Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:21]([C:29]1[N:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=2)=[CH:31][N:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[CH:37]=[CH:36][C:35]([C:32]4[CH:31]=[N:30][C:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:34][CH:33]=4)=[CH:40][CH:39]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Reactant: CCCCCCCCc1ncc(-c2ccc(Br)cc2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCCCCCc1ncc(-c2ccc(-c3ccc4c(c3)CC(CCCCCCCC)C4)cc2)cn1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
0.41 g (1.50 mM) of 2-octylindan-5-boronic acid, 0.45 g (1.30 mM) of 2-octyl-5-(4-bromophenyl)pyrimidine, 2.2 ml of ethanol, 4.2 ml of benzene, 2.1 ml of 2M-sodium carbonate aqueous solution and 0.07 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 200 minutes under stirring. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with ethyl acetate, followed by washing with saturated common salt aqueous solution. The organic layer was dried with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the organic layer and the resultant organic layer was evaporated to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent (toluene/acetone) and ethyl acetate to obtain 0.46 g of 2-octyl-5-[4-(2-octylpyrimidine-5-yl)phenyl]indan (Yield: 71.5%). ##STR301##
Reaction SMILES: [NH2:1][C@:2]([CH3:28])([CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.O>[CH2:26]([C@@:2]1([CH3:28])[NH:1][C:30](=[O:32])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:27]
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)OC(C)=N3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)OC(C)=N4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 187.7 %

Procedure:
To a solution of (2R)-2-amino-2-methyl-N-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]butanamide (Intermediate 205, 143 mg, 0.37 mmol) and TEA (0.21 mL) in ethyl acetate (2.5 mL) at 0° C., triphosgene (44 mg, 0.15 mmol) dissolved in ethyl acetate (2.5 mL) was added drop wise in 10 min. The reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was diluted with water (5 mL) and ethyl acetate (10 mL). Phases were separated and the aqueous was back-extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent affording the title compound (115 mg) as white solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][C:11]1[N:12]=[CH:13][N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][CH2:10][C:11]1[N:12]=[CH:13][N:14]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyldimethylsilylchloride (2.83 g, 18.76 mmol) was added to a suspension of 4-hydroxymethyl-1-triphenylmethylimidazole (5.80 g, 17.05 mmol) in DMF (200 mL) containing imidazole (3.48 g, 51.1 mmol). After 15 min, a clear colorless solution was obtained which was stirred at room temperature. When reaction was complete, the DMF was removed in vacuo and the residue patitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. The title compound was obtained as a clear gum.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])=[O:8])([CH3:3])[CH3:2].Cl.C([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])(C)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:35][CH2:34][CH2:33][C:32]([OH:31])=[O:36])=[O:13])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 8 %

