Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:28])=[C:15]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([C:24](OC)=[O:25])[O:21][N:20]=3)[N:16]=2)=[CH:8][CH:7]=1)[CH3:2].[BH4-].[Na+].O>CO>[OH:25][CH2:24][C:22]1[O:21][N:20]=[C:19]([O:18][CH2:17][C:15]2[N:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])=[CH:7][CH:8]=3)[O:13][C:14]=2[CH3:28])[CH:23]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(C(=O)OC)on3)c(C)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(CO)on3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of methyl 3-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)isoxazole-5-carboxylate (2.02 g) in methanol (25 mL) was gradually added sodium borohydride (250 mg) at 0° C. After stirring at room temperature for 16 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give ethyl (4-[4-({[5-(hydroxymethyl)isoxazol-3-yl]oxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl)acetate as colorless crystals (0.95 g, yield 46%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:28](=[O:29])[O:30][C@@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (127 mg, 0.364 mmol) was dissolved in 5 mL anhydrous DMF and cooled to 0° C., and a solution of (R)-tetrahydrofuran-3-yl chloroformate (65.4 mg, 0.436 mmol) in 200 μL DMF was added dropwise followed by the addition of triethylamine (74 mg, 0.10 mL, 0.73 mmol). The reaction was allowed to warm to room temperature. The reaction was complete after two hours. The mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to a yellow solid. Purification via silica gel chromatography using 98% CH2Cl2/2% MeOH gave (R)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as an off white solid (116 mg, 69%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][N:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Brc1ccc(OC2CCOC2)cn1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOC2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-bromo-5-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 21) in analogy to Example 1a): MS (ISN): 465.0 and 467.0 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[NH2:5][C:4]1[CH:3]=[C:2]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[C:13]#[N:14]
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(N)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)aniline (3.24 g, 13.5 mmol) in N,N-dimethylformamide (50 mL) was degassed by bubbling argon through the solution for 30 minutes. To the reaction was added zinc cyanide (0.872 g, 7.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.624 g, 0.54 mmol). The reaction was heated to 80° C. and stirred for 20 hours. The solvent was removed from the reaction under vacuum and the residue purified by silica chromatography (Biotage SP4, eluting 15% EtOAc in iso-hexane (4 column volumes) then a gradient from 15-30% (over 6 column volumes)) to yield the title compound as a colourless oil (2.20 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@@H:6]([CH3:8])[C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C@@H:2]1[CH2:7][C@@H:6]([CH3:8])[C:5](=[O:9])[C:4]([CH3:10])([CH3:11])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: C[C@@H]1C[C@@H](O)CC(C)(C)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@@H](C)C(=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 99.4 %

Procedure:
300 g of (4R, 6R)-4-hydroxy-2,2,6-trimethylcyclohexanone were dissolved in 154.7 ml of pyridine. The solution was treated dropwise at -3° C. to 0° C. within 10 minutes with 1.2 l of acetic anhydride and then stirred at room temperature for a further 4.25 hours. The reaction mixture was subsequently concentrated on a rotary evaporator at 60° C./16 mbar, whereby there were obtained 394.7 g of crude product as a yellow oil. Distillation of the crude product gave at about 95° C./0.07 mbar 378.4 g (99.4%) of (4R, 6R)-4-acetoxy-2,2,6-trimethylcyclohexanone as a colourless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][C@H:10]1[CH2:22][CH2:21][N:13]2[C:14]3[C:19]([CH:20]=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:12]1[CH2:11][C@@H:10]([CH2:9][C:1]#[N:2])[CH2:22][CH2:21][N:13]12
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC[C@H]1CCn2c(cc3ccccc32)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
18.0 g (367 mmol) of sodium cyanide were added to a solution of 65.0 g (233 mmol) of (6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl)methyl methanesulfonate in 500 ml of dimethylformamide and the mixture was heated at 70° C. for 24 hours. The mixture was partitioned between 1000 ml of water and 600 ml of ethyl acetate. The aqueous phase was extracted twice with 700 ml of ethyl acetate each time and the combined extracts were washed in twice with 500 ml of water each time, dried over magnesium sulfate and evaporated. The brown solid obtained was dissolved in ethyl acetate and the solution was filtered through a pad of silica gel. The solvent was removed in a vacuum and the residue was crystallized from methanol to give 25.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetonitrile as a light brown solid of melting point 100°-101° C.; [α]D20 -40.6° (c=0.84%, CH2Cl2).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([OH:52])[CH2:31][O:32]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.O>[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([O:52][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:31][OH:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a suspension of 6.17 g of 50% sodium hydride (washed with hexanes) in 245 ml of dry dimethylformamide was added 19.45 g of benzyl bromide at 0° C. A solution of 56.65 g of 4-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 60 ml of dimethylformamide was added dropwise with stirring at 0° C. under argon. The mixture was stirred overnight at room temperature, then poured into 1000 ml of iced water and extracted with petroleum ether. The organic phase was dried, the solvent removed and the residue dissolved in a mixture of 235 ml of methanol and 125 ml of tetrahydrofuran. A 500 mg portion of p-toluene sulfonic acid was added, the mixture was allowed to stand overnight and then the solvent was removed. The residue was dissolved in petroleum ether, washed with saturated aqueous sodium bicarbonate, dried and the solvent removed giving an oil. This oil was again subjected to treatment with p-toluenesulfonic acid in the solvent system described above, again giving an oil which was purified by HPLC, giving 23 g of the desired compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[C:4]([F:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[CH:3][C:4]=2[F:12])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc(F)c2ccoc2c1Br
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Yield: 77.5 %

