Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=3)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][N:43](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:26]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:24]([CH2:23][O:22][CH2:21][C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:42]#[N:43])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:25]=2)=[CH:35][CH:36]=1)#[N:41]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2cccc(Br)c2)CC1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2cccc(C#N)c2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of tert-Butyl 4-(3-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (150 mg, 0.238 mmol), zinc cyanide (33.6 mg, 0.286 mmol), palladium tetrakis triphenylphosphine (27.5 mg, 0.024 mmol), and dimethylformamide (1 mL) was charged to a conical vial and purged with nitrogen for 5 minutes. The vial was sealed and heated at 120° C. for 2 hours and then held at room temperature overnight. The resulting mixture was filtered through a syringe tip filter and applied directly to a silica gel column. Gradient elution with 5-40% ethyl acetate/hexanes afforded the product as a clear oil (83 mg, 61%). 1H-NMR (CDCl3, 500 MHz) δ ppm 7.76 (m, 2H), 7.68 (s, 1H), 7.56-7.64 (m, 4H), 7.45-7.49 (m, 1H), 7.38-7.43 (m, 2H), 7.34 (s, 1H), 3.69 (m, 2H), 3.45 (s, 2H), 3.05 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 576.17 (MH)+.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[C:27]([NH2:29])[CH:28]=1>>[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:29][C:27]2[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=2[CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[CH:11][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1)C(C)C
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Yield: 96.5 %

Procedure:
Synthesized from 4-(2-diisopropylaminoethoxy)benzoic acid hydrochloride (240 mg) and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (150 mg) according to an analogous synthetic method to Example 152, the title compound (264 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][C:9]([CH3:14])([CH3:13])[C@H:10]([NH2:12])[CH3:11]>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:12][C@@H:10]([C:9]([CH3:14])([CH3:13])[CH3:8])[CH3:11]
Reactant: COC(C=O)OC
Reactant: C[C@@H](N)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(CN[C@H](C)C(C)(C)C)OC
Reaction time: 2 h

Procedure:
2,2-Dimethoxyacetaldehyde (7.54 mL) was added to a solution of (R)-3,3-dimethylbutan-2-amine (5.06 g) in methanol (20 mL) and the mixture stirred for 2 h. A slurry of palladium on carbon (10%, 200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 66 h. The mixture was then filtered and concentrated in vacuo to afford (R)- N-(2,2-dimethoxyethyl)-3,3-dimethylbutan-2-amine (8.78 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.86 (dd, J=12.2, 5.5 Hz, 1H), 2.58 (dd, J=12.1, 5.9 Hz, 1H), 2.23 (q, J=6.4 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H), 0.89 (s, 9H)
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:40]=[C:30]2[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]2[N:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:40]=[C:30]4[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]4[N:28]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)c1cnc2nc(S)nn2c1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: CCOC(=O)c1cnc2nc(SC3=C(O)CC(CCc4ccc(OC)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.34 (t, J=7.1 Hz, 3H) 1.55-1.74 (m, 8H) 2.07 (m, 1H) 2.22 (m, 2H) 2.63 (d, J=8.2 Hz, 2H) 2.75 (d, J=17.6 Hz, 2H) 3.00 (d, J=15.0 Hz, 1H) 3.81 (s 3H) 4.38 (m, 2H) 7.06 (t, J=8.8 Hz, 1H) 7.25 (s, 1H) 7.27 (s, 1H) 7.30 (m, 1H) 9.13 (s, 1H) 9.26 (s, 1H). MS (APCI) calcd for C27H29ClN4O6S: 573.07; found M=573.1.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+].[NH4+].S(O)(O)(=O)=[O:9].C1(N)CCCCC1.C1(N)CCCCC1.S(O)(O)(=O)=[O:28].[CH:32]1([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[CH:45]1([NH:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:39]1([N:38]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[OH:28])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1.[CH:52]1([N:51]([CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[OH:9])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=S(=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: NC1CCCCC1
Product: ON(C1CCCCC1)C1CCCCC1

