Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:39]([CH3:41])[CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:24]2)[O:12]1>CCO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:39]([CH3:41])[CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24]2)[O:12]1
Reactant: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10% Pd—C (70 mg) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}(propan-2-yl)amino)cyclobutyl]propanoate (790 mg, 1.40 mmol) in EtOH (20 ml) and stirred under an atmosphere of hydrogen for 18 hours at RT. A further aliquot of 10% Pd—C (70 mg) was added and the reaction was continued stirring under hydrogen for 4 hours. This was filtered and evaporated in vacuo, and then evaporated from DCM (2×20 ml) to give 680 mg (quant.) of a white foamy solid; MS (ESI+) for C23H34N6O5 m/z 475.20 [M+H]+; HPLC purity 100% (ret. time, 1.11 min); 1N NMR (500 MHz, CHLOROFORM-d) δH ppm 8.29 (d, J=16.3 Hz, 1H), 7.97 (d, J=16.2 Hz, 1H), 6.86 (s, 2H), 6.05 (dd, J=4.3, 1.7 Hz, 1H), 5.66-5.43 (m, 1H), 5.00 (ddd, J=19.3, 6.3, 3.2 Hz, 1H), 4.30 (s, 1H), 3.47-2.85 (m, 2H), 2.60 (ddd, J=38.8, 24.1, 13.5 Hz, 2H), 2.19 (ddd, J=14.7, 11.9, 7.1 Hz, 2H), 2.07-1.94 (m, 2H), 1.81 (dd, J=65.1, 6.9 Hz, 3H), 1.66-1.46 (m, 5H), 1.45-1.22 (m, 4H), 1.00 (d, J=6.4 Hz, 3H), 0.89 (dd, J=12.2, 6.6 Hz, 3H).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([NH:10][NH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pent-4-enoic acid 0.1 M in DCM, tert-butyl carbazate (2 eq) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 eq) and the mixture was allowed to stir at RT overnight. DCM was added and the organic solution was washed sequentially with saturated aq. NaHCO3 followed by saturated aq. NaCl and then dried over Na2SO4. Removal of the solvent in vacuo yielded the title compound as colorless oil. This material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ: 7.33 (bs, 1H), 6.51 (bs, 1H), 5.88-5.75 (m, 1H), 5.10-4.99 (m, 2H), 2.43-2.38 (m, 2H), 2.32 (t, J 6.8, 2H), 2.03 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2[nH]ncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cn[nH]c1N1CCC[C@H](N)C1
Yield: 23 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 103 as a white solid (27 mg, 23%) over two steps. 1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.48 (s, 1H), 7.86 (s, 1H), 7.54-7.49 (m, 2H), 7.28 (t, J=12 Hz, 2H), 3.19 (d, J=8 Hz, 1H), 3.09 (d, J=8 Hz, 1H), 2.82-2.77 (m, 1H), 2.67-2.60 (m, 1H), 2.43 (t, J=12 Hz, 1H), 1.84-1.81 (m, 1H), 1.75-1.55 (m, 2H), 1.15-1.08 (m, 1H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[CH:4]=[CH:3]1>N.CO.[Ni]>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(C#N)cnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1ccc2cc(CN)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (210 mg, 1.3 mmol) in 10% NH3-MeOH (10 mL) was added Raney Nickel (0.5 mL, Raney (registered trademark) 2800 slurry in water), and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hrs. The mixture was filtered through a pad of Celite (registered trademark), washed with MeOH, the filtrate was concentrated to give 200 mg (93% yield) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](I)[CH:27]=1>CO>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:31]=1
Reactant: OB(O)c1c(O)cccc1Cl
Reactant: Cc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)cc1-c1c(O)cccc1Cl
Temperature: 105 °C
Yield: 80 %

Procedure:
(2-Chloro-6-hydroxyphenyl)boronic acid (250 mg, 1.450 mmol, 1 equiv), Pd(PPPh3)4 (168 mg, 0.145 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 1.8 ml, 3.63 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-2-iodo-1-methylbenzene (431 mg, 1.450 mmol, 1.0 equiv) in MeOH (1.00 mL) was to the above mixture. The mixture was heated at 105° C. overnight. Then, the crude reaction mixture was loaded on 12 g column and purified at 30% EtOAc/hexane to afford 5′-bromo-6-chloro-2′-methyl-[1,1′-biphenyl]-2-ol (345 mg, 80%). LCMS (M+1)=299.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:16]C)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].I[Si](C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCCc1cc(C(=O)OC)cc(Br)c1C
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)c(CCCO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chloroform (0.1 M) solution of methyl 3-bromo-5-(3-methoxypropyl)-4-methylbenzoate (1 eq., Amine 88, Step 2) was added iodotrimethylsilane (3 eq.). The resulting red solution was stirred at RT in darkness for 18 h. The reaction was quenched with methanol before the volatiles were removed in vacuo. The resulting residue was then taken up in ether, washed sequentially with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C:6](=O)[CH2:7][O:8]2.Cl.NCCCCN1C(=[O:30])CC2(CCCC2)CC1=O>C(O)C>[CH:12]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH2:6][C:5](=[O:30])[C:4]=2[CH:3]=1
Reactant: COc1cccc2c1CC(=O)CO2
Reactant: NCCCCN1C(=O)CC2(CCCC2)CC1=O
Agent: Cl
Solvent: CCO
Product: O=C1CCOc2ccccc21