Procedure:
Beginning with 1.27 gm (5.45 mMol) 4,6-difluoro-7-bromobenzofuran and 1.16 gm (5.72 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.51 gm (78%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)[OH:19])[C:12]=1[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
Into a round bottom flask was added {3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (6, 1.01 g, 2.28 mmol) in 5.00 mL of tetrahydrofuran. Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and purified by silica gel chromatography to give the desired compound (7, 914 mg, 91%). MS (ESI) [M+H+]+=442.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.N([Si](C)(C)C)[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:29]([NH2:27])=[O:30])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 70 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 12-chloro-4-iodo-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (10.0 g, 28.7 mmol) in dry DMF (300 mL) was added Pd(PPh3)2Cl2 (1.00 g, 1.44 mmol) and (Me3Si)2NH (86.1 mmol, 14.0 g). The mixture was stirred at 70° C. for 4 h under carbon monoxide atmosphere. After removal of the solvent, the residue was treated with ice-water. The solid was collected by filtration, dissolved in ethyl acetate (400 ml), dried over anhydrous Na2SO4, and concentrated to give 12-chloro-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (7.20 g, 97% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 265.1 [M+H+]
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[CH2:13][CH2:14][C:15](=[O:16])[C:7]1=[C:6]2[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26](=[O:27])[CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.[CH2:32]([O:34][C:35](=[O:47])[C@H:36]([CH2:45][SH:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:33]>C(Cl)Cl.CO>[C:41]([O:40][C:38]([NH:37][CH:36]([CH2:45][S:46][CH:25]1[CH2:24][C:23](=[O:28])[N:22]([CH2:21][C:20]2[CH:29]=[CH:30][C:17]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:4]=4)[CH:9]=[C:8]4[CH2:13][CH2:14][C:15](=[O:16])[C:7]=34)=[CH:18][CH:19]=2)[C:26]1=[O:27])[C:35]([O:34][CH2:32][CH3:33])=[O:47])=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CN5C(=O)C=CC5=O)cc4)c2c1)C(=O)CC3
Reactant: CCOC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(CSC1CC(=O)N(Cc2ccc(-c3c4c(cc5ccc(N(C)C)cc35)CCC4=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask equipped with a septum and a stir bar was charged with compound 17 (0.006 g, 0.015 mmol) in CH2Cl2/MeOH 1:1 (5 mL). N-Boc-L-cysteine ethyl ester (0.0036 g, 0.015 mmol) was added in one portion and the mixture mas stirred at rt for 10 min. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The solution was then concentrated under reduced pressure and the reaction residue was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 1:1, to provide 0.006 g of the title compound as a 1:1 mixture of two inseparable diastereomers (d1 and d2) in a 60% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][CH:7]1[CH2:9][CH2:8]1)[CH3:2].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][N:6]([CH:7]1[CH2:9][CH2:8]1)[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNC1CC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a vigorously stirred solution of 4.9 g (34 mmol) of cyclopropylamino-acetic acid ethyl ester in 50 ml of CH2Cl2 and 25 ml of saturated sodium hydrogen carbonate was added a solution of 8.4 g (37 mmol) of 4-(trifluoromethoxy)benzoyl chloride in 10 ml of CH2Cl2 and the reaction stirred for 1 h. The organic phase was then separated, dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 3:7] afforded 8.9 g (80%) of the title compound as a colorless oil. MS: 332.1 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>[N+]([O-])([O-])=O.[Ag+]>[Cl:11][C:6]1[N:5]([CH3:12])[N:4]=[C:3]([CH2:2][O:14][CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1nc(CBr)c([N+](=O)[O-])c1Cl
Reactant: CO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COCc1nn(C)c(Cl)c1[N+](=O)[O-]
Yield: 40 %

