Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([C:19](O)=[O:20])[CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].O1CCCC1.[BH4-].[Li+]>C(COC)OC>[OH:20][CH2:19][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: COC(CC[C@@]12CCCc3cccc(c31)NC2=O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1Nc2cccc3c2[C@@]1(CCCCO)CCC3
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
(S)-2a-(3-methoxycarboxypropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (4.1 g, 15 mmol) was dissolved in dimethoxyethane (60 ml). Then, tetrahydrofuran solution of 1.6 M lithiumborohydride (9.0 ml, 18 mmol) was added to the resulting solution and stirred at room temperature for two days. The solvent was evaporated from the reaction mixture, and ethyl acetate, water and hydrochloric acid (1N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was separated and purified by means of silica gel column chromatography, whereby 2.15 g (yield 58%) of the above-described object compound could be obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10]>C(Cl)Cl>[O:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10]
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccccn1)C(F)(F)F
Yield: 47.1 %

Procedure:
In analogy to GP 2, reaction of 11.3 g Intermediate 6 (47 mmol, 1 eq.), 5.6 mL dry pyridine (70 mmol, 1.5 eq.), 12 ml trifluoromethanesulfonic acid anhydride (70 mmol, 1.5 eq.) in 450 mL DCM yielded 12.2 g 2-pyridyl triflate (33 mmol, 70% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[CH2:32][O:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44](O)=[O:45])[C:39](=[O:47])[N:38]=1)=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]([O:33][CH2:32][C:31]3[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:29]([O:28][CH3:27])[CH:30]=3)=[O:35])=[N:38][C:39]2=[O:47])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1OC
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ccn(CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)n2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(3,4-dimethoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.73 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.71 (m, 2H), 7.03 (s, 1H), 7.02 (t, 1H), 6.94 (s, 2H), 5.09 (s, 2H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.21 (t, 1.2H), 4.06 (t, 0.8H), 3.99 (t, 1.2H), 3.85 (t, 0.8H), 3.75(s, 3H), 3.74 (s, 3H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[NH2:19][N:20]1[C:24]([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH3:36])=[N:26]2)=[N:23][N:22]=[C:21]1[SH:37].C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:9]1[S:14][CH2:15][C:6]([CH2:5][S:37][C:21]1[N:20]([NH2:19])[C:24]([N:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][C:27]([CH3:36])=[N:26]3)=[N:23][N:22]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(-c2ccccc2)n(-c2nnc(S)n2N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2ccccc2)n(-c2nnc(SCC3=C(C(=O)O)N4C(=O)C(N)C4SC3)n2N)n1
Temperature: 60 °C

Procedure:
A mixture of 1.36 g. of 7-aminocephalosporanic acid, 1.50 g. of 4-amino-5-(3-methyl-5-phenyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol and 0.84 g. of sodium bicarbonate in 40 ml. of pH 6.4 phosphate buffer is stirred and heated at 60° C. for 8 hours. The mixture is cooled to room temperature, filtered and the filtrate is extracted with ethyl acetate. The aqueous portion is acidified to pH 2.5 with 4 N hydrochloric acid. The precipitate is collected by filtration and dried, giving 0.8 g. of the desired product, I.R. 5.60μ (β-lactam carbonyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][O:15][CH3:16])=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][O:15][CH3:16])=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1n[nH]c(=O)c2cc(OC)ccc12
Product: COCc1nnc(Cl)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-methoxymethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[F:26][C:27]([F:40])([F:39])[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36]C(S)=[CH:34][CH:33]=1)=[O:30]>CC#N>[CH3:24][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=[C:12]([S:14][C:17]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([F:40])([F:26])[F:39])=[CH:37][CH:36]=3)[N:11]=2)[NH:23][N:22]=1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Solvent: CC#N
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(NC(=O)CC(F)(F)F)cc3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
An slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transforms from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. Filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the layers were separated and washed the aqueous with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:16]([NH:28][C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCN
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Product: CCCCCCCCCCCCNC(=S)C1(c2ccccn2)CCCS1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (10 g) in n-dodecylamine (15 g) is heated for 50 minutes at 110° C. The reaction mixture is chromatographed on silica gel (200 g) contained in a column of diameter 3.7 cm. Elution is carried out with a cyclohexane-ethyl acetate mixture (90:10 by volume; 1800 cc), one 300 cc fraction and three 500 cc fractions being collected. Fractions 2 to 4 are combined and concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C.; the residue (14.2 g) is dissolved in ethanol (75 cc). The solution, to which decolourising charcoal (0.3 g) is added, is filtered hot and then kept, after cooling, for 30 minutes at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (40 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The resulting product (11.5 g) is dissolved in boiling ethanol (75 cc) and the solution, to which decolourising charcoal (0.3 g) is added, is filtered hot and then kept, after cooling, for 30 minutes at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (50 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 35° C. N-n-Dodecyl-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (10.2 g), melting at 60° C., is thus obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=[O:5])#[N:2].[OH-].[Na+].Cl.[CH2:11](O)[CH3:12].O>O>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[N:7][NH:6]1
Reactant: CCO
Reactant: N#CCC(=O)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccn[nH]c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a mixture of glyoxal bis(sodium hydrogen sulfite) monohydrate (25.24 g, 88.8 mmol) in water (80 ml) was added slowly a solution of cyanoacetohydrazide (8 g, 80.7 mmol) in ethanol/water 2:1 (120 ml). The mixture was then heated to 40° C. for 30 min. The pH was adjusted to 12-13 by addition of 10 N NaOH and stirring was continued for 3 h at 40° C. and for 1 h at 60° C. The reaction mixture was then allowed to cool to ambient temperature over night. The pH was then adjusted to 1-2 by addition of conc. HCl and the resulting mixture was evaporated. The remaining solid was extracted with CHCl3 in a soxhlet-extractor for two days to obtain the title compound as a light brown solid (2.019 g, 16.67 mmol, 21%). 1H NMR (d6-DMSO): 8.07 (d, J=4 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 13.91 (s br, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[CH:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(-c2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(-c4cccnc4)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoic acid (15 mg; 0.054 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (29 mg; 0.11), and HATU (49 mg; 0.11 mmol) were dissolved in 1 mL of DMF, and the mixture was chilled to 0° C. Diisopropylethylamine (19 μL; 0.11 mmol) was then added, the cold-bath was removed, and the mixture was stirred overnight. The mixture was then poured into water and extracted with EtOAc. The organic portion was washed with NaHCO3 and brine, and the washes were extracted once with EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated. Chromatography (0-6.5% MeOH/0.5% NH4OH in CH2Cl2) provided 23 mg (0.043 mmol; 80%) of Example 160. ESI MS m/z 534 [C28H31N5O4S+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of 10 (1.06 g, 2.46 mmol) in 30 mL of CH2Cl2 was added triethylamine (0.62 mL, 4.45 mmol). 4-Toluenesulfonyl chloride (TsCl, 567 mg, 2.97 mmol) was added to this solution in one portion at 0° C., and the mixture was stirred at under Ar for 24 h allowing it to warm to room temperature slowly. The reaction was quenched by pouring into a mixture of water (100 mL) and chloroform (70 mL), separated organic layer, and the aqueous layer was further extracted with chloroform (100 mL). The combined organic layers were dried over sodium sulfate (Na2SO4) and concentrated. The crude product was chromatographed (SiO2, gradient, hexane/EtOAc 5:1 to 2:1) to give 1.08 g (1.85 mmol, 75%) of 11 as a clear colorless oil. Rf 0.65 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.79 (d, 2H, J=8.3 Hz, H-2 of tosyl), 7.68 (m, 4H, H-2 of phenyl), 7.44-7.35 (m, 6H, H-3 and H-4 of phenyl), 7.32 (d, 2H, J=8.7 Hz, H-3 of tosyl), 4.14 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.80 (t, 2H, J=5.3 Hz, CH2OSi), 3.66 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.64-3.54 (m, 10H, (OCH2CH2)2OCH2CH2OSi), 2.43 (s, 3H, CH3 of tosyl), 1.04 (s, 9H, C(CH3)3); MS (ESI) Calcd for C31H42O7SSiNa (M+Na+): 609.2. Found: 609.2.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:29])=[N:11][C:12]2[N:13]([N:23]=[C:24]([C:26]([O-:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:29])=[N:11][C:12]2[N:13]([N:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2nc(C(=O)[O-])nn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2nc(C(=O)O)nn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 99.1 %

