Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])=[CH:14][C:13]2=[O:26])[C:9]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg, 0.55 mmol) and 1-hydroxybenzotriazole (80 mg, 0.58 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 95 mg, 0.60 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (197 mg, 72%) as a white solid: LR-ES-MS m/z calculated for C26H32F2N4O4 [M]+ 502, observed [M+H]+ 503; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.35 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.48-1.85 (m, 7H) 3.89 (s, 2H) 4.26 (d, J=18.8 Hz, 1H) 4.64 (d, J=18.8 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 4.7 Hz, 1H) 5.03 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.20-7.50 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([CH:8]1[C:16]2[C:15](O)=[N:14][CH:13]=[N:12][C:11]=2[CH2:10][CH2:9]1)[CH3:7].C(#N)C>>[Cl:3][C:15]1[C:16]2[CH:8]([CH2:6][CH3:7])[CH2:9][CH2:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCC1CCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCC1CCc2ncnc(Cl)c21
Temperature: 80 °C
Reaction time: 15 h
Yield: 26.6 %

Procedure:
Phosphorous oxychloride (1.92 mL, 20.6 mmol) was added to a solution of 5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (1.13 g, 6.88 mmol) in acetonitrile (40 mL, 766 mmol) and heated to 80° C. The reaction was stirred at 80° C. for 15 hours. LCMS confirmed consumption of the starting material peak and conversion to a new product peak. The reaction was cooled to room temperature and concentrated under vacuum. The residue was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4. The crude solution was concentrated under vacuum to an oil. The crude was purified by silica gel chromatography (gradient: 10-50% EtOAc/Hexanes). Purification provided 4-chloro-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (334 mg, 1.83 mmol, 26.6% yield) as an oil. MS (APCI+) [M+H]: 183.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C(COC)OC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[C:5]([CH:28]([OH:29])[CH3:27])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13]1
Reactant: C1CO1
Reactant: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: CCCCCOc1c(OC)ccc(C2=NC(C)(C)CO2)c1C(C)O
Temperature: -60 °C
Yield: 38.2 %

Procedure:
2-(4-Methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (373 mg, 1.28 mmol, 1 eq) was dissolved in dimethoxyethane (7 ml). The solution was cooled to -60° C., and n-butyllithium (1.6M hexane solution)(1.76 ml, 2.82 mmol, 2.2 eq) was added dropwise. The mixture was stirred at said temperature for 1.5 hours. Ethylene oxide was added dropwise, and the mixture was stirred for 1.0 hour. The mixture was heated to room temperature, and further stirred for 2 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1-2/1) to give [6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methoxy-2-pentyloxyphenyl]ethanol (164 mg, 38.2%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][C:6]=1[CH3:18].C(O)C.[OH-].[Na+].Cl>O>[C:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:18])=[C:5]2[CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][C:2]=1[Cl:1])([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1Cl
Yield: 76.5 %

Procedure:
To 3-(2-chloro-4-phenylbenzyl)-5-methoxycarbonyl-2-methylindole (0.95 g), added are ethanol (5 ml), water (5 ml) and aqueous sodium hydroxide (0.29 g), and refluxed for 3 hours. The reaction mixture is cooled, and neutralized with HCl. This is extracted with ethyl acetate and water, and the organic layer is dried and concentrated. The resulting residue is crystallized from a small amount of a mixed solution of chloroform and ether. The crystal is taken out through filtration and dried to obtain 5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylindole (145) (0.701 g).
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](F)[C:6]([F:13])=[C:5]([F:14])[C:4]=1[F:15]>C(OCC)C>[N+:9]([C:8]1[C:3]([F:2])=[C:4]([F:15])[C:5]([F:14])=[C:6]([F:13])[C:7]=1[NH2:1])([O-:11])=[O:10]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Product: Nc1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
2-Nitro-3,4,5,6-tetrafluoroaniline was prepared using an adaptation of the method of Brooke et al., J. Chem. Soc. 802 (1961). Ammonia gas was bubbled through a solution of pentafluoronitrobenzene (3.00 g, 114.1 mmol) in 200 mL anhydrous diethyl ether for 4 h. During this time the color changed from clear white to a deep yellow and a white precipitate formed. The precipitate (ammonium fluoride) was separated by vacuum filtration and washed with ether (30 mL). The filtrate was rotary evaporated and the resulting orange crystals gave 3 spots on TLC (alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, activity II) on a 1.5"×20" column. The first band was collected and concentrated to yield a yellow solid 1.88 g (63.0%), mp 44.5-45 (lit. 42.5°-43.5° C.). 19F NMR (C6F6 external standard, δ-162.9) δ-149.9(m), -1.56.6(m), -162.0 (m), -178.3(m).
Reaction SMILES: [I-].[CH2:2]([C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:15]1[O:16]CC(C)(C)[N+]=1C)[CH3:3].C[OH:24]>[OH-].[Na+]>[CH2:2]([C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[C:15]([OH:16])=[O:24])[CH3:3]
Reactant: CO
Reactant: CCc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: CCc1c(C(=O)O)ccc(C(F)(F)F)c1C
Temperature: 25 °C