Procedure:
To a solution of crude compound (106) (0.4 g, 1.1 mmol) from above and beta-alanine tert-butyl ester hydrochloride (0.2 g, 1.1 mmol) in DMF (5 mL) was added diisopropylethylamine (0.41 mL, 2.3 mmol) followed by O-(benotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.44 g, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (50 mL), washed with 10% aqueous citric acid solution (30 mL), followed by saturated aqueous NaHCO3 solution (30 mL) and brine (2×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was then dissolved in anhydrous dichloromethane (5 mL) and cooled to 0° C. before a solution of hydrochloric acid (1 mL, 4 N in dioxane) was added. The reaction was stirred for 2 h at 0° C. and the solvent was removed in vacuo. The crude residue was purified by preparative LC/MS to afford 50 mg (8% yield over three steps) of the title compound (103). 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J=7.6, 1.6 Hz, 1H), 7.51–7.48 (m, 1H), 7.34–7.13 (m, 5H), 3.72 (q, J=6.0 Hz, 2H), 3.13–3.10 (m, 2H), 2.67 (t, J=6.4 Hz, 2H), 1.25 (d, J=6.8 Hz, 121). MS (ESI) m/z 414.3 (M+H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]2[CH2:24][CH2:23][C@:22]3([CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25]3)[C:21]2=[O:40])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[C:65](O)(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>>[C:65]([O:13][C@@H:14]1[CH2:15][CH2:16][C@H:17]([N:20]2[CH2:24][CH2:23][C@:22]3([CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:25]3)[C:21]2=[O:40])[CH2:18][CH2:19]1)(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (163.0 μL, 0.001035 mol) was added to a mixture of benzyl (5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (200.0 mg, 0.0005175 mol, this compound was prepared by using the procedures of example 472-a, step 1), and triphenylphosphine (271.4 mg, 0.001035 mol) in tetrahydrofuran (3.0 mL, 0.037 mol) at rt. The mixture was stirred at rt for 5 minutes, then benzoic acid (66.36 mg, 0.0005434 mol) was added. After stirring for an additional 2 h, the volatiles in the mixture were removed in-vacuo and the residue was purified by flash chromatography to afford the desired product.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:35][CH2:36][CH:37]=[CH2:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33]C)([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1]/[C:2](/[CH2:35][CH2:36][CH:37]=[CH2:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([OH:33])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[NH:19]2)[CH2:8]1)=[O:5]
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl) 3-methylhepta-2,6-dienoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13](=[O:15])[NH:51][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 10.00 g (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester in 80 ml DMF were added 5.85 g EDC, 4.67 g HOBt, 10.8 ml DIPEA and 3.2 ml benzylamine at 0° C. After stirring for 12 h the reaction mixture was concentrated, the residue was dissolved in dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 1:1 as eluent. Yield: 11.2 g colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:28])[C:10](=[O:27])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23](O)=[O:24])[C:16](=[O:26])[C:12]3=2)[C:7]1=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:52]([CH3:54])[CH3:53])C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:28])[C:10](=[O:27])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23]([N:52]([CH3:54])[CH3:53])=[O:24])[C:16](=[O:26])[C:12]3=2)[C:7]1=[O:29]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O

Procedure:
A solution of [11-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetic acid (25 mg, 0.05 mmol), BOP (28 mg, 0.06 mmol), diisopropylethylamine (7 mg, 0.07 mmol) and dimethylamine (0.11 mL, 2M in THF) in DMF (0.5 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH2:35]O)[CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH2:35][O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:32]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)N1CC(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC(COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Temperature: 25 °C

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-phenol (750 mg, Step C), K2CO3 (3 eq., 1.5 g) and 3-hydroxymethyl-azetidine-1-carboxylic acid benzyl ester (1.1 eq., 1.2 g) in DMF was heated to 80 C for 1 h. The solution was cooled to RT then filtered and concentraced under vacuum. The residue was dissolved in CH2Cl2 and washed with H2O twice, followed by brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using 5% MeOH/CH2Cl2 to provide the desired compound as a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (1.0 g) and triethylamine (0.06 ml) in ethyl acetate (50 ml) was hydrogenated under hydrogen atmosphere in the presence of platinum dioxide (0.05 g) at 0°-5° C. for 2 hours. After removal of the catalyst, the filtrate was washed successively with 2N hydrochloric acid, brine, 5% sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:33][O:32][CH2:31]2)=[C:26]([O:35][CH3:36])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:33][O:32][CH2:31]2)=[C:26]([O:35][CH3:36])[CH:25]=1
Reactant: COc1cc(Br)ccc1C1(O)COC1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)c(OC)c3)cc12
Temperature: 115 °C

Procedure:
To a solution of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (70 mg, 0.27 mmol) and 3-(4-bromo-2-methoxyphenyl)oxetan-3-ol (96 mg, 0.30 mmol) in toluene (1.2 mL), ethanol (0.6 mL), and tetrahydrofuran (0.6 mL) followed by the addition of 2M potassium carbonate aqueous (0.6 mL, 1 mmol). Nitrogen was bubbled through the reaction for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium, dichloromethane (25 mg, 0.031 mmol) was added and the reaction heated to 115° C. for 16 hours. The reaction was then cooled to room temperature and filtered through a pad of celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure and passed through silica yielding 104 mg of the title compound that was brought forward without further purification. MS (ES+) 386.1 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1

