Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](#[N:21])[CH3:20]>>[CH:1]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]([OH:15])[CH2:20][C:19]#[N:21])[CH:16]=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CCCCCCC2)c1
Product: N#CCC(O)c1cccc(OCC2CCCCCCC2)c1

Procedure:
Addition of acetonitrile to 3-(cyclooctylmethoxy)benzaldehyde gave 3-(3-(cyclooctylmethoxy)phenyl)-3-hydroxypropanenitrile as a yellow oil. Yield (0.90 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.25-7.31 (m, 1H), 6.91-6.95 (m, 2H), 6.84-6.89 (m, 1H), 5.01 (t, J=6.2 Hz, 1H), 3.72 (d, J=6.8 Hz, 2H), 2.74 (d, J=2.0 Hz, 2H), 1.97-2.04 (m, 1H), 1.33-1.79 (m, 14H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][NH:23][CH2:22][CH2:21]2>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][N:23]([C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14])[CH2:22][CH2:21]2
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)c1cnoc1-c1ccc(C)cc1)CC2
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (11 mg, 0.052 mmol, 1.2 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O4: 378.1580, found 378.1585.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]5)[CH2:29][CH2:28]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>C(Cl)Cl>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][N:35]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:34]5)[CH2:31][CH2:32]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)N=C=O
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCNC3)CC2)n1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCN(C(=O)NC(C)C)C3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.06 ml of isopropyl isocyanate was added to a solution of 0.2 g of the compound obtained in step 2.4 in 1.2 ml of DCM, at 0° C. The medium was stirred for 2 h at 0° C. then hydrolysed with 5 ml of water and diluted with 10 ml of DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.16 g of the expected product.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:8][CH3:9])[C:3](OCC)=[O:4].[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:8][CH3:9])[CH2:3][OH:4]
Reactant: CCOC(=O)C(N)(CC)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(N)(CO)c1ccccc1
Yield: 89.8 %

Procedure:
A solution of ethyl 2-amino-2-phenylbutanoate (0.162 g, 0.782 mmol) in 1:3 v/v water/ethanol (4 mL) was reacted with sodium borohydride (0.151 g, 3.908 mmol) at reflux for four hours. The reaction was concentrated and partition between water (5 mL), ethyl ether (10 mL) and 1N aqueous sodium hydroxide (0.39 mL). Solid sodium chloride was added to saturate the aqueous and separate the phases. The aqueous phase was separated and re-extracted with ethyl ether (2×20 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.116 g, 0.702 mmol, 90%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.59 (t, J=7.54 Hz, 3 H) 1.49-1.80 (m, 4 H) 3.44 (d, J=5.15 Hz, 2 H) 4.63 (t, J=5.52 Hz, 1 H) 6.89-7.76 (m, 5 H). MS (DCI) m/z 166 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([NH:31][C:32]([C@@H:34]([NH2:45])[CH2:35][C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][CH:37]=3)=[O:33])[CH:27]=[CH:28]2)=[CH:23][CH:22]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([CH2:35][C@H:34]([NH:45][C:18]([C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:10])=[O:11])=[O:20])[C:32](=[O:33])[NH:31][C:26]2[CH:27]=[CH:28][C:29]3[C:24](=[CH:23][CH:22]=[CH:21][CH:30]=3)[CH:25]=2)=[CH:37]1
Reactant: COc1cccc(S(=O)(=O)N2CCCC[C@H]2C(=O)O)c1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cccc(S(=O)(=O)N2CCCC[C@H]2C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)Nc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 0.78 g (2.60 mmol) of (S)-1-(3-methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid and 1.03 g (3.12 mmol) of (S)-2-amino-3-(1-indol-3-yl)-naphthalen-2-yl-propionamide in dichloromethane (100 ml) was added 0.16 g (1.30 mmol) DMAP followed by addition of 4-methylmorpholine 1.37 g (13.54 mmol), HOBT 0.84 g (6.25 mmol) and EDCI 1.39 g (7.29 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was then washed with water, dried (sodium sulfate). Chromatography on silica gel eluting with 50% ethyl acetate/heptane proved 1.2 g (1.96 mmol) of the title compound. 1H NMR (300 MHz, CDCl3): 1.34-1.01 (m, 5H); 2.07 (bd, 1H); 2.21 (dd, 1H); 3.43-3.48 (m, 3H); 3.83 (s, 3H); 4.34 (b, 1H); 4.98 (q, 1H); 6.98 (d, 1H); 7.09-7.47 (m, 11H); 7.68-7.80 (m, 4H); 8.15 (s, 1H); 8.21 (s, 1H); 8.40 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([F:30])[CH:29]=1)[NH2:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Reaction time: 72 h
Yield: 69.1 %

