Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[CH2:13][NH:12][C@@H:11]([CH2:14][OH:15])[CH2:10]1.[S:17](Cl)(Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][C:9]1([CH3:16])[CH2:13][N:12]2[S:17](=[O:19])(=[O:18])[O:15][CH2:14][C@H:11]2[CH2:10]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CN[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A solution of triethylamine (4.94 mL, 35.4 mmol) and (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride (1.0 M in DCM, 21.27 mL, 21.27 mmol) over 15 seconds. The reaction was maintained at this temperature for ˜3 h, allowed to warm to room temperature and stirred overnight (16 h). The mixture washed with aqueous 1 N HCl (30 mL×2), brine (40 mL), dried over MgSO4, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (708 mg, 3.70 mmol, 21% yield) as a white crystalline solid. MS (ESI) 192.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:36][O:37][C:38](Cl)=[O:39].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:36][O:37][C:38]([N:22]1[CH2:21][CH2:20][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23]1)=[O:39]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2ccc(OC)c3nc(NC(=O)c4ccc(F)cc4)sc23)CC1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of 0.1 g (0.24 mMol) 4-fluoro-N-[4-methoxy-7-piperidine-4-yl-benzothiazol-2-yl]-benzamide hydrochloride (1:1) in 3 ml THF were added 0.036 ml triethyl amine. At 0° C. 0.020 ml (0.26 mMol) chloro formic acid methyl ester was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phase were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.080 g (76%) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-piperidine-1-carboxylic acid methyl ester as a white solid. F.p.: 238-239° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:7]1[C:2]([N:14]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:9])[CH2:15]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CN(c2nccnc2Cl)CCN1
Temperature: 65 °C
Yield: 80 %

Procedure:
A mixture of 2,3-dichloropyrazine (2.80 g, 18.8 mmol), racemic 2-methylpiperazine (1.88 g, 18.8 mmol) and K2CO3 (3.90 g, 28.2 mmol) in acetonitrile (25 mL) was heated at 65° C. for 15 h with stirring. The reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography on silica gel using CHCl3/MeOH (15:1) as eluent to give 3.2 g (79%) of the title compound. MS m/z 213 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][N:13]2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.[ClH:22].C(OCC)C>CO>[ClH:22].[NH2:7][CH:8]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][N:13]2[N:12]=1)[CH2:9][CH3:10]
Reactant: CCC(NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCC(N)c1nn2cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of [1-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-carbamic acid tert-butyl ester (10 mg, 0.034 mmol) in absolute methanol (0.5 mL) was treated with 2 N HCl/diethyl ether (2 mL) and the mixture stirred at room temperature overnight. The resulting white suspension was concentrated under vacuum and the solid residue triturated with diethyl ether and dried under vacuum to give the title compound (6 mg, 77%) as white powder: 1H NMR (DMSO-d6) δ 1.08 (t, 3H, J=7.15 Hz), 2.02 (m, 1H), 2.11 (m, 1H), 4.20 (s, 1H), 6.60 (s, 1H), 7.03 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][CH2:21][C@H:12]1[C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH:11]1[CH2:23][CH2:22][CH2:21][C@H:12]1[C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]
Reactant: [H][H]
Reactant: O=C([C@@H]1CCCN1C(=O)OCc1ccccc1)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: O=C([C@@H]1CCCN1)N1CCOCC1
Yield: 98.7 %

Procedure:
In 100 ml of ethanol was suspended 4.9 g of compound (83) and after adding thereto 250 mg of 10% palladium carbon, the mixture was stirred for 4 hours in a hydrogen stream. After filtering off 10% palladium-carbon, ethanol was distilled off under reduced pressure from the filtrate to provide 2.8 g of crude N-(L-prolyl)morpholine (84).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].ClCCCN(CC)CC.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:22][CH3:21])[CH2:18][CH3:19])[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Agent: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
The N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea (150 mg) synthesized in Example 142 was dissolved in dimethylformamide (2.5 ml), and then potassium carbonate (150 mg) and 1-chloro-3-(diethylamino)propane (80 mg) were added and the mixture was heated and stirred at 60° C. for 2 hours. After cooling, water was added, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (10 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[N+:11]([C:14]1[C:15]([NH2:21])=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>C(O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]1[NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=2[N:21]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCO
Product: COc1ccccc1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Yield: 35.3 %

Procedure:
A solution of o-anisaldehyde (0.789 ml, 6.53 mmol) and 3-nitro-o-phenylenediamine (1 g, 6.53 mmol) in ethanol (30 ml) was heated to 90° C. for 20 hours in a sealed tube. The red reaction mixture was taken to dryness and purified by silica gel chromatography (Biotage 40M, 75% DCM in hexanes to 100% DCM) to give 163 (0.62 g, 2.303 mmol, 35.3% yield) as yellow solid. LRMS (ESI): (calc.) 269.3 (found) 270.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 12 h
Yield: 27.7 %