Procedure:
A 1-bromo-4-methyl-benzene of general formula F-1, where B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent as dimethylformamide at elevated temperature as for example 150-200° C. to obtain the 4-methyl-benzonitrile of general formula F-2. The 4-methyl-benzonitrile of general formula F-2 is brominated by the treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator like AIBN to obtain the 4-Bromomethyl-benzonitrile of general formula F-3.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:42])[C@H:15]([CH:39]1[CH2:41][CH2:40]1)[C@H:16]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1.[BH4-].[Li+].[OH-].[Na+]>C1COCC1.CCO.C(OCC)C>[Si:18]([O:17][C@@H:16]([C@H:25]1[CH2:29][O:28][C:27]([CH3:30])([CH3:31])[N:26]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:15]([CH:39]1[CH2:41][CH2:40]1)[CH2:14][OH:42])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)C2CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A solution of tert-butyl (4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.3 g, 5.5 mmol) in anhydrous THF (50 mL) and EtOH (1 mL) was cooled to −30° C. prior to the addition of lithium tetrahydroborate (0.24 g, 11 mmol) under an atmosphere of nitrogen. The reaction mixture was allowed to gradually warm to ambient temperature while stirring for 20 h. The crude reaction mixture was diluted with diethyl ether (36 mL) and cooled to 0° C. prior to the addition of 1 M NaOH (aq.) (36 mL). Upon separation of the layers that resulted, the aqueous layer was extracted with EtOAc several times and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (120 g silica gel, eluting with 0-40% EtOAc/hexanes) to afford the sub-title compound (1.27 g, 54%). LC/MS (ESI) m/z calc. for C22H43NO5SiNa: 452.3 [M+Na]+. found 452.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([C:19]#[N:20])[NH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([C:19]#[N:20])[N:17]([CH3:23])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2c[nH]c(C#N)c2)N=C1N
Agent: [Cs+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2cccc(Br)c2)(c2cc(C#N)n(C)c2)N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1H-pyrrole-2-carbonitrile (0.50 g, 1.40 mmol) in dimethylformamide was added cesium carbonate (0.639 g, 1.96 mmol) and methyl iodide (96 μL, 1.54 mmol). The reaction mixture was stirred overnight at room temperature while protected from moisture, diluted with chloroform and washed well with water. The organic phase was dried (Na2SO4), filtered through a short column of silica gel and evaporated to afford the desired compound as a tan solid, 0.524 g (quantitative yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: C=Cc1cn(COCCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 67.3 %

Procedure:
Benzoylchloride (410 mg, 2.9 mmol) was added to a solution of 1 (614 mg, 2.89 mmol) in dry pyridine (30 ml) and the reaction was allowed to proceed at 25° C. with stirring for 6 h. Removal of the solvent in vacuo and purification of the product by elution from a silica gel column using chloroform-methanol (99:1, v/v) as eluent gave 3 as a viscous oil (615 mg, 67.3%) which was used directly in the next reaction step.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:22])[C:18]([F:21])([F:20])[F:19])[C:13]([N+:23]([O-:25])=[O:24])=[C:12]([F:26])[CH:11]=2)[CH2:5][S@@:4](=[O:27])[CH2:3]1.[CH3:28][C:29]1([CH3:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH:38]=O)[CH:36]=2)[CH2:31][O:30]1.CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>>[CH3:28][C:29]1([CH3:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]4[CH:15]=[C:14]([O:16][C@@H:17]([CH3:22])[C:18]([F:21])([F:19])[F:20])[C:13]([N+:23]([O-:25])=[O:24])=[C:12]([F:26])[CH:11]=4)[CH2:5][S@@:4](=[O:27])[CH2:3]3)[CH:36]=2)[CH2:31][O:30]1
Reactant: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Reactant: CC1(C)OCc2ccc(C=O)cc21
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3ccc4c(c3)C(C)(C)OC4)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 1h, starting from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol (0.075 g, 0.19 mmol), 3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde (0.036 g, 0.203 mmol), NaOAc (0.032 g, 0.38 mmol) and NaBH3CN (0.013 g, 0.19 mmol) and was obtained as a light yellow foam after chromatographic purification on silica gel: TLC (EtOAc-MeOH 19:1) Rf=0.20; HPLC RtA=1.78 min; ESIMS [M+H]+=575; 1H NMR (400 MHz, CDCl3): δ 7.19 (m, 2H), 7.04 (s, 1H), 6.84 (s, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 4.76 (m, 1H), 4.25 (s broad, 1H), 3.94 (d, 1H), 3.76 (d, 1H), 3.53 (ddd, 1H), 3.37 (ddd, 1H), 2.8-3.15 (m, 5H), 2.14 (m, 2H), 1.52 (d, 3H), 1.48 (s, 6H).