Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[BH4-].[Na+].Cl>CCO.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of (1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (IX-1) (100 mg, 0.29 mmol) in EtOH (1.7 mL) and THF (0.5 mL) was added NaBH4 (22 mg, 0.58 mmol) at -50° C. and stirring was continued at -50° C. for 4 h. The reaction mixture was poured on ice, acidified with 1 N HCl and extracted with ether. After washing with sat. NaHCO3 -sol., brine and drying over MgSO4 the crude product was purified by silica gel column chromatography with hexane/EtOAc 5:1 to give (1 S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1) (51 mg, 51%) as a colorless oil. 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.2 Hz), 2.03-2.18 (3H, m),2.31-2.48 (2H, m),2.53 (1H, t,J=4 Hz),4.13 (2H, q,J=7.2 Hz), 4.21 (1H,bs), 5.26 (2H, s), 7.36-7.40 (5H, m); MS [EI]300 [(M--OEt)+ ];
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65]([C:67](=[O:71])[C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])[C:67]([C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:60])[S:63][CH:64]=4)=[O:71])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl) glyoxylic acid (303 mg : 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C., are added N- methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=2:1) to give 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)- glyoxylylamino]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (679 mg) as yellow foam. Yield : 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]=[C:20]=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[NH2:22][OH:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:21])[NH:22][OH:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Reactant: NO
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 86.7 %

Procedure:
Fourteen grams of 3-chloro-4-(2-naphthyloxy)phenyl isocyanate were dissolved in 60 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 13.5 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 13.5 g of the product was dissolved in 150 ml of a benzene-methanol (1:1) mixture, and 13 ml of dimethyl sulfate and 30 ml of 10 N sodium hydroxide were alternately added dropwise thereto at a temperature below 30° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-120 mesh; eluting solvent, tetrahydrofuran-benzene (1:1) mixture) to obtain 7.3 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. nD25.0 : 1.5860.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[CH2:12][NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:25]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[C:26]=[O:27]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[CH2:12][N:11]1[C:26](=[O:27])[NH:25][C:28]1[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1c(I)nn2c1CNC(CO[Si](C)(C)C(C)(C)C)C2
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CN(C(=O)Nc1ccc(C#N)cc1)C(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of Intermediate 351D (1.2 g, 2.58 mmol) in THF (12 ml) was added 4-isocyanatobenzonitrile (0.446 g, 3.09 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 16% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 351E (0.6 g, 38%) as a white solid. MS(ES): m/z=610 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (s, 1H), 7.75-7.63 (m, 4H), 5.24 (d, J=18.6 Hz, 1H), 4.85-4.77 (m, 1H), 4.47 (d, J=18.6 Hz, 1H), 4.35 (d, J=2.5 Hz, 2H), 4.30-4.22 (m, 2H), 3.73-3.64 (m, 2H), 1.31 (t, J=7.0 Hz, 3H), 0.76-0.71 (m, 9H), −0.04 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:35][CH2:34][C:24]3([O:32][CH2:31][C:27]4([CH2:30][CH2:29][CH2:28]4)[CH:26]([CH3:33])[O:25]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C([BH3-])#N.[Na+].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:35][CH2:34][CH:24]([O:25][CH:26]([C:27]3([CH:31]=[O:32])[CH2:28][CH2:29][CH2:30]3)[CH3:33])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C=O)CCC3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
A mixture of 3′-fluoro-4′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.64 g), sodium cyanoborohydride (0.33 g), boron trifluoride etherate (0.67 mL) and tetrahydrofuran (6 mL) was stirred at 70° C. for 20 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was mixed with Dess-Martin periodinane (0.49 g) and acetonitrile (5 mL), and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 32%).
Reaction SMILES: [CH3:1][C:2]([C:10]([Cl:12])=[CH2:11])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:13]([Br:16])(Br)[Br:14].[OH-].[K+]>C(Cl)Cl>[CH3:9][C:2]([C:10]1([Cl:12])[CH2:11][C:13]1([Br:16])[Br:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)Br
Reactant: C=C(Cl)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(c1ccccc1)C1(Cl)CC1(Br)Br

