Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[S:14])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:13](=[S:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/Cc1ccccc1C(O)=S
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=S)c1ccccc1C/C=C(\C)CCC=C(C)C
Yield: 54 %

Procedure:
In a manner identical to Example 15, 2-geranylthiobenzoic acid (2.03 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (1.0 ml), thereby yielding 1.52 g (54%) of the aimed compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:18][OH:19])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5].CN1CCOCC1.[CH3:27][C:28]1[N:32]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[O:35])[N:31]=[C:30]([C:45]([F:48])([F:47])[F:46])[CH:29]=1.ON1C2C=CC=CC=2N=N1.CC(N=C=NC(C)C)C>O1CCCC1>[OH:19][CH2:18][C@H:3]([NH:2][C:42]([CH:39]1[CH2:40][CH2:41][N:36]([C:34](=[O:35])[CH2:33][N:32]2[C:28]([CH3:27])=[CH:29][C:30]([C:45]([F:46])([F:48])[F:47])=[N:31]2)[CH2:37][CH2:38]1)=[O:43])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)[C@@H](N)CO)[C@@H]1CCCc2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N[C@@H](CO)C(=O)N(C)[C@@H]2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
A solution of (2S)-2-amino-3-hydroxy-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]propanamide monohydrochloride (546.33 mg, 2.2 mmol) (i.e. the product of Example 17, Step B) and N-methylmorpholine (222.53 mg, 2.2 mmol) in 8 mL of tetrahydrofuran was cooled to 0° C. and 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinylcarboxylic acid (638.56 mg, 2 mmol) (i.e. the product of Example 17, Step D) was added followed by N-hydroxybenzotriazole (27 mg, 0.2 mmol) and N,N-diisopropylcarbodiimide (265 mg, 2.1 mmol). The reaction mixture was stirred for 16 h at room temperature and filtered. The precipitate was washed with tetrahydrofuran and the resulting filtrate and washings were concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was washed with water, 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated in vacuo. The resulting product was purified by medium-pressure liquid chromatography on silica gel using 0-20% methanol in ethyl acetate as eluant to give 600 mg of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.Cl>CS(C)=O.O>[N:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1-napthoic acid (2 g, 10.6 mmol) in DMSO (5 mL), Cs2CO3 (14 g, 42.4 mmol) was added and stirred at RT 10 min. 4-Chloropyridine hydrochloride (1.9 g, 12.7 mmol) was added in one portion and the reaction mixture heated to 140° C. for 12 h. The reaction mixture was cooled to RT, diluted with water and made pH 5 using 6 N HCl, at which point a brown precipitate crashed out. The solid was filtered and rinsed with water and hexanes to yield the title compound.
Reaction SMILES: [CH2:1]([C:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][NH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:16]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:27](O)=[O:28])=[O:24])[N:18]=[CH:17]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C@@H:26]([NH:25][C:23](=[O:24])[CH2:22][CH2:21][C:19]2[N:18]=[CH:17][NH:16][CH:20]=2)[C:27](=[O:28])[N:8]2[CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: CCCCCC1(c2ccccc2)CNC1
Reactant: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)O)cc1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCC1(c2ccccc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 4 h
Yield: 53.7 %

Procedure:
70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and 100 mg (0.315 mmol) of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid are solubilized in 1 ml of DMF. 67 mg (0.345 mmol) of EDC and 47 mg (0.345 mmol) of HOBT are added to this solution. The whole is left to stir for 4 hours and is then treated with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 85 mg of N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 49%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[S:5].[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[S:5]
Reactant: Cc1ccccc1C(=S)Cl
Reactant: N#CC1CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccccc1C(=S)N1CC1C#N

