Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:30][C:31]#[N:32])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 76.8 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), bromoacetonitrile (0.0796 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with the exception that the product was extracted with two portions each of methylene chloride and EtOAc. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloride in hexane as the eluent gave {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as a white solid (0.170 g, 77%), mp 229–230° C. Elemental Analysis for C28H20N2O.0.05 CH2Cl2 Calc'd: C, 83.24; H, 5.01; N, 6.92. Found: C, 83.12; H, 4.77; N, 6.89.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][CH:25]=2)[C:12]2[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=2[C:14](OCOC)=[O:15])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)[C:12]2[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=2[CH2:14][OH:15])=[CH:29][CH:28]=1
Reactant: COCOC(=O)c1ccccc1C(c1ccc(OCOC)cc1)c1ccc(OCOC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2CO)cc1
Reaction time: 0.17 h
Yield: 83 %

Procedure:
In 500 ml of tetrahydrofuran was dissolved 74 g of methoxymethyl 2-[bis(4-methoxymethoxyphenyl)methyl]-benzoate obtained by Reference Example 3. The solution was ice-cooled, 10 g of lithium aluminum hydride was added thereto, and the mixture was stirred for 10 minutes. The reaction mixture was stirred for additional 30 minutes at room temperature, and ice cooled, and then 10 ml of water, 10 ml of aqueous 15% sodium hydroxide and 30 ml of water were added thereto in order. The mixture was filtered by use of a filter aid and then concentrated under reduced pressure to afford 53.54 g of the desired compound as an oily matter.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.BrC1C(N)=NC=C(Br)N=1.C(C1C=C[C:41]([O:44]C)=[CH:40]C=1)#C.[Li]CCCC.CC(N(C)C)=O>C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.CC(O)=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]3=[N:6][CH:7]=[C:2]([C:41](=[O:44])[CH3:40])[N:3]=[C:4]3[CH:10]=2)=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1ccc(-c2cc3nc(Br)cnc3n2COCC[Si](C)(C)C)cc1
Agent: Nc1ncc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3nc(C(C)=O)cnc3n2COCC[Si](C)(C)C)cc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
2-Bromo-6-(4-methoxyphenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.5 g, 3.5 mmol, prepared using A from 3,5-dibromopyrazin-2-amine with 1-ethynyl-4-methoxybenzene, B and C) in THF (20 mL) was cooled to about −75° C. then n-BuLi (1.44 mL, 3.45 mmol) was added dropwise keeping the temperature below −70° C. After about 5 min DMA (1.30 mL, 13.8 mmol) was added keeping the temperature below about −65° C. The mixture was stirred for about 30 min at about −75° C. then allowed to warm slowly to about 0° C. AcOH (˜0.5 mL) was added then the mixture was diluted with water (40 mL), saturated aqueous Na2CO3 (20 mL) and EtOAc (40 mL). The layers were separated then the organic layer was washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on an 80 g silica column with 85:15 DCM/EtOAc as an eluent to give 1-(6-(4-methoxyphenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanone (1.04 g, 76%): LC/MS (Table 2, Method a) Rt=3.42 min; MS m/z 398 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[N:3]=[C:2]([NH:24][NH2:25])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-isobutyl-9H-purin-6-yl)(4-chloro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:76]([CH:77]([CH3:79])[CH3:78])=[CH:75][C:74]([Cl:80])=[C:73]([CH3:81])[C:71]=2[N:72]=1>>[Cl:80][C:74]1[CH:75]=[C:76]([CH:77]([CH3:78])[CH3:79])[C:70]2[O:69][C:68]([S:67][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:36])[CH2:32][CH2:33]3)=[N:72][C:71]=2[C:73]=1[CH3:81]
