Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:20])=[N:11][N:12]([CH3:19])[C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([O:23][CH3:24])=O.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:20])=[N:11][N:12]([CH3:19])[C:13]=1/[C:14](=[CH:21]\[O:23][CH3:24])/[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(OCc2ccccc2)c(C)nn1C
Reactant: COC=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1c(OCc2ccccc2)c(C)nn1C

Procedure:
A solution of methyl (4-benzyloxy-1,3-dimethyl- pyrazol-5-yl)acetate (2.5 g, 9.1 mmol) and methyl formate (15 g, 250 mmol) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (60 % dispersion in oil) (0.55 g, 13.8 mmol) in anhydrous DMF (5 ml), while the temperature being maintained below 10° C. by cooling on ice. After stirring at room temeprature for 2 hous, the low boiling substances were remvoed under reduced pressure. To the residue was added potassium carbonate (2.5 g, 18.1 mmol), dimethyl sulfate (2.3 g, 18.2 mmol), and DMF (5 ml) under ice-cooling. After stirring at room temeprature for 3 hours, the mixture was distilled under reduced pressure to remove low boiling substances. The residue was diluted with ethyl acetate, successively washed with water, and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:1) to obtain (e)-methyl 2-(4-benzyloxy-1,3-dimethylpyrazol -5-yl)-3-methoxyacrylate (compound No. 1 in the Table 1) as a clear oil (2.1 g, 73%). Corresponding compound in Z-form (compound No. 2 in the Table 1) was also produced by the above reaction and recovered from the column.
Reaction SMILES: C[Al](C)C.[O:5]1[C:9]2([CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=3[F:21])[CH2:10]2)[O:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[O:29][CH2:28][CH2:27]2.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl>[O:8]1[C:9]2([CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:34])[C:31]4[CH:32]=[CH:33][C:24]([O:23][CH3:22])=[CH:25][C:26]=4[CH2:27][CH2:28][OH:29])=[CH:16][C:15]=3[F:21])[CH2:10]2)[O:5][CH2:6][CH2:7]1
Reactant: Nc1ccc(N2CCC3(C2)OCCO3)c(F)c1
Reactant: COc1ccc2c(c1)CCOC2=O
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(N3CCC4(C3)OCCO4)c(F)c2)c(CCO)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 2M solution of trimethylaluminum in toluene (14.9 mL) was added dropwise at 0° C. to a solution of 4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenylamine (5.3 g) in methylene chloride (100.8 mL). The reaction mixture was stirred for 15 min at 0° C. and then for 30 min at room temperature. Then a solution of 6-methoxy-isochroman-1-one (3.8 g) in methylene chloride (40 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. Then saturated Rochelle salt solution was carefully added and the mixture was stirred for 1 h at room temperature. The aqueous phase was extracted several times with methylene chloride. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 416.17 (C22H25FN2O5); MS (ESI): 417 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:20]1[CH2:19][CH2:18][N:17]([C:5]2[N:4]=[C:3]([N:2]([CH3:1])[CH3:23])[CH:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:6]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)cc1
Reactant: COc1ccccc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(c2nc(Nc3ccc(C)cc3)cc(N(C)C)n2)CC1
Temperature: 200 °C
Yield: 26.9 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2-(1-piperazinyl)-4,6-pyrimidinediamine (30 mg, 0.086 mmol), 1-(chloromethyl)-2-methoxybenzene (17 mg, 0.1 mmol) and triethylamine (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200° C. for 12 minutes. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:22].[OH-].[Na+]>C1COCC1.O>[C:3]([O:7][C:8]([N:10]([CH3:22])[C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(N(C)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 45 %

Procedure:
A flask is charged with a suspension of sodium hydride (60% in mineral oil) (0.109 g, 2.72 mmol) in THF (5 mL). The ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate (0.735 g, 2.70 mmol) is added, followed by iodomethane (175 μL, 2.70 mmol) and the resulting suspension is heated to reflux for 3 hours, then cooled to room temperature. Water is added, followed by 1.0 N NaOH. The basic phase is extracted with 3 portions of EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated to give a clear oil purified with flash chromatography. Yield 45%. HRMS (FAB) calculated for C12H18N2O4S+H 287.1065, found 287.1068.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C1(C)C=CC=CC=1.CCOCC>[C:2]1([C:1]2[N:17]=[N:16][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=c1cccc(-c2ccccc2)nn1
Yield: 39 %

