Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=O.[OH-].[Na+]>ClCCCl>[N:20]1[CH2:24][CH2:23][CH2:22][C:21]=1[N:20]1[CH2:24][CH2:23][CH:22]=[C:21]1[N:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=C1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C1=C(N2c3ccccc3Sc3ccccc32)N(C2=NCCC2)CC1
Reaction time: 4 h
Yield: 17 %

Procedure:
Phosphorus oxychloride (38.3 g., 0.25 mole) in 50 ml. of 1,2-dichloroethane is added in one portion to a stirred mixture of phenothiazine (49.8 g., 0.25 mole) and 2-pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2-dichloroethane. The mixture is stirred for 4 hr. at room temperature, permitted to stand for a period of 15 hr. and then poured into a mixture of 200 ml. of 5N sodium hydroxide and 100 g. of crushed ice. The 1,2-dichloroethane layer is separated and the aqueous layer extracted with 100 ml. of additional 1,2-dichloroethane. The combined 1,2-dichloroethane fractions are sequentially extracted with 300 ml. of 1.5N hydrochloric acid and 200 ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydroxide and extracted repeatedly with chloroform. After drying over magnesium sulfate, the chloroform solution is concentrated and the residual material thus obtained stirred with 200 ml. of acetone to remove the acetone soluble 10-[2-(1-pyrrolinyl)]phenothiazine by-product and filtered. The filter cake is washed with additional acetone and dried providing 14.1 g. (17% yield) of 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE as the free base, m.p. 199°-201° C. The bis-pyrrolinyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200-250 ml. of anhydrous ether providing the hydrochloride salt. Crystallization of the hydrochloride salt from absolute ethanol-anhydrous ether affords analytically pure 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL PHENOTHIAZINE[HYDROCHLORIDE solvated with 1/5 mole of ethanol as an off white solid, m.p. 237°-239° C. (corr.).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: Cc1nc2c(Br)c(C)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2c(Br)c(CBr)ccc2s1
Yield: 74 %

Procedure:
A mixture of 4-bromo-2,5-dimethyl-1,3-benzothiazole (5.8 g, 24 mmol), N-bromosuccinimide (5.12 g, 28.7 mmol), and benzoyl peroxide (0.580 g, 2.40 mmol) in carbon tetrachloride (100 mL) was heated at reflux overnight. The mixture was diluted with dichloromethane, washed with 1 N NaOH, brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified on silica gel, eluting with 0% to 50% EtOAc in hexane, to give the desired product (5.70 g, 74%). LCMS calculated for C9H8Br2NS(M+H)÷: m/z=319.9; found: 319.8.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:17]1[CH:18]=[C:13]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cn1nc(Cl)cc(Nc2ccn(CC(C)(C)O)n2)c1=O
Temperature: 90 °C
Yield: 59 %

Procedure:
A solution of 1-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (prepared as in U.S. Pat. No. 7,935,699 B2, Example 74, 139 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77.7 mg, 0.13 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 10% methanol in dichloromethane) to give 6-chloro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-2-methyl-2H-pyridazin-3-one (156 mg, 59%) as a light yellow solid.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[CH3:14][C-:15]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16]1.[Li+]>CCOCC>[Cl-:1].[Cl-:1].[CH3:20][C:17]1([Zr+2:13][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)[CH:18]=[CH:19][C:15]([CH3:14])=[CH:16]1
Reactant: [Zr+3]C1C=Cc2ccccc21
Reactant: Cc1cc[c-](C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1=CC(C)([Zr+2]C2C=Cc3ccccc32)C=C1
Reaction time: 17 h