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34](OB(O)O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=3[CH:22]=2)=[CH:35][CH:36]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A suspension of methyl 9-bromo-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.1 g) and 4-(2-butoxyethoxy)phenyl boric acid (1.77 g) and potassium carbonate (2.06 g) in toluene (25 ml), ethanol (2.5 ml) and water (2.5 ml) was stirred under argon atmosphere for 1 hour, and then tetrakis(triphenylphosphine)palladium (332 mg) was added. The mixture was refluxed for 5 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=9:1) to give methyl 9-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.7 g) as a yellow oily material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]=O)=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[O:25].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[NH:38][C:37]3[CH:36]=[CH:35][C:23]([C:24](=[O:25])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=4)=[CH:22][C:21]=3[N:20]=2)=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C)c1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(CCC(=O)OC(C)(C)C)cc4C)nc3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid tert-butyl ester (200 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (Example 5-1, step 6) (194 mg) in DMSO (10 mL) was added Yb(OTf)3 (93 mg). The solution was stirred at room temperature for 18 h then the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (amino-column) using hexanes/ethyl acetate (1:4) and gave 3-{4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid tert-butyl ester as a red solid. MS (ESI)m/z 498 (M+H). 1H NMR (Acetone-d6, 400 MHz) δ 11.73 (s, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 7.94 (t, 1H), 7.69 (m, 3H), 7.12 (s, 1H), 7.07 (s, 2H), 2.90 (t, 2H), 2.58 (t, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.16 (s, 6H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH2:11][O:12][CH2:13][CH2:14]O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:43]([O:42][C:40]([C@@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([CH2:14][CH2:13][O:12][CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:35]1)=[O:41])[CH3:44]
Reactant: COc1cccc(C(=CCOCCO)c2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(OC)c2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 2-(3-(3-methoxyphenyl)-3-phenyl-2-propen-1-yloxy)ethanol (52 g, 0.18 mol) and triethylamine (46 g, 0.46 mol) in dry toluene (200 ml) kept under a nitrogen atmosphere was cooled below 10 C and a solution of methanesulphonyl chloride (41.7 g, 0.36 mol) in dry toluene (200 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1 h at 5° C. and then for 0.5 h at approximately 15° C. Water was added (250 ml) and the mixture was stirred at room temperature for 0.5 h. The separated organic phase was washed with a 5% sodium bicarbonate solution, brine and dried (Na2SO4). The mixture was filtered and the filtrate was reduced to approximately 500 ml in vacuo. Ethyl (R)-3-piperidinecarboxylate (57.2 g, 0.36 mol) and potassium carbonate (62.8 g, 0.46 mol) were added and the mixture was heated at reflux temperature for 48 h. The cooled reaction mixture was filtered and the solid was washed with toluene and ethyl acetate successively. The combined organic filtrates was evaporated in vacuo to an oily residue which was dissolved into ethyl acetate (250 ml). Water (150 ml) was added and pH was adjusted to 4 with 10% citric acid solution. The phases were separated and the organic phase was washed with water (150 ml). The combined aqueous phases was extracted with ethyl acetate (150 ml) and then discarded. The combined organic phases was washed with a 5% sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in toluene (150 ml) and a solution of tartaric acid (42 g) in water (120 ml) was added. The phases were separated and the organic phase was extracted with another solution of tartaric acid (12 g) in water (50 ml). The combined aqueous extracts was extracted with ethyl acetate (200 ml) which was discarded. Ethyl acetate (200 ml) was added to the acidic aqueous phase which was made alkaline with excess of a sodium bicarbonate solution. The separated organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated in vacuo to give 46.6 g (60%) of (R)-N-(2-(3-(3-methoxyphenyl)-3-phenyl-2-propen1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]2)=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)=[CH:14][N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3c(cn2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 100 °C