Procedure:
1.86 g. 2-Methylthiobenzoyl chloride is dissolved in 14 ml. anhydrous diethyl ether and this solution is added dropwise at ambient temperature to a solution of 0.68 g. 2-cyanoaziridine in 8.6 ml. aqueous 2 N sodium carbonate solution and then stirred for 2 hours, whereafter the ethereal phase is separated off and evaporated to give 1.72 g. of residue which is triturated with 4 ml. isopropanol. There is thus obtained 1.35 g. 1-(2-methylthiobenzoyl)-2-cyanoaziridine; m.p. 67°-69° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([Cl:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:17])[CH:11]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield).
Reaction SMILES: [S:1]([O-:11])([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])=[O:2].[C:12](I)([C:15]([C:18]([C:21]([C:24]([C:27]([C:30]([C:33]([F:36])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13]>>[S:1]([OH:11])([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]=[CH:10][C:12]([F:14])([F:13])[C:15]([F:16])([F:17])[C:18]([F:19])([F:20])[C:21]([F:22])([F:23])[C:24]([F:25])([F:26])[C:27]([F:29])([F:28])[C:30]([F:32])([F:31])[C:33]([F:36])([F:35])[F:34])(=[O:2])=[O:3]
Reactant: C=CCOCCOS(=O)(=O)[O-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Product: O=S(=O)(O)OCCOCC=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Crystalline allyloxyethyl sulfate (Na salt) from the preparation shown in example 2 was perfluoroalkylated using the procedure of example 7 and C8F17I to produce 2-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundec-2-enyloxy)ethyl hydrogen sulfate.
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=O)[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].CN(C)C=O.C(Cl)(=O)C([Cl:32])=O>>[Cl:32][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CCC(C2)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
20.15 g (0.062 mo l) of 4-hydroxy-3-(2-methyl-6-trifluoromethyipyridine-3carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are suspended in 50 ml of oxalyl chloride, and 0.1 ml of dimethylformamide are added dropwise. After the intensive evolution of gas has ceased, the mixture is kept at a bath temperature of 45° C. for another 1.5 hours and then evaporated, and the residue is suspended in a little ethyl acetate and admixed with stirring at 0° C. with hexane. Filtration gives 19.19 g (90% of theory) of 4-chloro-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of m.p. 137-138° C.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.BrC1C=CC([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=C(C=1)C=O>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])=[CH:25][CH:26]=1
Reactant: Cc1ccc(Sc2ccc(Br)cc2C=O)cc1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: Cc1ccc(Sc2ccc(C=O)cc2C(F)(F)F)cc1
Yield: 100 %

Procedure:
Using 4-fluoro-5-(trifluoromethyl)benzaldehyde (0.20 g, 1.0 mmol), 4-[(4-methylphenyl)thio]-3-(trifluoromethyl)benzaldehyde (0.30 g, 100%) was obtained in a manner similar to the synthesis of 5-bromo-2-[(4-methylphenyl)thio]benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1Cl)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(C#N)cc1Cl
Temperature: 135 °C

