Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)[C:12]2[N:16]([CH2:17][CH2:18][O:19][Si](C)(C)C)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)[C:12]2[N:16]([CH2:17][CH2:18][OH:19])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3n2CCO[Si](C)(C)C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3n2CCO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 10 Step A (0.13 mmol, 73 mg) in 2 mL of dioxane was added a solution of LiOH (1.25 mmol, 30 mg) in 1 mL of H2O. The resulting solution was stirred at 40° C. overnight. The reaction mixture was taken up in a pH 7 buffer solution and EtOAc. The mixture was acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford the acid as a beige solid. MS (ESI): m/z 450 (M+H). HPLC A: 2.05 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: [C-]#N
Reactant: Nc1nc(Cl)nc(N2CCc3ccccc32)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(N)nc(N2CCc3ccccc32)n1
Reaction time: 2 h
Yield: 26.2 %

Procedure:
4-Chloro-6-(2,3-dihydro-indol-1-yl)-[1,3,5]triazin-2-ylamine (Intermediate 40, 680 mg, 2.48 mmol), potassium cyanide (323 mg, 4.96 mmol) and 18-crown-6 (328 mg, 1.24 mmol) were charged to a round-bottomed flask then taken up in DMF (12 mL). The resulting mixture was lowered into a heating block preheated to 110 C and stirred under nitrogen for 2 h and then at room temperature for 56 h. The reaction was then diluted with EtOAc (60 ml) and extracted with 5% aq. sodium carbonate solution (2×10 ml), brine (10 ml) and dried further over anhydrous magnesium sulfate. After evaporation of the solvent the crude residue was purified by FCC over silica gel eluting with heptane:EtOAc 1:0 to 8:2 to 1:1 to 0:1 and the column flushed with THF to give the title compound (155 mg, 26%). Method B HPLC-MS: MH+ requires m/z=239. Found: m/z=239, Rt=1.36 min (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:17][N:12]2C(=O)[O:14][CH2:15][C:11]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1.CCOC(C)=O.N1C=CN=C1.[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CCO.[OH-].[Na+].[Cl-].[Na+].O.C(Cl)Cl>[Si:39]([O:14][CH2:15][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:17][NH:12]1)([C:36]([CH3:38])([CH3:37])[CH3:35])([CH3:41])[CH3:40]
Reactant: O=C1OCC2(c3ccccc3)C=C(c3cc(F)ccc3F)CN12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1
Temperature: 60 °C