Yield: 96 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (536 mg, 2.01 mmol), tert-butyl 7-amino-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (500 mg, 2.01 mmol), cesium carbonate (1.44 g, 4.40 mmol) and 1,4-dioxane (30 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, Xantphos (98.4 mg, 0.170 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91.6 mg, 0.100 mmol) were added, and the reaction mixture was heated at 100° C. for 6 h. After this time, the reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 96% yield (840 mg) of 226a as a yellow solid: mp 126-128° C.; 1H NMR (500 MHz, CDCl3) d 8.60 (d, 1H, J=2.5 Hz), 8.10 (s, 1H), 7.79 (s, 1H), 6.95 (d, 1H, J=2.5 Hz), 6.55 (s, 1H), 4.53 (s, 2H), 3.64 (t, 2H, J=5.0 Hz), 3.59 (s, 3H), 2.77 (t, 2H, J=5.0 Hz), 1.49 (s, 9H); MS (ESI+) m/z 435.0 (M+H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][C@H:16]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]([C@@H:47]5[CH2:51][CH2:50][C@H:49]([CH3:52])[N:48]5C(OC(C)(C)C)=O)[NH:45][CH:46]=4)=[CH:38][CH:37]=2)[CH:30]=[CH:29]3)[N:25]=1)=O)(C)(C)C.C(Cl)Cl>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:52][C@@H:49]1[NH:48][C@H:47]([C:44]2[NH:45][CH:46]=[C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:31]4[CH:30]=[CH:29][C:28]5[C:33](=[CH:34][CH:35]=[C:26]([C:24]6[N:25]=[C:21]([C@@H:16]7[CH2:17][CH2:18][C@H:19]([CH3:20])[NH:15]7)[NH:22][CH:23]=6)[CH:27]=5)[CH:32]=4)=[CH:37][CH:38]=3)[N:43]=2)[CH2:51][CH2:50]1
Reactant: C[C@H]1CC[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7CC[C@H](C)N7)n6)ccc5c4)cc3)c[nH]2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
TFA (0.500 mL, 6.49 mmol) was added dropwise to a stirred solution of tert-butyl (2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinecarboxylate (228 mg, 0.324 mmol) in DCE (6 mL). During the addition, precipitate formed which hindered the stirring. DCM (˜10 mL) was added and the slurry was stirred while the remaining TFA was added. The reaction was stirred at rt for 30 min, additional TFA was added (˜0.5 mL) and the reaction was stirred 3 h. The reaction was concentrated to yield a TFA salt of 2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole (102 mg, 113 mg, 114 mg) as an orange solid. LC-MS retention time 2.756 min; m/z 503.14 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.32 (s, 1H), 8.17 (s, 1H), 8.01 (app t, J=8.2 Hz, 2H), 7.85-7.95 (m, 6H), 7.80 (s, 1H), 7.73 (s, 1H), 5.02 (app q, J=8.0 Hz, 2H), 3.92 (dddd, J=8.7, 7.0, 6.9, 4.8 Hz, 2H), 2.52-2.67 (m, 4H), 2.38-2.49 (m, 2H), 1.95-2.07 (m, 2H), 1.55 (app dd, J=6.7, 4.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (25.0 g, 178 mmol) and hydroxylamine hydrochloride (13.7 g, 198 mmol) in ethanol (14.2 mL) and water (42.9 mL) was added ice (82.4 g). Then a solution of sodium hydroxide (18.1 g, 455 mmol) in water (21.4 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (27.0 g, 97%) which was obtained as an off white solid. MS: m/e=155.1 [M]+.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])[N:46]=3)[CH2:38][CH2:37]2)=O)[N:26]=1>COCCOC.C(Cl)(Cl)Cl>[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])[N:46]=3)[CH2:38][CH2:37]2)=[S:10])[N:26]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=S)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (88 mg) is added to a solution of cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811, 200 mg) in 1,2-dimethoxyethane (1 ml) and chloroform (0.4 ml). The reaction mixture is stirred at 70-80° C. overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (80 mg, 39%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[Cl:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCCl)c3)ccc1-2

Procedure:
To a solution of the 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 51 (2.00 g, 34.75 mmol) and 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in 8 mL of acetonitrile was added 7 mL of 2M of potassium carbonate in water followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.55 G, 0.476 mmol). This reaction mixture was heated on a Biotage microwave at 140 C for 10 minutes. The cooled reaction mixture was diluted with EtOAc, filtered to remove a black ppt, then washed with water×1, saline×1, then dried over Na2SO4, concentrated and purified by MPLC on a 12 gram silica column, eluting with 10-80% EtOAc/heptanes to give 8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (1.6 g) as a yellow powder.