Procedure:
Picolinic acid (13.0 g, 106 mmol) was added to a solution of 1,1'-carbonyldiimidazole (17.11 g, 106 mmol) in dry dimethylformamide (100 mL) and the reaction stirred for 1 hour, before introduction of 3,5-difluoroaniline (15.0 g, 116 mmol). After 3 days, the reaction mixture was poured into saturated sodium bicarbonate solution (1 L) and extracted with ether (2×500 mL). The organic layers were dried and concentrated to give a solid, which was recrystallized from a mixture of ether and petroleum ether to give N-(3,5-difluorophenyl)-2-pyridinecarboxamide (17.15 g, 69%) m.p. 111°-113° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]#[N:23])[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[O:12])=[C:9]([CH:24]([CH3:26])[CH3:25])[C:8](=[O:27])[NH:7][C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([N:5]1[C:10]([C:11]([C:13]2[CH:14]=[C:15]([CH2:20][CH2:21][C:22]#[N:23])[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[O:12])=[C:9]([CH:24]([CH3:25])[CH3:26])[C:8](=[O:27])[NH:7][C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C(=O)c2cc(C)cc(C=CC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCn1c(C(=O)c2cc(C)cc(CCC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 17 h
Yield: 66.4 %

Procedure:
3-[3-(3-Butyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (Compound 74) (180 mg, 0.474 mmol) was stirred with 10% palladium on carbon (20 mg) in anhydrous ethanol (10 mL) at room temperature under an atmosphere of hydrogen. After 17 hr., the reaction mixture was filtered through a celite pad and the pad was washed with ethanol and chloroform. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 120 mg (66%) of 3-[3-(3-butyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-propionitrile (76) as a white foam. Recrystallization from ether-hexane resulted in a white solid. m.p. 172-173° C.; 1H-NMR (300 MHz, CDCl3) δ 0.79 (3H, t, J=7.5 Hz), 1.12-1.24 (8H, m), 1.45-1.59 (2H, m), 2.30 (1H, m), 2.46 (3H, s), 2.68 (2H, t, J=7.2 Hz), 3.00-3.15 (3H, m), 3.79 (1H, m), 7.44 (1H, s), 7.63 (2H, s), 8.89 (1H, s); m/z (EI) 381 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc(F)c1Cl
Reaction time: 3 h

Procedure:
3-chloro-4-fluoro-2-methylbenzoic acid (I57)(0.754 g, 4 mmol) in dichloromethane (DCM) (30 mL) was cooled to 0° C., before oxalyl chloride (0.385 mL, 4.40 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours, before the solvent was evaporated in vacuo. The remaining residue was then azeotroped with toluene to yield the product in 0.819 g.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([C:15]#[N:16])=O>S(=O)(=O)(O)O.C(#N)C>[Cl:10][C:11]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:12]=1/[C:13](=[N:5]/[NH:6][C:7]([NH2:9])=[NH:8])/[C:15]#[N:16]
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: N#C/C(=N\NC(=N)N)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 45 h
Yield: 66 %

Procedure:
Aminoguanidine bicarbonate (1.75 moles) was dissolved in 9.3-10.0 M sulphuric acid solution. A solution of 2,3-dichlorobenzoyl cyanide (1 mole) in acetonitrile was added and the suspension stirred at 20-30° C. for 42-48 hours. The crude product was filtered and washed with water. The solid was added to sodium hydroxide solution below 35° C., then the product was filtered, washed with water and dried at 80-90° C. to obtain 1.5 as a yellow solid in 66% yield.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:10]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:9][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: CCOC(=O)CCC(N)=O
Product: CCOC(=O)CCc1nc(CCl)co1
Yield: 7.2 %

Procedure:
In substantially the same manner as in Reference Example 31, ethyl succinamidate was allowed to react with 1,3-dichloroacetone to give ethyl 4-chloromethyl-2-oxazolepropionate as an oily product. The yield was 7.2%.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:21][CH:22]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)OC)cc3)n2n1
Temperature: 145 °C
Yield: 67.3 %