Procedure:
A suspension of 1.75 g (5.6 mmol) 1-7 in 15 mL of EtOH and 10 mL of 3 M NaOH was heated at 60° C. for 3 h, cooled to room temperature and dumped into a separatory funnel with EtOAc and brine. The layers were separated, the aqueous phase was extracted twice with EtOAc, the combined organic phases were washed twice with brine, dried over Na2SO4, and concentrated to provide a white solid. To this flask was added 30 mL of CH2Cl2. 1.5 g (22.3 mmol) of imidazole and 1.76 g (11.7 mmol) of TBSCl, and the resultant suspension was stirred overnight. The reaction was diluted with CH2Cl2, washed twice with water, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide 1-8 as a white solid. Data for 1-8: 1HNMR (500 MHz, CDCl3) δ 7.6-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.75 (s, 1H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (d, 1H), 3.75 (d, 1H), 0.9 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28](=[O:51])[C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:50])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)=[CH:31][CH:30]=3)[CH2:20][CH2:19][C:18]2=[O:52])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[CH3:49][C:46]1[CH:47]=[CH:48][C:43]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([C:28]([N:21]3[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:17]([CH2:16][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[C:18](=[O:52])[CH2:19][CH2:20]3)=[O:51])=[CH:30][CH:31]=2)=[O:50])=[CH:44][CH:45]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCNCC4)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
To a solution of 1-[(4-tert-butoxycarbonyl-1piperazinyl)carbonylmethyl]-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (150 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride - ethyl acetate solution, and then the mixture was stirred at ambient temperature for 12 hours. The solvents were evaporated in vacuo and the residue was diluted with saturated aqueous sodium bicarbonate solution, and then the aqueous layer was extracted with ethyl acetate. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (20% methanol in chloroform) to give 5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-[(1-piperazinyl)carbonylmethyl]-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (58 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH2:5][CH2:4][O:3]1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19]([NH:11][C:8]1[S:9][C:10]2[C:2]([CH3:12])([CH3:1])[O:3][CH2:4][CH2:5][C:6]=2[N:7]=1)=[O:20]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC1(C)OCCc2nc(N)sc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)C(C)(C)OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of Example 89E (1.0 g, 5.6 mmol) in THF (30 mL) were added 5-chloro-2-methoxy-benzoic acid (1.86 g, 10.0 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (1.91 g, 10.0 mmol, Aldrich), 1-hydroxybenzotriazole (1.35 g, 10.0 mmol) and triethylamine (3.5 mL, 3.5 mmol, Aldrich). The mixture was stirred overnight at room temperature. The reaction mixture was then diluted with 1 M aqueous NaHCO3 (20 mL) and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-5% methanol in dichloromethane to afford 1.55 g (78%) of the title compound. MS (ESI+) m/z 353 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=O)s1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(C)s1
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To 5-methyl-thiophene-2-carboxaldehyde (5 g, 40 mmol) in CH2Cl2 (100 mL) is added methyl (triphenylphosphoranylidene) acetate (13.3 g, 40 mmol). The solution is stirred for 72 hours. After this time, the solution is concentrated. The residue is slurried in Et2O. The solution is filtered through a bed of Celite. The collected liquid is concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc/hexanes to 60% EtOAc/hexanes to give the title compound (4.5 g, 25 mmol) as an oil.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:20])[C@@H:7]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH:8]([CH3:10])[CH3:9])[CH2:2][CH2:3][CH3:4].N[C@H](C(NCCCC)=[O:27])C(C)C.C(O)(=O)C1C(=CC=CC=1)O>>[CH2:1]([NH:5][C:6](=[O:20])[C@@H:7]([NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH:8]([CH3:9])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](N)C(C)C
Reactant: CCCCNC(=O)[C@@H](NCc1ccccc1O)C(C)C
Agent: O=C(O)c1ccccc1O
Product: CCCCNC(=O)[C@@H](NC(=O)c1ccccc1O)C(C)C

Procedure:
The title compound is prepared according to the representative synthesis of aminophenol 2a except after the second step; H2N-Val-NHn-Bu is treated with salicylic acid under the standard amide formation conditions outlined in the first step. The resulting off-white solid is purified by silica gel chromatography (5:1 hexanes:ethyl acetate) to afford 2c as a white solid. M.p.=123-125° C. IR (neat): 3279 (w), 3090 (w, br), 2930 (m), 1620 (s), 1605 (s), 1547 (s), 1530 (s), 1454 (s), 1371 (m, br), 1229 (m), 756 (s), 643 (m) cm−1; 1H NMR (400 MHz, CDCl3): δ 12.07 (1H, s), 7.51 (1H, d, J=8.0 Hz), 7.40-7.36 (1H, m), 7.29 (1H, br s), 6.97 (1H, dd, J=8.4, 0.9 Hz), 6.85-6.81 (1H, m), 6.00 (1H, br s), 4.36 (1H, t, J=7.7 Hz), 3.39-3.30 (1H, m), 3.27-3.19 (1H, m), 2.25-2.17 (1H, m), 1.54-1.47 (2H, m), 1.39-1.30 (2H, m), 1.03 (3H, d, J=3.3 Hz), 1.01 (3H, d, J=3.2 Hz), 0.91 (3H, t, J=7.3 Hz); 13C NMR (100 MHz, CDCl3): δ 170.8, 169.8, 161.4, 134.5, 126.3, 119.0, 118.5, 114.4, 58.9, 39.6, 31.7, 31.6, 20.2, 19.3, 18.7, 13.8; HRMS Calcd for C16H25N2O3[M+H]+: 293.18652. Found: 293.18532. [α]20D=−34 (c=0.63, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][NH:6][CH:7]=O.[AlH4-].[Li+].CCOCC>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][NH:6][CH3:7]
Reactant: COc1ccc(CNC=O)c(OC)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CNCc1ccc(OC)cc1OC
Temperature: 25 °C
Yield: 80.6 %