Procedure:
Into a 100 ml round bottomed flask equipped with magnetic stirring was added 4.5 g (25 mmol) of 1-(α,α-dimethylbenzyl)-1-chloroethylene, 25 g (100 mmol) of bromoform, 27 g of methylene chloride, 0.37 g of N,N′-dibenzyl-N,N,N′N′-tetramethylethylenediammonium dibromide, and 12.4 g (100 mmol) of 45% aqueous KOH. Rapid stirring overnight gave a 20% conversion to the desired cyclopropane. Washing the aqueous layer with water and resubmitting with fresh bromoform, catalyst, and KOH overnight gave further conversion. A third submission was deemed adequate. The aqueous washed organic layer was evaporated in vacuo and chromatographed on silica gel using 2% diethyl ether in hexane yielding 4.2 g of 1-(α,α-dimethylbenzyl)-1-chloro-2,2-dibromocyclopropane.
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.NC1CCCC2C=C(C(=O)C)C=CC1=2.[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]([NH:49][S:50]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)(=[O:52])=[O:51])[CH2:45]C(O)=O)=[CH:40][CH:39]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>Cl.CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[C:18]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:8]([NH:7][C:6](=[O:21])[CH2:45][CH:44]([C:41]1[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=1)[NH:49][S:50]([C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:60])([F:62])[F:61])[CH:54]=1)(=[O:51])=[O:52])[CH2:9][CH2:10][CH2:11]2)(=[O:20])[CH3:19]
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: CC(=O)c1ccc2c(c1)CCCC2NC(=O)OC(C)(C)C
Agent: CC(=O)c1ccc2c(c1)CCCC2N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.33 h

Procedure:
A mixture of (6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (Step e, 543 mg, 1.88 mmol, 1.0 eq) in HCl/EtOAc (4.7 M, 20 mL) was stirred at RT for 200 min. The solvent was removed with a rotary evaporator, and the resulting 1-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen chloride was dried in vacuo. A mixture of 1-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen chloride, 3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (882 mg, 2.26 mmol, 1.2 eq), EDC (Aldrich, 649 mg, 3.38 mmol, 1.8 eq), HOBt (Aldrich, 51 mg, 0.376 mmol, 0.2 eq) and DIEA (Aldrich, 486 mg, 3.76 mmol, 2.0 eq) in CH2Cl2 (20 mL) and DMF (5 mL) was stirred at RT overnight. The reaction was quenched with H2O (100 mL). The crude was extracted with CH2Cl2 (150 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-5% MeOH—CH2Cl2) afforded the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 563 (M+1).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH2:22][O:23][CH2:24][C:25]#[CH:26])=[N:20][N:19]=[C:18]2[CH2:27][NH2:28])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:29]1(=[O:43])[N:33]([CH2:34][C:35](Cl)=[O:36])[C:32](=[O:38])[C:31]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]12.CN(C)C=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH2:22][O:23][CH2:24][C:25]#[CH:26])=[N:20][N:19]=[C:18]2[CH2:27][NH:28][C:35](=[O:36])[CH2:34][N:33]2[C:32](=[O:38])[C:31]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]3[C:29]2=[O:43])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C#CCOCc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the above product (817 mg) and 27.5% hydrogen bromide/acetic acid (3 ml) is stirred at room temperature for 1.5 hours. The resultant solution is mixed with dry ether (30 ml) to give a precipitate. The precipitate is washed with dry ether (20 ml) twice to give 5-chloro-2-(3-aminomethyl-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl)-benzophenone hydrobromide. To a suspension of this hydrobromide in dry benzene (20 ml), 2-phthalimidoacetyl chloride (1.6 g) is added at room temperature. The resultant mixture is mixed with dry dimethylformamide (10 ml) and stirred at room temperature for 3 hours. The reaction mixture is poured into saturated aqueous sodium bicarbonate (50 ml)/water (50 ml) and stirred under ice-cooling for 30 minutes. The precipitate is filtered, washed with water and ether in order and dissolved in methylene chloride (about 50 ml). The organic layer is dried over magnesium sulfate and evaporated to remove the solvent. The residue is recrystallized from methylene chloride/ethanol to give 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl]-benzophenone (682 mg) as crystals melting at 245° to 246° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: NC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(N)=O)c2)c1C