Procedure:
To a yellow-orange suspension of indenylzirconium trichloride, IndZrCl3, (1.00 g, 3.20 mmol, 1.00 equiv.) in ether (30 mL) was added lithium 1,3-dimethylcyclopentadienide (0.32 g, 3.20 mmol, 1.00 equiv.). The reaction quickly turned yellow with much precipitate. The reaction was stirred 17 hours and then evaporated in vacuo, leaving yellow solid. The solid was extracted with dichloromethane (20 mL, then 2×10 mL) and the extracts were filtered to give yellow solid and a yellow solution. The solution was evaporated in vacuo, leaving bright yellow solid. Yield 1.07 g (90%). 1H NMR(CD2Cl2): δ 2.09 (s, 3H, Me), 5.65 (d, 2H), 5.94 (t, 1H), 6.48 (d, 2H), 6.82 (t, 1H), 7.28 (m, 2H, Ind), 7.64 (m, 2H, Ind).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27](Cl)(=[O:29])[CH3:28].CCN(CC)CC>C(Cl)Cl>[C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26])(=[O:29])[CH3:28]
Reactant: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a mixture of 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (140 mg, 1.0 eq) in DCM (8 mL) was added acetyl chloride (1.5 eq) and Et3N (2.0 eq), the mixture was stirred at room temperature overnight. At the end of reaction, the mixture was concentrated and water was added then extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated until the aim product precipitated, filtrated and washed with some DCM to afford 1-(4-acetamido-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (90 mg, 59%). MS (ESI) 389.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.56 (s, 1H), 8.77 (d, J=3.9 Hz, 2H), 8.51 (d, J=4.2 Hz, 1H), 8.27 (d, J=3.9 Hz, 2H), 7.72 (m, 2H), 7.23 (t, J=4.5 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.55 (t, J=4.2 Hz, 1H), 6.57 (t, J=4.2 Hz, 1H), 3.05-3.15 (m, 1H), 2.90-3.05 (m, 1H), 2.60-2.75 (m, 1H), 2.05-2.15 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CCCCCCCCCC(O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCCCCCCCCC(O)CC(=O)O
Reaction time: 1 h
Yield: 90 %