Procedure:
Under a nitrogen atmosphere, 2,4-dichlorophenol (500 mg, 3.067 mmol) was diluted in DMF (15 mL). Cesium carbonate (3 g, 9.202 mmol) was then added followed by 2,5-difluoronitro-benzene (976 mg, 6.135 mmol). The reaction was heated to 90° C. and allowed to stir for 12 hours. Then, 500 uL of water was added and was heated for an additional 4 hours. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3×60 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (5%-20% EtOAc/hexanes) gave 1-(2,4-dichlorophenoxy)-3-fluoro-2-nitrobenzene (257 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: CCCNCCC
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1
Yield: 87 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and dipropylamine (Aldrich), the title compound was obtained as a white solid in 87% yield.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])(C)(C)C.[C:18]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO.CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (12%, 64 ml) was added to a cold solution of Boc-derivative 3 (21.1 g, 91.7 mmol) in MeOH (190 ml) and stirred overnight at room temperature. The next day additional acid (30 ml) was added and stirring was continued for another 10 h. The reaction mixture was filtered, washed with CHCl3, concentrated and dried in vacuo overnight. The product was suspended in DMF (300 ml) with DIEA (42 ml), cooled to 0° C. and a solution of Bt-derivative 2 (29 g, 90.5 mmol) in DMF (100 ml) was added into the reaction mixture. The cooling bath was removed and the stirring was continued overnight. The solvent and DIEA were removed in vacuo at 45° C., the residue was suspended in CHCl3/H2O mixture, washed with H2O, aq. KHSO4 (20%), H2O, aq. NaHCO3 (2 times with each), dried (Na2SO4), concentrated in vacuo, and triturated with petr. ether. Yield 22.32 g (78%). mp: 134-1350. 1H (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.65-1.95 (m, 4H), 2.20-2.26 (m, 4H), 3.19 (q, J=6.15, 2H), 3.23-3.35 (m, 4H), 4.82 (bs, 1H), 6.40 (bs, 1H), 6.68 (bs, 1H). 13C (CDCl3): 14.77, 24.92, 25.66, 26.43, 28.38, 33.59, 33.84, 33.92, 34.35, 38.83, 39.66, 79.35, 156.56, 172.65, 173.12. ESI-MS: 338.2 (MNa+), 316.0 (MH+), 216.0 (MH+-Boc).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.Cl.[O:11]1CCOCC1>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:11])[CH:3]=1
Reactant: C1COCCO1
Reactant: Clc1cc(Br)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Br)cc(Cl)n1
Yield: 76 %

Procedure:
A solution of 4-bromo-2,6-dichloropyridine (1.0 equiv.) in dioxane and aqueous sodium hydroxide (15% by weight solution, 1:1 ratio, 0.55 M) was heated in the microwave for 30 min at 150° C. The solution was cooled to room temperature and neutralized with concentrated HCl (pH=˜6) and extracted with ethyl acetate three times. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was dried under vacuo to give 4-bromo-6-chloropyridin-2-ol as an off-white solid in 76% yield. LCMS (m/z) (M+H)=207.9/209.9, Rt=0.60 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 60e (0.18 g, 0.666 mmol) in EtOH (10 mL) was added 1N aqueous NaOH (2.5 mL, 2.5 mmol). The mixture was stirred at room temperature for 4 d. The solvent was evaporated and 1N aqueous HCl was added, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product 60f was purified by preparative reverse phase chromatography. MS m/z (M+H+) 257.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([Cl:17])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]2[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:9]3[CH:10]=[C:11]([Cl:17])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (0.62 g, 15 mmol, 60% oil dispersion) was added to a stirred solution of methyl 2-bromo-7-chloro-5H-pyrido[3,2-b]indole-4-carboxylate (3.5 g, 10.3 mmol) in dry DMF (30 mL) under nitrogen in an ice bath. After 5 min, 1-(chloromethyl)-4-methoxybenzene (1.82 mL, 13 4 mmol) was added and the reaction was removed from the bath and left stirring at RT overnight. The reaction was diluted with EtOAc, washed with water (4×) and then brine. Removal of the solvent followed by step gradient silica gel radial chromatography with hexane containing 25 to 50% DCM afforded impure methyl 2-bromo-7-chloro-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (4.0 g) as a light yellow fully solid that was used as such. MS (ESI) m/z 460.95 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.31 (1H, d, J=8.24 Hz), 7.69 (1H, s), 7.47 (1H, d, J=1.53 Hz), 7.34 (1H, dd, J=8.39, 1.68 Hz), 6.78-6.82 (2H, m), 6.73-6.76 (2H, m), 5.63 (2H, s), 3.78 (3H, s), 3.73 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:28][C:29](=[O:31])[CH3:30])C=CC=CC=1>C1(C)C=CC=CC=1>[O:31]=[C:29]([CH3:30])[CH:28]=[CH:1][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCc1c(C)c(C)c(C)c(C)c1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCc1c(C)c(C)c(C)c(C)c1C=CC(C)=O
Yield: 87.3 %

