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part E (300 mg, 1.02 mmol) was taken up in 4 mL CH2Cl2 and cooled to 0° C. Oxalyl chloride (0.1 mL, 1.22 mmol) was added slowly and stirring continued for 0.5 h. A slurry of 6-aminonicotinic acid (211 mg, 1.53 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) was added slowly and stirring continued at room temperature for 16 h. Three drops of conc. HCl was added and the organic phase was washed with brine. The organic phase was dried (Na2SO4), filtered and evaporated. The product was purified by silica gel chromatography (12 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.70 (m, 1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.52 (m, 3H), 7.34 (m, 6H), 5.46 (m, 1H), 4.60 (br s, 1H), 4.31 (m, 1H), 2.54 (m, 2H), 2.09 (m, 2H). MS: m/z (MH+) 416.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH2:6]([N:9]1[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][O:11][S@@:10]1=[O:17])[CH2:7][CH3:8].I([O-])(=O)(=O)=[O:19].[Na+]>C(OCC)(=O)C.O.[Ru](=O)=O>[CH2:6]([N:9]1[C@@H:13]([CH2:14][CH2:15][CH3:16])[CH2:12][O:11][S:10]1(=[O:19])=[O:17])[CH2:7][CH3:8]
Reactant: CCCC1CO[S@](=O)N1CCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H]1COS(=O)(=O)N1CCC
Yield: 93.7 %

Procedure:
Ruthenium dioxide hydrate (3 mg) and a phosphate buffer solution (pH 7.4, 28.7 mL) were subsequently added to a solution of (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide (5.74 g) in ethyl acetate (46 mL) under ice-cooling and stirring. Sodium periodate (7.06 g) was added to the solution under ice-cooling and stirring, and then vigorously stirred at room temperature for 30 minutes. The suspension was filtered, and the insoluble matter was washed with ethyl acetate (17 mL). The filtrate and the washings were combined. The organic layer was separated and washed subsequently with a saturated aqueous sodium hydrogen carbonate solution (11.5 mL), an aqueous 10% sodium thiosulfate solution (11.5 mL) and a saturated aqueous sodium chloride solution (11.5 mL). Anhydrous sodium sulfate and activated carbon (0.57 g) were added to the organic layer and stirred at room temperature for 1 hour. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was added with tetrahydrofuran (8.6 mL) and concentrated under reduced pressure at 40° C. or lower to give (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (5.83 g, 94% yield) as an orange-brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:10]1[N:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-n2nccn2)c(CO)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2nccn2)c(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a stirred solution of (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanol (100 mg, 0.53 mmol) in chloroform (3 mL), thionyl chloride (76 mg, 0.63 mmol) was added dropwise at 0° C. and stirred for 1 h. Then the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 solution (5 mL) was added and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to yield the title compound (100 mg, 91%). [TLC Rf=0.59 (ethyl acetate/hexane 30:70)].
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:19])[NH:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NCCSc2ccsc21
Solvent: O
Solvent: c1ccncc1
Product: S=C1NCCSc2ccsc21

Procedure:
acb) 1.0 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5(2H)-one was heated under reflux for 5 hours together with 15 ml of pyridine and 1.35 g of phosphorus pentasulfide. After cooling the mixture was poured into 90 ml of water and the crystals were removed by filtration,. After chromatography on silica gel, the product was recrystallized from ethyl acetate. There was obtained 3,4-dihydro-thieno-[2,3-f][1,4]thiazepine-5(2H)-thione as yellow crystals of m.p. 138°-139°.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccc(F)nc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 6-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 4 hours, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 4 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2) to afford, after trituration with diethyl ether, the compound (28) as a yellow powder (45 mg, 6%). IR νmax (cm-1): 2215 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.36 (1H, dd, J5″-4″=8.5 Hz, J5″-F=2.1 Hz, H5″), 7.41 (1H, d, J7′-6′=8.9 Hz, H7′), 7.49 (1H, d, J4′-6′=2.4 Hz, H4′), 7.76 (1H, s, H3), 7.78 (1H, s, H2′), 8.52 (1H, td, J5″-4″=J5″-F=10.1 Hz, J4″-2″=1.8 Hz, H4″), 8.67 (1H, d, J2″-4″=1.8 Hz, H2″), 11.66 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (5′-methoxy), 102.0 (C4′), 108.2 (C2), 109.7 (1C, d, 2JC—F=37 Hz, C5″), 110.0 (C3′), 112.4 (C6′), 113.2 (C7′), 118.0 (C1), 124.0 (C3a′), 127.7 (C2′), 129.5 (1C, d, 4JC—F=4 Hz, C3″), 130.7 (C3), 132.3 (C7a′), 140.7 (1C, d, 3JC—F=8 Hz, C4″), 148.2 (1C, d, 3JC—F=15 Hz, C2″), 154.6 (C5′), 162.6 (1C, d, 1JC—F=237 Hz, C6″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 294.1052 (calcd for C17H13N3OF, 294.1043).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:23][C:24]([NH2:26])=[NH:25]>CO>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2ccc(C)cc2)cc1C
Solvent: CO
Product: Cc1ccc(-c2cc(C)c(C(=O)N=C(N)N)cc2S(C)(=O)=O)cc1