Procedure:
Purification by distillation (Kugelrohr, 135° C./0.2 torr) gave ethyl 3-hydroxy-12-tridecenoate as a colorless oil (12.3 g, 80% yield). To this ester (10.8 g, 42.2 mmol) in dioxane (50 ml) at room temperature was added 1M NaOH (50 ml). After one hour, the resulting slurry was diluted with water and washed twice with hexane. The aqueous layer was acidified with 10% citric acid, and the resulting solid collected by filtration and dried in vacuo to give 3-hydroxy-12-tridecenoic acid as a white solid, mp 62°-64° C. (8.65 g, 90% yield). To a solution of this hydroxy-acid (8.60 g, 37.6 mmol) in DMF (27 ml) at room temperature were added t-butyl-dimethylsilyl chloride (10.8 g) and imidazole (9.7 g). The reaction was stirred for 24 hours, poured into ice water (250 ml), and extracted three times with hexane. The extracts were combined, dried (Na ), filtered, and evaporated to give the bis-silyl derivative as a light yellow oil (14.5 g, 84% yield).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:32]2[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:11][CH:10]=1>O1CCCC1.C(N(CC)CC)C.ClCCl.[Cu]I.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>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:32]2[CH:33]=[CH:34][C:35]([C:7]#[C:6][CH2:5][NH:4][CH:1]3[CH2:3][CH2:2]3)=[CH:36][CH:37]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCNC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCNC3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Cyclopropyl-N-(prop-2-ynyl)amine (105 mg, 1.103 mmol) was added to a solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (336 mg, 0.613 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL). The mixture was degassed and copper(I) iodide (19 mg, 0.1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days, diluted with dichloromethane (40 mL), washed with water (2×15 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(N-cyclopropylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([C:23](Cl)=[O:24])[CH2:20][C:19]1([F:22])[F:21]>[Cu]Br.C1(C)C=CC=CC=1>[F:21][C:19]1([F:22])[CH2:20][C:18]1([C:23]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:24])[CH3:17]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC1(C(=O)Cl)CC1(F)F
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C(=O)C#Cc2ccc(Cl)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
13.7 g (0.1% mol) of p-chlorophenyl-acetylene are added to a mixture of 10.1 g (0.1 mol) of triethylamine, 1.4 g (0.01 mol) of copper(I) bromide and 55 ml of toluene, and the mixture is stirred for 30 minutes at room temperature under argon. After the reaction mixture has been heated to 55° C., 15.5 g (0.1 mol) of 1-methyl-2,2-difluoro-cyclopropanecarbonyl chloride are added dropwise. After this, the mixture is stirred for 8 hours at 90° C., and then cooled and filtered. The filtrate is washed in succession with dilute aqueous hydrochloric acid and water and concentrated under reduced pressure. 19.2 g of a dark oil remain, which is distilled using a bulb tube. At 0.1 mbar and a jacket temperature of 120° C., a yellow oil passes over which solidifies on standing. 8.4 g (33% of theory) of 2-(4-chlorophenyl)-ethin-1-yl 2,2-difluoro-1-methylcycloprop-1-yl ketone of melting point 67°-68° C. are obtained. ##STR65##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@:11]1([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@:11]1([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[S:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(C(=O)Nc2ccccc2Br)CCCN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@]1(C(=S)Nc2ccccc2Br)CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of EXAMPLE 5B (1.25 g) in toluene (12 mL) was added Lawesson's reagent (1.212 g) and the mixture heated at reflux for 5 hours. After cooling, the solid was filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and the solution washed with 5% aqueous citric acid and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and the residue purified by flash chromatography on silica gel using 4:6 to 6:4 dichloromethane/hexane to afford the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:19])([F:8])[F:7].[C:20](OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCCCCC>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][C:10]([OH:19])=[C:9]2[C:6]([F:7])([F:8])[F:5]
Reactant: CCOC(C)=O
Reactant: O=C1C=Cc2ccccc2C1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cccc2c(C(F)(F)F)c(O)ccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (0.33 mL, 4.52 mmol) was added dropwise at about 5° C. to a stirred solution of 3,4-dihydro-1-hydroxy-5-methyl-1-(trifluoromethyl-2(1H)-naphthalenone (1.04 g, 4.26 mmol) and 4-(dimethylamino)pyridine (3.5 mg) in pyridine (0.73 mL) under dry nitrogen. The reaction mixture was stirred and allowed to warm slowly to 25° C. (about 45 min). The reaction was judged to be complete by tlc using silica gel thin layer plates and 20% (v/v) ethyl acetate in hexane as the mobile phase. The reaction mixture was poured onto ice and extracted with diethyl ether. The ether extract was washed with water and a saturated solution of NaHCO3 in water, dried (MgSO4) and concentrated under reduced pressure to give the title compound (961 mg, 100% yield). A small sample, purified by sublimation (30°-34° C., 0.05 mm), had mp 83°-84° C.; nmr (CDCl3) δ 2.65 (s, 3H), 7.1 (d, J=9 Hz, 1H), 7.25 (m, 1H), 7.35 (q, J=8 Hz, 1H), 7.85 (m, 1H), 8.05 (d, J=9 Hz, 1H); uvλmax (MeOH) 335 nm (ε 2,770), 322 (2,420), 293 (4,050), 281 (4,680), 222 (46,400); Anal Calcd for C12H9F3O: C, 63.72% H, 4,01%; Found: C, 63.47% H, 3.96%.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][C:16]1SC=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1C=CC(CC(Cl)=O)=[CH:23]1.C([C@H]1COC(=O)N1)C1C=CC=CC=1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][C:16]1[CH:20]=[CH:19][S:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccs1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=C(Cl)Cc1ccsc1
Agent: O=C1N[C@@H](Cc2ccccc2)CO1
Product: O=C(Cc1ccsc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 68 %

Procedure:
According to the procedure described in Example 17(a) for the preparation of 4(S)-benzyl-3-(2-thien-2-yl-acetyl)-2-oxazolidinone, 3-thiopheneacetyl chloride and (S)-(−)-4-benzyl-2-oxazolidinone furnished in 68% yield 4(S)-benzyl-3-(2-thien-3-yl-acetyl)-2-oxazolidinone as a solid, mp 80-1° C. 1H NMR: δ 7.33-7.24 (m, 5H), 7.15-7.09 (m, 3H), 4.72-4.65 (m, 1H), 4.39, 4.28 (AB quartet, 2H, J=15.9 Hz), 4.22-4.15 (m, 2H), 3.26 (dd, 1H, J=3.2, 13.4 Hz), 2.77 (dd, 1H, J=9.4, 13.4 Hz). Anal. Calculated for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.80; H, 5.04; N, 4.69; S, 10.70.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][C:17]1[C:18]([NH:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1.O1CCCC1>C(O)(=O)C>[Cl:16][C:17]1[C:18]([N:23]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]([CH:12]([CH3:13])[CH3:14])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(CC(=O)C(C)C)=NOC
Reactant: NNc1ncccc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(C)C)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.1 %