Procedure:
0.04 mole of 5-methoxychroman-3-one is dissolved in 10 ml of ethanol. At the same time, 1 g of N-(4-aminobutyl)-8-azaspiro[4.5]decane 7,9-dione hydrochloride is dissolved in 10 ml of ethanol, and the solution of chromanone obtained above is added to this solution. 0.16 g of sodium hydroxide in solution in 10 ml of ethanol is then added thereto. The mixture is stirred for one hour at ambient temperature, filtered and placed in a hydrogenating apparatus. 0.5 g of palladized carbon is added, the apparatus is purged with nitrogen and then with hydrogen, and the mixture is hydrogenated at ambient temperature and pressure. The mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up in ethyl acetate and gaseous hydrochloric acid is added thereto. The mixture is allowed to precipitate and is drained.
Reaction SMILES: C([O:5]O)(C)(C)C.[CH2:7]([OH:17])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:10]([C@@H:9]1[O:5][C@H:8]1[CH2:7][OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(C)OO
Reactant: CCCCCCC/C=C/CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CCCCCCC[C@@H]1O[C@H]1CO
Reaction time: 0.5 h

Procedure:
A flame-dried 100 mL round bottom 3-necked (RB3N) flask (note 1) filled with thermometer, stopcock, septum, and stirbar was purged with argon, charged with 4 A molecular sieves (300 mg; note 2) and 30 mL of dichloromethane (note 3), and cooled to -22° (30% ethylene glycol/water/dry ice). R,R-(+)-diethyl tartrate (97 mg; 47 mmol; note 4) and titanium(IV)isopropoxide (91 mg; 0.32 mmol; note 5) were added, and the mixture was stirred at -22±2° for 10 min. t-Butyl hydroperoxide (2.2 mL of a 5.8M dichloromethane solution; note 6) was added, and the mixture was stirred at -22±2° for 30 min. A solution of trans-2-decen-1-ol (1.00 g; 6.4 mmol; note 7) in dichloromethane, was then added. The mixture was stirred under argon at -22±2° until analysis (note 8) indicated >95% reaction (2.5 hr).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: N#CCCC=C1CCCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: NCCCCC1CCCN(Cc2ccccc2)C1

Procedure:
8.0 g (33.3 mmol) 4-(1-benzylpiperidin-3-yliden)-butyronitrile are dissolved in 80 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred at ca. 50° C. under hydrogen atmosphere until consumption of the theoretischen amount of hydrogen to be taken up (ca. 5 days). The mixture is filtrated from the catalyst and the solvent is removed under vacuum. The residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/10/1). After drawing off the solvent, a colorless oil remains which is further processed without additional purification. Yield: 3.9 g (47%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:11][C:12]=2[C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH3:19])[C:14]=2[CH:20]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:18][C:16]1[N:15]([CH3:19])[C:14]2[CH:20]=[C:6]([CH2:4][OH:3])[C:7]3[CH2:8][CH2:9][CH:10]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:11][C:12]=3[C:13]=2[N:17]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3c(c(CO)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of 250 mg (0.7 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid ethyl ester in 10 ml tetrahydrofuran was cooled to 0° C. and 927 μl (0.93 mmol) lithium aluminium hydride solution (1 M in THF) were added dropwise. The temperature was raised to room temperature and the reaction stirred for 1 h. To the reaction were cautiously added 1.5 ml water and 1.5 ml 6 M sodium hydroxide solution and the mixture was extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=1:1) and crystallized with diisopropyl ether to afford 101 mg (45%) of the title compound as a beige solid. m.p. 279°-281° C.
Reaction SMILES: [CH:1]([C@H:5]1[C@@H:14]([NH:15]C(=O)[O-])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1)=[CH:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([C@H:5]1[C@@H:14]([NH2:15])[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=C[C@@H]1CC2(CC[C@@H]1NC(=O)[O-])OCCO2
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H]1CC2(CC[C@@H]1N)OCCO2
Yield: 91.2 %