Procedure:
N-(2,4-Dimethoxy-benzyl)-formamide (0.50 g, 2.6 mmol) was added slowly to a suspension of the lithium tetrahydroaluminate (0.19 g, 5.1 mmol) in ether (30 mL, 200 mmol) at −78° C. The reaction mixture was warmed slowly to rt and stirred at rt under an atmosphere of Argon over night. The reaction was quenched at 0° C. by the sequential addition of 0.19 ml of H2O, 0.19 ml of 15% aq NaOH solution, and 0.57 ml of the H2O. The inorganic solids were removed by filtration and washed with ether. The ether filtrate was washed with water and brine, dried over Na2SO4. Evaporation of the solvent gave the product as a pale yellow oil (0.38 g, 82%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[C:6]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(Cn2ccnc2)c2cc(OC)ccc21
Agent: BrB(Br)Br
Product: C=CCn1cc(Cn2ccnc2)c2cc(O)ccc21
Yield: 44.1 %

Procedure:
The procedure described in Example XLVII was repeated except that 1-allyl-3-(imidazol-1-ylmethyl)-5-methoxyindole (1.34 g.) and boron tribromide (1.91 ml.) were the reactant and reagent respectively employed under these same conditions. After basification with sodium bicarbonate, the aqueous layer was extracted with three-100 ml. portions of ethyl acetate and the combined organic extracts were washed with water and subsequently dried over anhydrous magnesium sulfate. Evaporation of the solvent then gave a solid product, which later was crystallized from ethanol to afford pure 1-allyl-5-hydroxy-3-(imidazol-1-ylmethyl)indole (yield, 0.56 g.), m.p. 165°-167° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylformamide (20 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) at 65° C. for 5 days. The mixture was cooled to 25° C. and partitioned between water and dichloromethane. The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to give the title compound (0.57 g, 42%). MS (DCI/NH3) m/z 272 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J=6.25 Hz, 6 H) 1.61 (m, 3 H) 3.89 (m, 2 H) 4.99 (s, 2 H) 5.98 (dd, J=7.54, 2.76 Hz, 1 H) 6.06 (d, J=1.84 Hz, 1 H) 7.14 (d, J=7.72 Hz, 1 H) 7.39 (m, 5 H).
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>>[C:9]1([CH3:8])[CH:16]=[CH:15][C:12]([CH2:13][NH:14][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: Cc1ccc(CN)cc1
Reactant: COC=CC(C)=O
Product: CC(=O)C=CNCc1ccc(C)cc1