Procedure:
A mixture of 3.0 g of ethyl 2-methoxyimino-5-methyl-4-oxohexanoate, 2.4 g of 3-chloro-2-hydrazinopyridine, 50 ml of tetrahydrofuran and 100 ml of acetic acid was stirred at room temperature for 20 hours, and then heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with methyl t-butyl ether two times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and an aqueous saturated chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.07 g of ethyl 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:14][O:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([OH:12])=[N:11][C:2]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2c(O)nc(Cl)nc2c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N3CCCC3)nc2c1
Temperature: 100 °C

Procedure:
2-chloro-7-methoxyquinazolin-4-ol (165 mg, 0.783 mmol) and pyrrolidine (0.130 mL, 1.567 mmol) were dissolved in THF (2 mL) and heated to 100° C. for 2 h in a sealed tube. The reaction was cooled and the volatiles were removed under vacuum. The crude solid was collected and washed with water, filtered and dried to give 7-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-ol which was carried to the next step without further purification. MS: MS m/z 246.2 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 158c (190 mg, 0.35 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (26.5 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 1 h and quenched with aqueous NH4Cl. It was then concentrated under reduced pressure and the residue was extracted with dichloromethane. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 158 (70 mg, 37%) as white solid. MS-ESI: [M+H]+ 545.3. 1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=13 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.26 (s, 1H), 4.90 (s, 1H), 4.44-4.43 (m, 2H), 3.61 (s, 3H), 2.69-2.65 (m, 2H), 1.40 (s, 9H), 1.19 (t, J=8.0 Hz, 3H)
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40].C(Cl)Cl.CCOC(C)=O>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:45]4[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(S(C)(=O)=O)CC3)CC2)n1
Yield: 84.8 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (from Example 3) (0.20 g, 0.37 mmol) and 1-(methylsulfonyl)piperazine (0.31 g, 1.9 mmol) in THF (100 mL) was refluxed for 2 days. The solvent was then removed under vacuum, and the residue was diluted with water to give a white solid, which was collected and dried. Chromatography on alumina eluting with CH2Cl2/EtOAc (9:1) gave 0.22 g (84% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 4.01 (m, 4H), 3.88 (m, 4H), 3.79 (m, 4H), 3.38 (m, 4H) 3.23 (m, 4H), 3.11 (dd, J=8.5, 6.0 Hz, 2H), 2.92 (dd, J=8.4, 6.0 Hz, 2H), 2.75 (s, 3H), 2.60 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.ClC1N=C(Cl)C2OC=CC=2N=1.N1CCC(CO)CC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OCC1CCN(c2nc(Cl)nc3ccoc23)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Clc1nc(Cl)c2occc2n1
Agent: OCC1CCNCC1
Solvent: ClCCl
Product: O=CC1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A flask was charged with (1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methanol (11.2 g, 41.8 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Arkpharm], piperidin-4-ylmethanol), DCM (200 mL) and Dess-Martin periodinane (18.6 g, 43.9 mmol). The mixture was stirred at rt for about 3 h. The mixture was diluted with DCM (100 mL) and washed with an aqueous solution of 1 N Na2CO3 (200 mL). The aqueous layer was extracted with DCM (2×100 mL). The combined extracts were washed with brine, dried over Na2CO3, filtered, and evaporated under vacuum. The residue was purified by column chromatography eluting with 20-80% EtOAc/heptane (120 g silica gel) to provide 1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidine-4-carbaldehyde (10 g, 90%): LC/MS (Table 2, Method u) Rt=1.22 min.; MS m/z: 266 (M+H)+.