Procedure:
To a stirred solution of 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (13 mg, 0.03 mmol) in THF (1 mL) was added LiOH-H2O (9 mg, 0.21 mmol) in H2O (0.1 mL). After heating to 40° C. for 1 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure afforded 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (13 mg, 100%) as a white solid.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1)=[O:2].[CH3:41][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:4]1)[CH3:41]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reaction time: 3 h

Procedure:
tert-Butyl (3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (360 mg) was dissolved in THF (4 ml), a solution (1M, 1.95 ml) of methyl magnesium bromide in THE was added under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (325 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:67][CH:68]=[CH2:69].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:69][CH:68]=[CH2:67])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (90 mg in 3 ml 33% methylene chloride in cyclohexane) allyl trichloroacetimidate (27 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (20 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27](O)=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:39](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+].CN(C)C(=O)C>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27]([NH2:39])=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)O)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(N)=O)cc1OCC2
Reaction time: 1 h

Procedure:
A mixture of 55 mg (0.135 mmol) of (S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid, N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (57.0 mg, 0.150 mmol), N,N-Diisopropylethylamine (52.2 uL, 0.300 mmol) and Ammonium chloride (8.02 mg, 0.150 mmol) in N,N-Dimethylacetamide (3.0 mL, 32 mmol) was stirred for 1 hour. The mixture was concentrated in vacuum, the residue triturated with water, 0.01 N aq HCL, water, dried in vacuum and subjected to RP HPLC and then chiral purification to give 375. Yield 12 mg. M/z 408.2, calc. 407.21. 1H NMR (400 MHz, DMSO) δ 8.19 (d, J=8.9, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.04 (s, 1H), 6.36 (dd, J=9.0, 2.4, 1H), 6.07 (d, J=2.4, 1H), 5.91 (dq, J=13.3, 6.5, 1H), 4.44 (d, J=6.5, 4H), 4.01-3.93 (m, 1H), 3.57 (t, J=7.0, 1H), 3.24 (d, J=9.0, 1H), 2.23 (dd, J=12.1, 6.9, 1H), 1.98 (dd, J=14.8, 11.3, 3H), 1.47 (dd, J=6.6, 3.3, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH2:36])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(S)-2-(2-amino-5-chloro-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared following Procedure A using 2-amino-5-chloro-benzoic acid (1.23 g, 7 mmol), (S)-2-amino-3-(4′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (2.43 g, 7 mmol), HBTU (3.19 g, 8.4 mmol) and DIEA (2.46 mL, 14 mmol) in DMF (35 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave the title compound as yellow solid (3.25 g, 6.49 mmol,).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:29][CH3:30])[CH:32]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(CC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then 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 amorphous solid (0.54 g, 62%).