Procedure:
A solution of 1.8 g of methyl 2-methyl-4-(4-methylphenyl) -5-methylsulphonylbenzoate [obtainable by reacting methyl 3-methylsulphonyl-4-bromo-6-methylbenzoate with tolylboronic acid] and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours and the solvent is then removed. The residue is treated with water and the crop of crystals which remains is filtered off with suction and treated with dilute sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-(4-methylphenyl)-5-methylsulphonylbenzamide is obtained, m.p. 222°-224°.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC=CC=1CS(Cl)(=O)=O)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[C:49]#[N:50])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: N#Cc1ccccc1CS(=O)(=O)Cl
Product: N#Cc1ccccc1CS(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared from 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7 as a white solid in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CO>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
To a mixed suspension of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) and hexamethyldisilazane (16.42 g) in toluene (60 ml) was added sulfuric acid (0.80 g) dropwise and the silylation reaction was carried out at an internal temperature of 110˜120° C. for 6 hours. After completion of silylation, the toluene was distilled off to recover a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (13.72 g) and ethyl bromoacetate (3.40 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 6 hours. After completion of reaction, the reaction mixture was cooled to an internal temperature of ≦70° C. and ethyl acetate (80 ml) was added. Then, methanol (60 ml) was added dropwise over 30 minuets. After completion of dropwise addition, the mixture was cooled to ≦20° C. and stirred for 1 hour. The resulting crystal crop was harvested by filtration, washed serially with methanol (40 ml) and water (100 ml) and dried to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (28.16 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[N:6][C:7]=1[Cl:8].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:3][C:4]([CH3:9])=[CH:5][N:6]=1
Reactant: Cc1cnc(Cl)c(N)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 5-amino-6-chloro-3-picoline (9.54 g, 66.9 mmol) in pyridine (200 mL) was added 2-nitrobenzoyl chloride (13.65 g, 73.6 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature (18 h). The dark mixture was then diluted with water (1500 mL) and sat. sodium bicarbonate solution was added until the pH reached 8. The precipitate was collected by filtration, rinsed with water (30 mL×3) and dried to afford N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide as a pale solid (17.70 g, yield: 91%).
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][CH2:3][CH2:2]1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O>[CH:16]([N:4]1[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:1][CH2:2][CH2:3]1)=[O:18]
Reactant: CCOC(=O)C(=NOC)C1=CSCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOC)C1=CSCCN1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Ethyl 2-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.8 g.) was added to a mixture of acetic anhydride (7.7 g.) and formic acid (3.48 g.), which was warmed at 50° C. for 2 hours previously, under ice-cooling, and stirred at room temperature overnight. After adding chilled water (100 ml.) to the resultant solution, the solution was extracted with ethyl acetate three times. The extract was washed with a saturated aqueous solution of sodium chloride once, an aqueous solution of sodium bicarbonate four times and a saturated aqueous solution of sodium chloride once in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diisopropyl ether (15 ml.). The crystals were collected by filtration and washed with diisopropyl ether to give ethyl 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.0 g.), mp. 94° to 96° C.