Procedure:
3-Aminobenzamide (5 mmol, 1.0 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting precipitate was filtered from the mixture, then washed with ethanol. The white solid product was used without further purification (m.p. 237.8° C.-238.8° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>COCCOC.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>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[CH2:39][O:38][C:26]1[CH:25]=[CH:24][C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]=1[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3F)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (112 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (24.81 mg, 0.02 mmol) and sodium carbonate (0.72 ml, 0.72 mmol) were added to a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared by Example 81; 150 mg, 0.36 mmol) in 1,2-dimethoxyethane (3 ml), and the mixture was heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified by MDAP to yield the title compound. 58 mg.
Reaction SMILES: [F:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]([OH:7])[CH2:5][OH:6].O([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Si:30]([O:7][CH:4]([CH2:5][O:6][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]([F:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](C(O)CO)[C@@H](F)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a 500 mL RBF containing tert-butyl (1S,2R)-1-fluoro-3,4-dihydroxy-1-phenylbutan-2-ylcarbamate (98.00 mg, 327 mmol) was added DCM (5 mL) and the mixture was allowed to stir at 0° C. for 5 min. At this time, TEA (274 μA, 1964 mmol) and tert-butyldimethylsilyl triflate (188 μl, 818 μmol) was added to the mixture via syringe. The reaction was allowed to stir for 30 min and then quenched with sodium bicarbonate (50 ml, sat). The aq. layer was extracted with DCM (3×25 ml). The combined organics were washed with brine, dried with sodium sulfate and passed through a plug of silica gel and concentrated to give 203 mg of a yellow oil that was taken directly to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=3)[N:11]3[CH:27]=[CH:28][N:29]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2.CC([O-])(C)C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>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].C1COCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:17]1[CH:18]=[C:14]([C:12]2[N:11]3[CH:27]=[CH:28][N:29]=[C:10]3[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH2:31][CH:30]5[O:37][CH:34]([CH2:35][CH2:36]5)[CH2:33]4)=[CH:3][CH:4]=3)[N:13]=2)[CH:15]=[N:16]1
Reactant: C1CC2CNCC1O2
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(-c3ccc(Br)cc3)cc3nccn23)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2nc(-c3ccc(N4CC5CCC(C4)O5)cc3)cc3nccn23)cn1
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a flask charged with 7-(4-bromophenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation L; 0.250 g, 0.531 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (0.430 g, 3.80 mmol), and potassium 2-methylpropan-2-olate (0.119 g, 1.06 mmol) was added 6 mL of THF at ambient temperature with stirring. Argon was bubbled through the reaction for 10 minutes before dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.0436 g, 0.106 mmol) and tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) were added. Argon was bubbled through the reaction for 15 minutes before the reaction was sealed and allowed to proceed at 40° C. for 4 hours. The reaction was charged with more tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) and purged with argon for 5 minutes before it was sealed and allowed to proceed at 40° C. for 7 hours. The reaction mixture was diluted with DCM and aqueous saturated sodium bicarbonate (2 mL) and stirred for 30 minutes. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 1% methanol in DCM to afford 3-(4-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.133 g, 0.265 mmol, 49.0% yield). MS (apci) m/z=503.2 (M+H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:11].[O:20]1C2C(=CC=CC=2)C(=O)CC1C1C=CC=CC=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH:10]1[CH2:9][C:8](=[O:20])[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:11]1
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Reactant: O=C(C=Cc1ccccc1O)c1ccc(Cl)cc1Cl
Product: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccccc21

Procedure:
2-Hydroxy-2',4'-dichlorochalcone, as described in Arch. Pharm. 295, 16 (1962), was cyclized to the flavanone by the procedure described in Bull. Soc. Chem. France 674 (1973). Two recrystallizations from methanol gave 3 g of 2',4'-dichloro flavanone as pale tan crystals, m.p. 91°-92° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][S:21][CH3:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21][CH3:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CSCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: CSCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.6 %

Procedure:
Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethyoxyimino)-methyl]-benzamide (104.8 mg, 0.184 mmol) was dissolved in methylene chloride (anhydrous, 10 mL). Borane-pyridine complex (140 μL, 1.38 mmol) and then dichloroacetic acid (115 μL, 1.38 mmol) were added thereto with cooling the reaction vessel in an ice-bath under a nitrogen atmosphere. The ice-bath was removed, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resultant yellow residue was purified by silica gel column chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent). The resultant fraction was concentrated under reduced pressure and the oily residue was triturated with 5% ethyl acetate/hexane to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethoxyamino)-methyl]-benzamide (110 mg) as a white solid.