Procedure:
To a mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (386 mg, 1.43 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (310 mg, 1.72 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.07 mmol) and potassium carbonate (296 mg, 2.15 mmol) was added 3:1 acetonitrile/water (5 mL). The resulting mixture was heated at 145° C. (microwave) for 800 s. The reaction was then filtered and concentrated. The residue was dissolved in methanol, and then filtered again. The filtration was finally purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford methyl 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoate (312 mg, 67% yield) as a yellow solid: 1H NMR (CHLOROFORM-d) δ: 8.22-8.34 (m, 2H), 8.09-8.20 (m, 2H), 7.93 (s, 1H), 7.71 (d, J=9.6 Hz, 1H), 6.51 (d, J=9.6 Hz, 1H), 3.97 (s, 3H), 3.41-3.53 (m, 2H), 1.72 (t, J=7.2 Hz, 2H), 1.50 (dd, J=15.0, 7.5 Hz, 2H), 1.02 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 325.2 [(M+H)+, calcd for C18H21N4O2 325.2].
Reaction SMILES: [C:1]([O:8][NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:69]([N:71]1[CH2:86][CH2:85][CH2:84][C@H:72]1[C:73]([NH:75][C@H:76]([C:81]([OH:83])=[O:82])[C@H:77]([CH2:79][CH3:80])[CH3:78])=[O:74])=[O:70])[CH2:63][C:64]1[N:68]=[CH:67][NH:66][CH:65]=1)=[O:60])[C@H:55]([CH2:57][CH3:58])[CH3:56])=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:31])[NH:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.O1CCOC[CH2:89]1>>[C:1]([O:8][NH:9][C@H:10]([C:11]([NH:13][C@H:14]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:69]([N:71]1[CH2:86][CH2:85][CH2:84][C@H:72]1[C:73]([NH:75][C@H:76]([C:81]([OH:83])=[O:82])[C@H:77]([CH2:79][CH3:80])[CH3:78])=[O:74])=[O:70])[CH2:63][C:64]1[N:68]=[CH:67][NH:66][CH:65]=1)=[O:60])[C@H:55]([CH2:57][CH3:58])[CH3:56])=[O:52])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=1)=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:31])[NH:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:12])[CH3:89])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1COCCO1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)CNOC(=O)OC(C)(C)C)C(C)C)[C@@H](C)CC)C(=O)O
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](C)NOC(=O)OC(C)(C)C)C(C)C)[C@@H](C)CC)C(=O)O
Yield: 84 %