Procedure:
A mixture of diethyl 2-(2-chloro-4-cyanobenzyl)malonate (9.0 g, 0.03 mol), sodium chloride (2.12 g, 0.04 mol), and water (0.86 g 0.05 mol) in 30 mL of DMSO was heated to 135° C. and then the temperature was gradually raised to 170° C. over a 3 h period. The mixture was diluted with water and extracted with ether. Evaporation and distillation gave ethyl 3-(2-chloro-4-cyanophenyl)propanoate as an oil: 5.8 g; bp 138°-140° C. (0.1 mm Hg) Anal. calcd for C12H12ClNO2 : C, 60.64; H, 5.09; N, 5.89. Found: C, 60.48; H, 5.08; N, 5.84. ##STR29##
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O>C1COCC1>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([N:8]1[CH2:7][CH2:6][S:5][C:4]1=[S:3])=[O:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: SC1=NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a suspension of NaH (60 percent, 1.06 g, 26.5 mmol) in dry THF (10 mL) cooled at zero degrees C was added a solution of 2-mercaptothiazoline (3.0 g, 25.17 mmol) in dry THF (20 mL) followed by stirring at zero degrees C for 10 minutes. To the mixture was added trimethylacetyl chloride (3.1 mL, 25.17 mmol), the resultant mixture was then stirred at 25° C. for two hours. Water was added to the reaction mixture followed by extraction with ethyl acetate (100 mL), dry over anhydrous Na2SO4, and removal of the solvent in vacuo to give a crude product. Flash column chromatography of the crude product (silica gel, 17 percent ethyl ether in petroleum ether) afforded Compound 226 (4.68 g, 91 percent): pale-yellow solid; mp 48°-50° C.; Rf =0.19 (silica, 17 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2980. 1808, 1738, 1480, 1463, 1396, 1388, 1286, 1251, 1139, 1044, 1003, 874 cm-1 ; 1H NMR (300 MHz, CDCl3) δ4.21 (t, J=7.3 Hz, 2 H, NCH2CH2S), 3.51 (t, J =7.3 Hz, 2 H, NCHH2CH2S), 1.41 (s, 9 H, C(CH3); MS (FAB+) m/e (rel intensity) 204 (M+H, 100), 120 (27); HRMS for C8H14NOS2 (M+H), calcd 204.0517, found 204.0500.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[C:40]([O:42][C:43]([F:46])([F:45])[F:44])[CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:31][CH3:32])[C:13]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28]CC)=[O:27])[CH2:22][CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:9]=1)=[O:7].[OH-].[Li+].Cl.CS(C)=O>O1CCOCC1>[Cl:1][C:2]1[CH:41]=[C:40]([O:42][C:43]([F:46])([F:44])[F:45])[CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:31][CH3:32])[C:13]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:9]=1)=[O:7]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3Cl)cn(CC(F)(F)F)c12
Temperature: 25 °C

Procedure:
40 mg (0.059 mmol) of the compound of Example 3 are dissolved in 2 ml of dioxane, and 293 μl (5 eq.) of a 1M solution of lithium hydroxide are added, and the mixture is stirred at RT until the reaction is complete (2 days). The reaction mixture is acidified with 1N hydrochloric acid, a little DMSO is added, and the entire crude solution is separated by preparative HPLC (method 5). 25 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccccn2)CCN(C)C1
Yield: 26.1 %

Procedure:
2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole (20 mg, 0.06 mmol) was hydrogenated in methanol (2 ml) with 10% Pd—C (10 mg) at 1 atm of hydrogen to obtain 5 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indole after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its HCl salt by treatment of ethanolic HCl.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28]([O:30]CC)=O.[CH3:33][CH:34]([CH3:39])[CH2:35][CH2:36][NH:37][NH2:38]>O1CCOCC1>[CH3:33][CH:34]([CH3:39])[CH2:35][CH2:36][N:37]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:4]=2[C:28](=[O:30])[NH:38]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: CC(C)CCNN
Solvent: C1COCCO1
Product: CC(C)CCN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
150 mg (0.295 mmol) of the compound from Example 6A were dissolved in 3 ml of dioxane, and 91 mg (0.885 mmol) of (3-methylbutyl)hydrazine were added. The mixture was stirred at 120° C. for 3 h and then concentrated. The residue was taken up in DMSO and purified by preparative HPLC (Method 10). This gave 43 mg (29% of theory) of the target compound.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[CH3:17])[C:8]#[N:9].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([CH2:6][CH2:5][OH:4])[C:8]#[N:9])=[C:11]([CH3:17])[CH:12]=1
Reactant: COC(=O)CC(C#N)c1ccc(Br)cc1C
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(C#N)CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Lithium borohydride (4.99 g, 0.2290 mol) was added to a room temperature solution of 3-(4-bromo-2-methyl-phenyl)-3-cyano-propionic acid methyl ester (43.08 g, 0.1527 mol) in THF (500 mL) and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0° C., and a solution of 10% KHSO4/Na2SO4 was slowly added until pH 1-2 was reached. The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 7/3) to give 27.3 g (87% yield) of 2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyronitrile as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C@H:22]([O:26][CH2:27][C:28]([CH3:30])=[CH2:29])[C@@H:23]([OH:25])[CH3:24])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:31])[N:8]2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(B(CC)CC)C.[BH4-].[Na+].C(Cl)Cl>C1COCC1>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C@H:22]4[C@H:23]([CH3:24])[O:25][C:28]([CH3:30])([CH3:29])[CH2:27][O:26]4)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:31])[N:8]2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1[C@@H]1OCC(C)(C)O[C@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mercuric trifluoroacetate (3.92 g, 9.19 mmol) was added portionwise to N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-((1R,2S)-2-hydroxy-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxamide (3.59 g, 8.03 mmol) in THF (160 mL) at room temperature. Mercuric oxide red (1.99 g, 9.19 mmol) was added and the resulting reaction mixture was stirred at room temperature. After 1 h the reaction was cooled to −78° C. and triethylborane (16.84 ml, 16.84 mmol) was added dropwise followed by sodium borohydride (579 mg, 15.31 mmol) portionwise. After 1 h at −78° C. the reaction was allowed to warm gradually to room temperature. The resulting mixture was quenched by the addition of brine and EtOAc, separated, dried over Na2SO4 and concentrated under reduced pressure. DCM (200 ml) and Biotage Si-Thiol (17 g, 1.4 mmol/g load, ˜3 eq) were added and the resulting suspension was stirred at room temperature for 18 h. The reaction was filtered, washed with DCM and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 90-95% EtOAc in iso-hexane afforded the title compound (>95% ee);
Reaction SMILES: Cl[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].Cl[C:17]1C(OCC(O)=O)=NC(Cl)=C(Cl)C=1>>[CH3:17][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCOc1ccc(Cl)cc1Cl
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Product: Cc1cc(Cl)ccc1OCCCC(=O)O