Procedure:
A solution of ethyl 4-(2-formyl-3,4,5,6-tetramethylphenyl)butyrate (5 g) and 1-triphenylphosphoranylidene-2-propanone (6 g) in toluene (100 ml) was boiled under reflux for 24 hours. The toluene was removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (eluant chloroform) to give ethyl 4-[2-(3-oxo-1-butenyl)-3,4,5,6-tetramethylphenyl]butyrate (5 g) as a pale brown oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.24 (3H,t); 1.6-2.0 (2H,m); 2.1-2.4 (14H,m); 2.40 (3H,s); 2.5-2.8 (2H,m); 4.11 (2H,q); 6.12 (1H,d); 7.71 (1H,d).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][C:5]4[NH:6][C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)=[N:8][C:4]=4[CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Ic1ccc2[nH]c(CN3CCCC3)nc2c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4[nH]c(CN5CCCC5)nc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole (200 mg, 0.61 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (131 mg, 0.61 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]([C:17](=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28][C:29]1[N:34]=[C:33]([C:35](Cl)=[O:36])[CH:32]=[CH:31][N:30]=1>N1C=CC=CC=1.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:35]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([S:28][CH3:27])[N:34]=2)=[O:36])[N:15]([C:17](=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(NC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(F)cc1
Reactant: CSc1nccc(C(=O)Cl)n1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)N(C)C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 4-{N′-[2-(4-fluoro-phenyl)-acetyl]-N′-methyl-hydrazino}-piperidine-1-carboxylic acid tert-butyl ester, 9, (3.7 g, 10.1 mmol) in pyridine (10 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride (2.9 g, 15.2 mmol). The reaction mixture is stirred at room temperature for 2 hours then diluted with 0.1 N HCl and extracted three times with CH2Cl2. The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo. Purification over silica (EtOAc/hexanes 1:1) affords 1.058 g (20% yield) of the desired product. ESI/MS: 518.2 (M+H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: CCCCS
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCSC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
542 mg (1.89 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone, 212 mg (2.36 mmole) of butyl mercaptan, 381 mg (3.77 mmole) of triethylamine and 1.04 g (3.78 mmole) of diphenylphosphoryl azide were dissolved in 10 ml of N,N-dimethylformamide and the solution was allowed to stand overnight at room temperature. After dilution with ethyl acetate, the mixture was washed with water several times and then dried. The solvent was distilled off and the residue (1.25 g) was purified by column chromatography through 23 g of silical gel, eluted with mixtures of hexane and ethyl acetate in volume ratios ranging from 4:1 to 2:1, to give 649 mg (yield 96%) of the title product. Recrystallization from hexane gave colourless needles, melting at 56.5°-57° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.[N:13]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:1][C:2]1[C:3]([S:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:21])=[O:20])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1cc(S(=O)(=O)N2CCCCC2)c(O)c2c1CCC2=O
Yield: 32.5 %

Procedure:
Into a solution of 2 g of 7-hydroxy-4-methyl-1-indanone in 10 ml of dichloroethane was added 2.27 g of 1-piperidine sulfonyl chloride. Then 10 g of anhydrous aluminum chloride was gradually added to the mixture and stirred, and the reaction mixture was refluxed by heating for 8 hours. The reaction mixture was extracted with 200 ml of chloroform, washed with water, then the chloroform was removed by evaporation under a reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to obtain 1.24 g of 7-hydroxy-4-methyl-6-(1-piperidinesulfonyl)-1-indanone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][NH:12]3)[CH:5]=[CH:4][N:3]=1.IC.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[CH3:26])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCN3)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazine (i.e. the product of Step A) (50.0 mg, 0.15 mmol), iodomethane (0.019 mL, 0.31 mmol) and potassium carbonate (63 mg, 0.46 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 2 h, followed by at 50° C. for 1 h and then at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-80% ethyl acetate in hexanes as eluant to give 37.4 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([C@@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)([CH3:28])[CH3:27])[N:12]=1>C(Cl)Cl.C(=O)([O-])O.[Na+].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH3:28])([CH3:27])[C@@H:29]([OH:30])[CH2:33][OH:32])[N:12]=1
Reactant: CC1(C)OC[C@@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step iii) (0.37 g) in DCM (10 mL) was added iron (III) chloride hexahydrate (0.66 g) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with sat. sodium hydrogencarbonate solution and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using a MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white solid. Yield: 0.16 g