Procedure:
0.6 g. (0.5 mmoles) of Boc-Arg(Tos)-Val-Tyr-Ile-His-Pro-Ile-OH (prepared in Step 2 of Example 1) are dissolved in 5 ml. of a 8 M solution of hydrochloric acid in dioxane. The solution is allowed to stand for 20 minutes whereupon the free heptapeptide (Rf4 = 0.1) is precipitated with dry ether, filtered and washed with ether. It is immediately dissolved in 20 ml. of dimethyl formamide, the pH-value is adjusted to 8 with triethyl amine and 0.7 g. (1.9 mmoles) of Boc-OAla-OPFP are added. After 30 minutes the solution is evaporated and the residue is dissolved in 30 ml. of a 3:1 mixture of chloroform and dimethyl formamide. The solution is shaken with a 10% aqueous citric acid solution and subsequently with water. After drying and evaporation the residue is triturated with ethyl acetate, filtered and washed to give 0.55 g. (84%) of the title compound. Rf4 = 0.43; Rf5 = 0.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:34])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc([N+](=O)[O-])c4)cc3)c2cc1OC
Yield: 34.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (83 mg) was dissolved in toluene (6 ml) with heat, 3-nitrophenyl isocyanate (384 mg) was added, and the admixture was refluxed with heat for 40 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 44 mg of the title compound (yield: 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:10][N:11]([CH2:17][C:18]([O:20]CC)=[O:19])[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)=[N:10][N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:12]=2[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (Example 8) (0.48 g, 1.0 mmol) in tetrahydrofuran (THF) (10 mL) was added 1.5 mL of 1N aqueous lithium hydroxide at 25° C. under nitrogen and the mixture stirred for 24 hours at 25° C. The reaction mixture was extracted with two portions diethyl ether and the aqueous layer was acidified with dilute aqueous HCl. This was extracted with two portions ethyl acetate which was washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid as a white crystalline solid (0.41 g, 93%). Elemental analysis for C19H14N2F4SO4Calc'd: C, 51.58, H, 3.19, N, 6.33. Found: C, 51.18, H. 3.23, N, 6.19;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1ccc(COc2cc(C)n(-c3cc(Cl)ncc3C)c(=O)c2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-4-hydroxy-6,5′-dimethyl-[1,4′]bipyridinyl-2-one of part A (6.0 g, 20.1 mmol) in N,N-dimethylformamide (20 mL) was added 4-methoxybenzylchloride (2.73 mL, 20.1 mmol), potassium carbonate (6.93 g, 50.2 mmol) and 18-crown-6 (100 mg). The slurry was heated at 60° C. for 3 h and was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product as a light yellow solid (4.6 g): MS (ES) m/e 371 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:22])[C:3]([NH:5][C@@H:6]([CH3:21])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25](O)=[O:26].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:19]([C:16]1[S:15][C:14]([NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:25](=[O:26])[C@@H:24]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH3:23])[CH3:22])[CH3:21])=[N:18][CH:17]=1)=[O:20]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 72 (255 mg, 0.539 mmol), N-alpha-t-BOC-L-Alanine (117 mg, 0.620 mmol), 1-hydroxy-7-azabenzotriazole (36.7 mg, 0.269 mmol), CH2Cl2 (10 mL), N-methylmorpholine (250 μlit, 2.27 mmol), EDC (124 mg, 0.647 mmol), and stirring at room temp for 18 h, 215.3 mg (80%) of the title compound is obtained as a white solid. The desired product crystallized out of the reaction, is collected by vacuum filtration and dried under high vacuum for several hours. LC/MS (Condition A): ret. T=2.70 min, (M+H)+ 499.26. 1H NMR (500 MHz, methanol-d4) δ ppm 9.61 (1 H, d, J=2.14 Hz), 7.96 (1 H, d, J=2.14 Hz), 4.16-4.38 (2 H, m), 3.92-4.07 (1 H, m), 3.43 (2 H, t, J=6.26 Hz), 1.88 (2 H, t, J=5.95 Hz), 1.26-1.51 (18 H, m).
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][NH:7][CH3:8].[Mg](N(C)C)Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([OH:35])[C:23](=[O:34])[N:24]([CH3:33])[C:25]=2[C:29]([O:31]C)=O)[C:20]1=[O:36]>ClCCl.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([OH:35])[C:23](=[O:34])[N:24]([CH3:33])[C:25]=2[C:29]([N:7]([CH3:8])[CH3:6])=[O:31])[C:20]1=[O:36]
Reactant: CNC
Reactant: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: CC(C)[Mg]Cl
Agent: CN(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
To THF (80 mL) cooled to −10° C. was added iPrMgCl (2M in THF, 60 mL). Dimethylamine (2M in THF) was then added at −10 to 0° C., the mixture then stirred for 1 hour at −5 to −10° C. The resulting suspension of ClMgNMe2 at −10° C. was allowed to warm to 0° C., and a solution of methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (10.0 g) in dichloromethane (100 mL) was added over 20 minutes at 0° C. The mixture was then stirred until reaction was complete by HPLC. The reaction mixture was quenched with 1N HCl (335 mL). The organic layer was collected and the aqueous layer extracted with CH2Cl2 (35 mL). The organic phases were then combined and washed with brine (35 mL). Volatiles were evaporated to give the title product as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:3]=1.[Br-].[Al+3].[Br-].[Br-]>ClC1C=CC=CC=1>[OH:1][C:2]1[C:11]2[C@@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:3]=1
Reactant: CC1(C)Oc2cc(C3CCCCC3)cc(O)c2[C@H]2CC(=O)CC[C@H]21
Agent: [Al+3]
Agent: [Br-]
Solvent: Clc1ccccc1
Product: CC1(C)Oc2cc(C3CCCCC3)cc(O)c2[C@@H]2CC(=O)CC[C@H]21

Procedure:
dl-cis-1-hydroxy-3-cyclohexyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one was treated with aluminum bromide in chlorobenzene according to the process of Example 5 to provide dl-trans-1-hydroxy-3-cyclohexyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.