Procedure:
It can be seen from the NMR spectrum which is then measured that DCHAS has been formed. Traces of oxime, ammonium sulfate, CHAS, cyclohexylamine hemisulfate and dicyclohexylamine hemisulfate can be discerned as impurities in the NMR spectrum.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([CH3:10])[CH:12]=1)=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: Cc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CCCCCBr)cc1C
Reaction time: 0.5 h

Procedure:
6-Bromohexanoyl chloride (2.0 g) was added to o-xylene (20 ml), and aluminum chloride (1.4 g) was added at -20° C., which was followed by stirring for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 2.6 g of 6-bromo-1-(3,4-dimethylphenyl)-1-hexanone.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:25]([C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12])=[CH2:26]
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 81 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (200 mg, 0.64 mmol) [prepared in Example 99], potassium carbonate (438 mg, 3.17 mmol), bis(tri-t-butylphosphine)palladium(0) (324 mg, 0.64 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (77 mg, 0.32 mmol) in 1,4-dioxane (5.3 ml) and H2O (1 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (135 mg, 0.515 mmol, 81% yield) as a yellow oil: LCMS (ES) m/z=250 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[C:15]([CH3:28])[N:14]=1>>[CH3:12][C:13]1[C:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[C:15]([CH3:28])[N:14]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)c(C)n1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c(C)n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared as the corresponding hydrochloride salt from 7-aminoquinoline (D55) (25 mg, 0.17 mmol) and 4-(2,6-dimethyl-3-pyridyl)benzoic acid (D56) (21 mg, 0.09 mmol) as a brown solid. 1H NMR (250 MHz, DMSO) δ (ppm): 9.15 (d, 1H), 9.01 (s, 1H), 8.94 (d, 1H), 8.28 (m, 5H), 7.84 (m, 2H), 7.72 (d, 2H), 2.79 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@@H:14](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:15])[CH:6]=1.[C:28]1([C@H:34]([CH3:37])[CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@H:14]([NH:36][CH2:35][C@H:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:37])[CH3:15])[CH:6]=1
Reactant: C[C@H](CN)c1ccccc1
Reactant: COC(=O)Cc1cccc(OCC[C@H](C)OS(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCC[C@@H](C)NC[C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66.2 %

Procedure:
A solution of {3-[(S)-3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.51 mmol) and (S)-2-Phenyl-propylamine (0.19, 0.77 mmol) in acetonitrile (30 ml) was treated with solid potassium carbonate (0.149, 1.02 mmol). The reaction was heated to reflux and stirred for six days. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (0.12 g, 40%). MS m/e 356.6 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:10]([C:9]1[CH:12]=[C:13]([CH:14]=[CH:15][C:8]=1[O:7][C:6]1[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:4]([F:3])[CH:5]=1)[CH2:16][O:17][C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1)#[N:11]
Reactant: N#Cc1cc(CO)ccc1Oc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cc(F)cc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][OH:17])=[NH:15])=[C:12]([Cl:20])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:27]1([O:33]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]3[NH:16][O:17][C:27](=[O:33])[N:15]=3)=[C:12]([Cl:20])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nc(Br)sc1COc1ccc(C(=N)NO)c(Cl)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(Br)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-N-hydroxy-benzamidine (199 mg, 0.5 mmol) was dissolved in 6 ml dichloromethane. Pyridine (55 mg, 0.7 mmol) and phenylchloroformate (108 mg, 0.7 mmol) were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 25 ml acetonitrile and 0.4 ml 1,8-Diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 142 mg 3-[4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: C(O[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[O:8][C:7]([CH3:34])([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:6]1)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:16]([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[C:19]([CH3:22])([CH3:21])[CH3:20])[O:8][C:7]([CH3:34])([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)[CH:6]=[CH:5]2)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2