Procedure:
A solution of ((7S,8S)-7-(but-1-enyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate (7.7 g, 0.0221 mol) in 80 mL of MeOH was treated with 1.5 g of 10% Pd/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give 4.3 g of (7R,8S)-7-(butyl)-8-(amino)-1,4-dioxa-spiro[4.5]decane. This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-benzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CO>O1CCCC1.O.ClCCl>[C:1]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:44]2[CH2:45][CH2:46][CH:41]([C:39]([C:31]3[S:30][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=3)=[O:40])[CH2:42][CH2:43]2)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3ccccc3)C2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5s4)CC3)CCN(C(=O)c3ccccc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Combine 1-benzoyl-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.20 g, 0.46 mmol) and 4-(benzothiazole-2-carbonyl)-piperidine (0.11 g, 0.46 mmol), and sodium carbonate (0.098 g, 0.92 mmol) in tetrahydrofuran/water (15/4) (30 mL). Heat to reflux. After 4 days, cool to ambient temperature and evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10/1 ethyl acetate/methanol to give a residue. Combine the solid with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Dry the residue in vacuo at 82° C. to give the title compound: Rf=0.21 (silica gel, 10/1 ethyl acetate/methanol); mp; 74-76° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 176 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 486 [M+H]; Rt=1.06 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:4]=[CH:3][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-bromo-2-chloropyrimidine (500 mg) in DMF (5 mL) was added ethyl acrylate (1.41 mL), palladium(II) acetate (29 mg), tris(2-methylphenyl)phosphine (118 mg), and N,N-diisopropylethylamine (1.35 mL). The mixture was stirred at 100° C. for 4 hours. The resulting mixture was allowed to cool to ambient temperature, poured into brine, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (90:10 v/v) to give ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (494 mg) as a yellow powder.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN>CN1CCOCC1.CN(C=O)C.CN1CCOCC1.CN(C=O)C>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71e) i)) and 34 mg (0.196 mmol) of N-methoxycarbonyl-(L)-valine (Example 73b) are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) of HBTU are added and the mixture is stirred at RT. Since, after 3 days, there is still unreacted hydrazine present, a further 0.3 equivalents in each case of N-methoxycarbonyl-(L)-valine and HBTU in 0.48 ml of 0.3M NMM/DMF is added. After 18 h the reaction mixture is concentrated by evaporation under HV, the residue is dissolved in methylene chloride and washed with saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with methylene chloride, and the organic phases are dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.17; tRet (V)=14.6 min; FAB-MS (M+H)+ =718.
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][C:11](O)=[O:12])[O:6][N:5]=1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41]>O1CCCC1.CO>[CH:17]1([CH2:16][CH2:15][CH2:14][C@@H:9]([C:7]2[O:6][N:5]=[C:4]([C:2]([NH2:1])=[O:3])[N:8]=2)[CH2:10][C:11]([NH:41][OH:40])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[Si](C)(C)ON
Reactant: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of (3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (Preparation 6) (6.00 g, 19.42 mmol) in anhydrous tetrahydrofuran (200 ml) was cooled to 0° C. then treated with N-methylmorpholine (2.40 ml, 22.0 mmol) and isobutyl chloroformate (2.8 ml, 22.0 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (7.0 ml, 60.0 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (50 ml) and stirred for a further 30 minutes. This mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was recrystallised from isopropyl acetate (500 ml) to afford the title compound as a white solid (4.46 g). Chiral HPLC analysis indicated this material to be 87.6% ee. A sample of this material (2.9 g) was dissolved in ethyl acetate (450 ml) at reflux then allowed to cool. The precipitate was filtered off and the solvent was removed from the filtrate under reduced pressure to afford a white solid, which was then recrystallised from isopropyl acetate (120 ml) to afford the title compound (1.42 g). Chiral HPLC analysis showed this material to be 98.3% ee.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH2:8][NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:7]=1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3[CH:29]=[CH:28][NH:27][N:26]=3)=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16]1>>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([N:27]2[CH:28]=[CH:29][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:24]=3)=[N:26]2)=[CH:7][C:6]=1[CH2:8][NH:9][C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)NCc1cc(Br)ccc1Cl
Reactant: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Product: CNC(=O)NCc1cc(-n2ccc(-c3ccc4c(c3)CCCO4)n2)ccc1Cl

Procedure:
N-[(5-bromo-2-chlorophenyl)methyl]-N′-methylurea (i.e. the product of Step A) (0.61 g, 2.2 mmol) was reacted with 3-(3,4-dihydro-2H-1-benzopyran-6-yl)-1H-pyrazole (i.e. the product of Step A of Synthesis Example 1) (0.40 g, 2.0 mmol) using a procedure analogous to Step B of Synthesis Example 1 to provide the title product, a compound of the present invention, as a solid (0.03 g).