Procedure:
To a mixture of 10g (0.052 mole) of 4-benzoylbutyric acid in 300 ml of toluene, hydrazine was added in one portion and the reaction was heated to reflux until all water had ceased to azeotrope. The reaction mixture was cooled and the toluene was stripped off in vacuo. The residue was dissolved in 200 ml Et2O and washed with H2O (100 ml) and brine (100 ml). The ether extract was dried over anhydrous MgSO4, filtered and stripped to yield an orange semisolid which was triturated with ether to yield 3.8 g (39%) of the desired product as a yellow solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33]C)=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1>C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.51 g (21.3 mmol) LiOH was added to a solution of (R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (crude product from Example 24g) in 80 mL THF and the reaction mixture was stirred for 3 h at RT. The THF was eliminated i.vac., the aqueous phase was washed with EtOAc, acidified with 10% HCl and the aqueous phase was extracted exhaustively with EtOAc. The combined organic phases were evaporated down i.vac., suspended in diethyl ether, filtered, the residue was dried and then purified by chromatography (silica gel, DCM/MeOH/AcOH 90:10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
55 mg (0.16 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 68 mg (82% of theory)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:15][C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:22]([C:16]1([OH:15])[CH2:21][CH2:20][N:19]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:18][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2cc(C(=O)CN3CCC(O)(Cc4ccccc4)CC3)ccc2N1

Procedure:
A mixture of 5-(chloroacetyl)-2(1H,3H)-indolone (2.05 g, 9.78 mmol), 4-hydroxy-4-benzylpiperidine (1.87 g, 9.78 mmol), potassium carbonate (2.97 g, 21.49 mmol), and potassium iodide (0.08 g, 0.48 mmol) in acetonitrile (200 ml) was refluxed overnight. The reaction was cooled and filtered through a celite™ pad. The filtrate was concentrated to give an orange foam which was flash chromatographed on silica gel with ethyl acetate elution. This afforded 0.79 g of oily yellow solid product. NMR 9.41 (br s, 1H), 7.91 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.28-7.14 (m, 5H), 6.90 (d, J=8 Hz, 1H), 3.76 (s, 2H), 3.52 (s, 2H), 2.78-2.73 (m, 4H), 2.43 (t, J=10.5 Hz, 2H), 1.86-1.76 (m, 2H), 1.50 (br d, J=12 Hz, 2H), 1.36 (br s, 1H). IR(KBr) 2920, 2815, 1710, 1685, 1615, 1240, 1115. FAB HRMS calcd for C22H25N2O3 (MH+): 365.1867. Observed m/e: 365.1883.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(F)c3)nc12

Procedure:
From 3-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+31.0° (c=0.70, CHCl3), ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)(=O)=O>CC(C)=O>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][NH:20][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccco1
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (5.0 g, 22.7 mmol) was added in three portions over a 10 minute period to a stirring solution of furfuryl amine (6.6 g, 68 mmol) in acetone (200 mL) cooled to 0° C. via an ice water bath. After addition of the sulfonyl chloride was complete the ice bath was removed and the solution was stirred for 1 hour at ambient temperature. The mixture was concentrated and subjected to silica gel chromatography (90% ethyl acetate, 8% hexanes and 2% acetic acid) to afford 4.4 of 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (4.4 g, 68%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): 4.04 (d, 2H, J=6 Hz), 6.13 (d, 1H, J=3.2 Hz), 6.25 (m, 1H), 7.43 (m, 1H), 7.83 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.36 (t, 1H, J=6 Hz), 13.4 (bs, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C([O-])(=O)C.N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>ClCCCl.O.C(Cl)Cl>[CH:14]1([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: OB(O)C1CC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(cnn2C2CC2)c1
Temperature: 70 °C
Yield: 70.6 %