Procedure:
The title compound 58 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.103 g, 1 mmol) and 4-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow oil. (Yield 0.19 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]([NH:14][NH2:15])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c(C(=O)NN)s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To ethyl 2,4-dimethylthiazole-5-carboxylate (Prep25, 50 g, 0.27 mol) in ethanol (200 mL), hydrazine hydrate (64 g, 1.08 mol) was added. The mixture was stirred at 90° C. overnight. After cooling to room temperature, the solvent was removed under vacuum to afford 41 g of crude product as a solid. The crude was purified by FC to give 23 g pure title compound product (y=50%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:3][C:4](=[O:19])[CH2:5][CH2:6][CH:7]([CH3:18])[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17]1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:18])[CH2:6][CH2:5][C:4](=[O:19])[CH2:3]1
Reactant: [H][H]
Reactant: CC1C=CCCCCCCC=CC(C)CC(=O)CC1
Agent: [Pd]
Agent: CC1/C=C/CCCCCC/C=C/C(C)CC(=O)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CCCCCCCCCCC(C)CC(=O)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A Parr bottle was charged with 3,14-dimethylcyclohexadeca-4E,12E-dien-one (0.203 g, 0.77 mmole), ethyl acetate (36 ml), ethanol (4 ml) and 5% palladium-on-carbon (0.050 g). The vessel was pressurized to 43 psi with hydrogen gas and the solution was shaken vigorously for 2 hours. The pressure was brought down to atmospheric pressure and the reaction mixture was filtered through a pad of Celite and the solvents were removed by distillation under reduced pressure to afford 3,14-dimethylcyclohexadecan-1-one (0.206 g, 100% yield). C18H34O (266.47 g/mole). 1HNMR (500 MHz, CDCl3): 0.861 (dd, 3H), 0.909 (dd, 3H), 1.38-1.03 (m, 20H), 1.62-1.38 (m, 3H), 2.10-1.98 (m, 1H), 2.18-2.11 (m, 1H), 2.43-2.33 (m, 3H) ppm. 13CNMR (125 MHz, CDCl3): 20.44, 20.80, 24.15, 25.21, 26.47, 26.50, 26.76, 27.06, 27.47, 29.10, 29.45, 31.31, 34.50, 35.61, 40.24, 50.48, 211.86 ppm. IR (νmax(cm−1)): 2930(s), 2910(s), 2856(s), 1713(s), 1460(s), 1412(w), 1375(m), 1146(w), 1096(w), 1059(w). MS (m/z): 266(M+), 251, 237, 223, 208, 152, 139, 125, 109, 97, 85, 69, 55, 41.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11](Br)Br)[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.S(=O)(=O)(O)[OH:29]>>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:29])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C(Br)Br)oc23)c1=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
60 ml of concentrated sulfuric acid was added to 12.0 g (22.5 mmol) of 3-(4-chloro-2-dibromomethyl-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, followed by stirring at 50° C. for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was crystallized from isopropyl ether to obtain 7.6 g (yield: 88.4%) of the desired product as pale yellow crystals. Melting point: 180-183° C.
Reaction SMILES: C([O:4][CH:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[CH:6]1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][CH:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[CH:6]1[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1NC(=O)C=C(c2cccc(C)c2)C1c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C2=CC(=O)NC(O)C2c2ccncc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 6-acetoxy-4-m-tolyl-5,6-dihydro-1H-[5,4′]bipyridinyl-2-one (200 mg, 0.6 mmole) in THF (2 mL) and water (2 mL) at r.t. was added LiOH (51 mg, 1.2 mmole) in one portion. The reaction mixture was stirred at that temperature for 10 min before quenching the mixture with aqueous NH4Cl. The reaction was quenched with 1.45 mL of 1N HCl the resulting white precipitate was filtered, rinsed with water and dried to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][C:23](=[O:26])[CH2:24][NH2:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CC[O:36][CH2:35]C1)C.C(Cl)(Cl)=O>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]1[C:23](=[O:26])[CH2:24][NH:25][C:35]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CCOCC1
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.83 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide in 50 ml of dichloromethane was cooled to 0° C. under nitrogen and treated with 0.76 ml of N-ethylmorpholine and 1.34 ml of a 1.93M solution of phosgene in toluene. The mixture was left to warm to room temperature and was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with 2M aqueous hydrogen chloride and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulphate and evaporated. Trituration of the residue with diethyl ether gave 0.783 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo 1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 92.4 %

Procedure:
To a 100 mL 2-necked round bottom flask equipped with a septurn and nitrogen inlet was added 3.0 g (9.5 mmol) of the (R)-(-)-methyl acetate prepared in Example D dissolved in 55 mL of dry toluene. The solution was cooled to -78° C. (CO2 /acetone) and 12 mL (12 mmol) of a 1.0M solution of DIBAL-H in toluene was added slowly (5 minutes) with stirring. The reaction mixture was stirred for 1 hour at -78° C. and poured into 100 g of ice and 100 mL of CHCl3. The reaction flask was rinsed with 100 mL of CHCl3 and the mixture was stirred vigorously for 30 minutes. After separation of the CHCl3 layer, the aqueous phase was washed with 100 mL of CHCl3 and the combined CHCl3 extracts were washed once with brine 80 mL, dried (Na2SO4) and concentrated leaving 2.5 g (93%) of the title aldehyde as a clear colorless oil of better than 95% purity (1H-NMR). The aldehyde was not further purified owing to its instability to temperatures above 60° C. and to silica gel: αD22 -33.71° (c=0.330, EtOH); 1H-NMR (CDCl3)δ9.47 (d, J=2.0 Hz, 1H), 7.33-7.32 (m, 4H), 4.95 (d, J=2.0 Hz, 1H), 0.92 (s, 9H), 0.10 (s, 3H), 0.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)nc(OCc2ccccc2)n1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
4-Chloro-6-methoxy-2-(methylsulfonyl)pyrimidine (Compound III-29) (0.80 g, 0. 0036 mol) and benzyl alcohol (Compound II-64) (0.39 g, 0.0036 mol) were dissolved in toluene (10 ml), and then 60% sodium hydride (0.16 g, 0.0036×1.1 mol) was added while cooling with ice. After stirred for one night at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off to afford a crude product (0.92 g), which was then purified on silica gel column chromatography to obtain the compound (I-346) as an oily product.