Procedure:
4-(2,4-dichlorophenoxy)butyric acid (2,4-DB), or ((3,5,6-trichloro-2-pyridinyl)oxy)acetic acid (triclopyr)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:7]([OH:9])=O)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:36][C@@H:37]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55]([C@@H:57]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:68]([C@H:37]([NH:36][C:7](=[O:9])[CH:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[NH:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55](=[O:56])[C@H:57]([C:58]([CH3:60])([CH3:61])[CH3:59])[NH:62][C:63]([O:64][CH3:65])=[O:66])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1)[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)NC(NC(=O)OC)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
The product from Example 169A (13.2 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.25 mL) and N-hydroxybenzotriazole (13 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (18.4 mg, 0.10 mmol) were added followed by the product from Example 2C (34.2 mg, 0.06 mmol). Triethylamine (9 uL, 0.06 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was concentrated and the crude residue was purified on a 2 mm preparative silica gel TLC plate (5% CH3OH/CHCl3) to give an amorphous solid (38.4 mg, 83%). 1H NMR (CDCl1) δ 8.65 (d, 1H), 7.86 (d, 2H), 7.78-7.60 (m, 2H), 7.27-7.11 (m, 9H), 6.94-6.70 (br s, 1H), 6.36-6.24 (br s, 1H), 6.24-6.04 (br d, 1H), 6.02-5.84 (br d, 1H), 5.41-5.25 (m, 2H), 4.23-4.10 (m, 1H), 4.10-3.95 (q, 1H), 3.75 (d, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.63 (s, 3H), 2.98-2.8 (m, 3H), 2.8-2.65 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:2]
Reactant: CCNCC
Reactant: O=C(CBr)c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: CCN(CC)CC(=O)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 38.1 g (0.52 mol) of diethylamine in 80 mL of toluene and cooled in an ice bath to 0° C. add dropwise a solution of 65.0 g (0.26 mol) of 2-bromoacetonaphthone in 300 mL of toluene. Stir the reaction mixture overnight. Monitor the progress of the reaction by thin-layer chromatography on silica gel (ethyl acetate:hexane, 1:1). Extract the reaction mixture with 3×150 mL of 3N HCl. Adjust the pH of the combined aqueous layers to pH=10 with 50% sodium hydroxide then extract with 3×150 mL of methylene chloride. Combine the extracts and dry over sodium sulfate. Remove the solvent in vacuo, and chromatograph the resultant oil on 2200 g of silica gel, eluting initially with methylene chloride and later with ethyl acetate. Combine the fractions containing product and remove the solvent in vacuo to obtain the title compound.