Procedure:
A mixture of methyl 1H-indazole-5-carboxylate (970 mg, 5.5 mmol), cyclopropylboronic acid (946 mg, 11 mmol), cupper (II) acetate, [2,2′]bipyridyl (860 mg, 5.5 mmol) in 1,2-dichloroethane (50 mL) was heated at 70° C. for 2 hrs. The mixture was added saturated aqueous NH4Cl (70 mL) followed by the addition of DCM (30 mL) and water (30 mL), extracted with DCM (30 mL×2), dried over Na2SO4, filtered through a pad of Celite (registered trademark) the filtrate was concentrated to give a pale brown solid, which was purified by column chromatography on silica gel (hexane/EtOAc=8/1) to give 840 mg (71% yield) of the titled compound as a off-white solid.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[C:31](=[O:32])[N:30]2[CH:25]1[S:26][CH2:27][C:28]([CH3:36])=[C:29]2[C:33]([OH:35])=[O:34])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[CH:7]([O:35][C:33]([C:29]1[N:30]2[CH:25]([S:26][CH2:27][C:28]=1[CH3:36])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2=[O:32])=[O:34])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A solution of diphenyldiazomethane (116.5 g) in acetonitrile (800 cc) is added dropwise, in the course of 45 minutes, at a temperature of between 25° and 30° C., to a solution of 7-tert.-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (188.6 g) in acetonitrile (2,100 cc). The reaction mixture is stirred for 16 hours at 22° C. and is then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is redissolved in ethyl acetate (2 liters) and the solution is washed with 2 N hydrochloric acid (700 cc) and then with a saturated aqueous sodium bicarbonate solution (700 cc) and a saturated aqueous sodium chloride solution (700 cc). The solution is dried over sodium sulphate, treated with decolorising charcoal, filtered, and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is dissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) is added, and the mixture is heated to the reflux temperature and then allowed to cool. The crystals which have appeared are filtered off, washed with diethyl ether (3×250 cc) and then dried. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino- 3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (191 g) is obtained in the form of white crystals (m.p.=179° C.). On concentrating the mother liquor to 500 cc. a second fraction of product (32.6 g, m.p.=178° C.) is obtained.
Reaction SMILES: Cl.CO.C(O)(=O)C(O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Cl)[CH:38]=4)[CH2:32][CH2:31]3)=[O:29])[CH3:26])[O:21][CH2:20][CH2:19][O:18]2)=[CH:13][CH:12]=1.[H][H].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]([N:30]3[CH2:31][CH2:32][CH:33]([O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:34][CH2:35]3)=[O:29])[CH3:26])[O:18][CH2:19][CH2:20][O:21]2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension prepared from 2.25 g of 5% palladium on carbon, 400 ml of methanol, 0.2 ml of saturated HCl/methanol and 11.19 g (19.3 mmol) of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(3-chlorophenoxy)piperidine oxalate was shaken under 50 psi hydrogen at 50° for 4 hours. The mixture was allowed to cool to room temperature and filtered, and the solvent was evaporated to provide an oil. The oil was shaken with saturated sodium carbonate, extracted with ether, dried over potassium carbonate, filtered, and the solvent evaporated to provide 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl}-N-methylaminoacetyl}-4-phenoxypiperidine.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 85 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea described in Example 44A (303.02 mg, 1.04 mmol) in THF: DMF (2:1, 6 mL) was added NaH (95%, 28.9 mg, 1.144 mmol), stirred for 5-10 min at ambient temperature. Then (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline, (300 mg, 1.04 mmol) described in Example 27A was added as solution in DMF:THF (2:1). The reaction mixture was then stirred overnight. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine successively. The organic layer was dried (Na2SO4) concentrated to dryness to afford the pure 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (480 mg, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.28 (m, 5H), 6.50 (s, 1H), 4.35 (t, 2H), 4.05 (s, 3H), 3.82 (t, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CSc1ccc(CC(=O)c2cncc(Br)c2)cc1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(C/C=C/c2ccccc2)C(=O)c2cncc(Br)c2)cc1
Temperature: 25 °C

Procedure:
To 1-(5-bromo-3-pyridinyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone in DMF (2.5 mL) at 0° C. was added NaH (15 mg, 0.5 mmole). The reaction was stirred 30 minutes, at which point cinnamyl bromide (0.1 g, 0.5 mmole) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with H2O and extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C@H:4]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:5]2[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.O.CO.C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[NH:1][C:2]1[S:3][C@H:4]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:5]2[N:6]=1
Reactant: COC(=O)Cl
Reactant: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-amino-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (220 mg, 1.00 mmol) and Na2CO3 (212 mg, 2.00 mmol) in THF (10 mL) and water (10 mL) was added methyl chloroformate (0.08 mL, 1.1 mmol) at 0° C. After stirred for 2 h, the reaction mixture was condensed to give a residue, which was dissolved in MeOH (8 mL) and DCM (20 mL). After filtration the solution was concentrated under vacuum to give a residue, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 Detect prep HPLC): Column, SunFire Prep C18; mobile phase, Water with 0.03% ammonia and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm.] to give the title compound as a white solid (201 mg,72%). (ES, m/z)[M+H]+279.0; 1H NMR (300 MHz, D2O) δ6.46-6.49 (d, J=6.9 Hz, 1H), 4.25-4.29 (dd, J=6.6 Hz, 6.9 Hz, 1H), 3.95-3.99 (dd, J=6.0 Hz, 6.3 Hz, 1H), 3.74-3.78 (m, 1H), 3.74 (s, 3H), 3.51-3.68 (m, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[Cl-].[Li+].[CH2:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=[CH2:38]>O1CCCC1.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:38]([C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:37]=[CH2:36]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F
Reaction time: 5 h

Procedure:
In a 250 ml single neck round bottom flask, under a nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole (4.97 g, 9.22 mmol), lithium chloride (1.17 g, 27.65 mmol), allyltributyltin (4.27 g, 12.90 mmol), and bis(triphenylphosphine)palladium(II) chloride (301.03 mg, 0.369 mmol) in anhydrous tetrahydrofuran (99 ml). The resulting mixture was stirred for five hours at reflux, followed by the addition of an additional 0.15 mg of the palladium catalyst. The contents were then stirred overnight. The progress of the reaction was monitored by thin layer chromatography. The desired title product was further purified by flash chromatography.