Procedure:
A solution of 3-bromomethyl-5-chloro-1-methyl-4-nitropyrazole (5.0 g, 19.6 mmol) in methanol (50 ml) was treated with silver nitrate (5.75 g, 33.8 mmol) and the mixture heated under reflux for 2 hours. The cooled reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and the aqueous phase extracted with a further quantity of ethyl acetate (50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. Chromatography on silica gel, eluting with a 97:3 mixture of dichloromethane and methanol, gave the title pyrazole as a white solid (1.6 g, 40%), m.p. 59°-63° C. Found: C,34.65; H,3.83; N,20.05. C6H8ClN3O3 requires C,35.05; H,3.92; N,20.44%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:40]([CH3:47])([CH2:44][CH2:45][CH3:46])[C:41](Cl)=[O:42])[CH3:39]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:41](=[O:42])[C:40]([CH2:38][CH3:39])([CH3:47])[CH2:44][CH2:45][CH3:46])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 78.4 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.18 g (7.3 mmol) of 2-ethyl-2-methylvaleryl chloride, to provide 956 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 38.2 %

Procedure:
To a solution of Boc-D-Tyrosine-Methyl ester (0.950 g, 3.217 mmol), 4-Phenoxyphenyl-boronic acid (0.688 g, 3.217 mmol), and triethylamine (228 mL, 16.083 mmol) in anhydrous dichloromethane (DCM) (79.2 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.445 g, 3.217 mmol), and the resulting mixture was stirred at room temperature for about 42 hours. The reaction mixture was washed with 60 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×30 mL). The organic layers were combined, washed with 60 mL of brine, and seperated. Organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.57 g, 50%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 1.59 (s, 1H), 2.99-3.11 (m, 2H), 3.67-3.73 (m, 3H), 4.57 (d, 1H, J=7.2 Hz), 4.99 (d, 1H, J=8 Hz), 6.92 (d, 2H, J=8.8 Hz), 6.99-7.01 (m, 5H), 7.07-7.10 (m, 3H), 7.31-7.35 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1)(C)(C)C.[ClH:26]>CCOC(C)=O>[ClH:26].[ClH:26].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reaction time: 2 h

Procedure:
A solution of {2-[3-(4-cyano-3-fluoro-benzyl)-3H-imidazol-4-yl]-ethyl}-carbamic acid tert-butyl ester (1.0 g, 0.0029 mmol) in EtOAc (30 mL) was cooled to −20° C. and saturated with HCl gas. The cooling bath was removed and the reaction was stirred for 2 hr. The solvent was removed in vacuo to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.[C-:17]#[N:18].[Na+]>CN(C=O)C.[OH-].[Na+]>[C:17]([CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (0.75 g, 2.60 mmol) and NaCN (0.255 g, 5.21 mmol) in DMF (5 mL) was stirred at room temperature for 50 min. The reaction mixture was cooled down to room temperature, diluted with 0.5 N NaOH (10 mL) and extracted with EtOAc (2×20 mL), and EtOAc layers were combined, washed with 0.5 N NaOH (10 mL), dried (Na2SO4), concentrated and the crude residue was purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-20%) to afford tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.40 g, 65.6% yield). LCMS (MH+-tBu): 179.0 (MH+), 0.68 min; 1H NMR (400 MHz, CDCl3) δ ppm 9.28 (s, 1H), 8.32 (s, 1H), 7.59 (br. s., 1H), 3.91 (s, 2H), 1.57 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COCCOCCOCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COCCOCCOCCCCCCCCS(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture of 40 g of 8-[2-(2-methoxyethoxy)ethoxy]-1-octanol, 35.31 g of tosyl chloride and 200 ml of pyridine was stored in a chill room overnight, then poured into water and extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid and saturated aqueous sodium bisulfite, dried and the solvent removed, giving the desired compound as an oil which was used without further purification in Example 8.