Procedure:
A mixture of 2.4 g of 4,6-diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 56), 0.1 g of p-toluenesulfonic acid monohydrate and 50 ml of benzene was heated under reflux for 1 hour. The reaction solution was cooled, washed with a saturated aqueous solution of sodium bicarbonate, and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give the title compound as a yellow oil.
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[OH:17][C@@H:18]1[CH2:23][C@H:22]([C:24]#[N:25])[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19]1.[CH3:28][C:29]1[C:37](O)=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[N:32][NH:33]2>C1(C)C=CC=CC=1>[CH3:26][C:21]1([CH3:27])[CH2:20][CH2:19][C@@H:18]([O:17][C:37]2[C:29]([CH3:28])=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)[CH2:23][C@@H:22]1[C:24]#[N:25]
Reactant: CC1(C)CC[C@H](O)C[C@@H]1C#N
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](C#N)C2)ccc2[nH]ncc12
Reaction time: 4 h
Yield: 36.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 90%-cyanomethylenetri-n-butylphosphorane (1.05 g, 4.05 mmol) in toluene (5 ml) was added dropwise to a solution of cis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile (500 mg, 3.37 mmol) in toluene (12 ml) at room temperature, followed by adding thereto the 4-methyl-1H-indazol-5-ol (507 mg, 3.54 mmol) obtained in Example 402, and the resulting mixture was heated to 100° C. After 4 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. The aqueous layer was re-extracted with chloroform and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanecarbonitrile (351.1 mg, 46%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.O[C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:27]([O:29]C)=[O:28]>C(Cl)(Cl)Cl>[CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C@H:26]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:27]([OH:29])=[O:28])=[CH:22][CH:23]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1

Procedure:
Prepared from 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenol (Example 14) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: [a]25/D =-19.09° (8.538 mg/mL, CHCl3); NMR (CDCl3); δ8.30 (s, 1 H), 7.91 (d, J=8 Hz, 1 H), 7.73 (d, J=8 Hz, 1 H), 7.55-7.24 (m, 10 H), 7.14-7.09 (m, 2 H), 7.05 (ddd, J =8, 7, 1 Hz, 1 H), 6.70 (d, J=8 Hz, 1 H), 5.09 (dd, J=8,5 Hz, 1 H,), 3.42 (m, 2 H); MS (EI): [M+] 474 (100%); Anal Calc. for C31H22O3S: C, 78.46, H, 4.67, N, 0.00. Found: C, 77.09, H, 4.60, N, 0.03 Analytical HPLC purity (98.5%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (59 mg, 0.20 mmol) and tert-butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (46 mg, 0.19 mmol) was added EtOH (2.0 mL), followed by DIPEA (100 mg, 0.772 mmol). The mixture was stirred at 110° C. for 15 h. After cooling to the room temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (51 mg, 67%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(-n2cnc3cc(Cl)c(Cl)cc32)cc1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A mixture of 5,6-dichlorobenzimidazole (94 mg, 0.50 mmol), 4-fluorobenzaldehyde (0.064 mL, 0.60 mmol), and potassium carbonate (83 mg, 0.60 mmol) in dimethylsulfoxide (3 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature, and water was added. The precipitated product was collected by filtration and washed with water and ethanol to afford 5,6-dicloro-1-(4-formylphenyl)benzimidazole (90 mg, 62%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1>CCOC(C)=O.CCOCC.Cl.CCOCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: COCCOc1cccc(OCCOc2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCOc1cccc(OCCOc2nccnc2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
The product obtained in Step 1 above was dissolved in a mixture of EtOAc (18 mL) and ether (9 mL) and 5 M HCl/ether (9 mL) was added. The mixture was stirred at room temperature for 3 h. The precipitatated hydrochloride salt was filtered off and washed thoroughly with ether. The hydrochloride was dissolved in EtOAc/MeOH/Et3N (100:40:5) and purified by column chromatography on silica using NH3-satd. EtOAc/CH3OH (100:15) as eluent. The combined pure fractions were concentrated in vacuo and the resulting oil was dried (˜0.8 torr, room temperature) to give 0.36 g (69%) of the title product. HRMS m/z calcd for C19H26N4O4 (M)+ 374.1954, found 374.1947.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:42]([CH2:38][CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, Ex. 2, Step 1 (320 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-butanesulfonyl chloride (93 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 230 mg (57%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=4[F:37])=[O:28])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:12]=1)=[O:7].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:11]3[CH:12]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:7])[S:9][CH:10]=3)[CH:18]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: COC(=O)CNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)NCC(=O)O)c4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate (60 mg, 0.11 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1 ml of 1M NaOH (1.0 mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetic acid as white solid. Yield: 50 mg, 86%.