Procedure:
A solution of 960 mg (2.25 mmol) 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide in 10 ml MeOH and 5 ml 20% NaOH was heated to 70° C. for 17 h The yellow solution was cooled to rt, MeOH distilled off, the residue acidified with conc. HCl to pH 1 and extracted three times with tert-butyl methyl ether. The combined organic phases were washed twice with brine, dried over Na2SO4, filtered and evaporated: 2-Ethyl-3-methyl-4-trifluoromethyl-benzoic acid was obtained as yellow solid: MS (ISN): 231.06 ((M−H)−.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([OH:28])=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH:15]=2)=[C:18]([CH3:27])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1

Procedure:
A solution of 2.77 g (7.3 mmol) of (4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy) phenyl]methanone in 200 ml ethyl acetate with 1.0 g of 10% palladium on carbon is hydrogenated on a Parr apparatus for 2.5 hours at 50 psi and room temperature, then filtered and evaporated to give [5-(4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl](4-fluorophenyl) methanone.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[C:25](=[O:31])[NH:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([CH3:33])=[C:11]([Cl:32])[CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[Cl:32][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:33])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[C:14]2[O:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](=[O:31])[NH:26][CH:27]1[CH2:28][CH2:29][CH2:30]1)=[O:19]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2cc(Cl)c(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2nc(C(=O)O)cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c2cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 3.2 g 6-Chloro-4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml THF were added 6.7 ml aqueous NaOH (1 M) at 0° C. After 4 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 2.78 g.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:27][CH3:28])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.8 mL, 13.0 mmol) was added to a mixture of N2-phenylpyridine-2,3-diamine (800 mg, 4.32 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (960 mg, 4.75 mmol), HOAt (650 mg, 4.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (910 mg, 4.75 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminobutyric acid (610 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (580 mg), HOAt (410 mg) and triethylamine (1.0 mL) were added and stirring at RT continued for 1 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a dark oil. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.67 min [M+H]+ 371.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:44]1[C:48]2([CH2:52][CH2:51][NH:50][CH2:49]2)[CH2:47][N:46]([C:53](=[O:56])[CH2:54][CH3:55])[CH2:45]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12]([N:50]2[CH2:51][CH2:52][C:48]3([CH2:44][CH2:45][N:46]([C:53](=[O:56])[CH2:54][CH3:55])[CH2:47]3)[CH2:49]2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CCC(=O)N1CCC2(CCNC2)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C2)C1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (153 mg, 0.23 mmol) and 1-(3,7-diazaspiro[4.4]nonan-3-yl)propan-1-one (101 mg, 0.46 mmol) in DMF (2 mL) was added Et3N (70 mg, 97 μL, 0.70 mmol). The reaction vessel was sealed and heated at 90° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine (2×). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 0-60% EtOAc in DCM to yield tert-butyl N-[[4-[5-[3[bis(tert-butoxycarbonyl)amino]-6-(3-propanoyl-3,7-diazaspiro[4.4]nonan-7-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (133 mg, 75%). LC/MS m/z 763.9 [M+H]+.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.O.C([O-])(=O)C.[Na+].[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[CH3:23]>C(#N)C>[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)c1ccc(CCl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(CNc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
To a 1-liter (1) 3-necked round-bottomed flask equipped with an overhead stirrer, reflux condenser and dropping funnel and containing a stirred mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm (~65° C.) water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The temperature of the resulting yellow solution was stabilized at about 70° C. and a solution of 33.8 g (0.20 mole) of 4-(1-methylethyl)benzyl chloride in 75 ml of acetonitrile was added over 70 minutes. The solution was then refluxed for an additional 31/2 hrs, and 95 ml of acetonitrile was removed by distillation over a 30 minute period, during which time 50 ml of concentrated hydrochloric acid (con. HCl) was added dropwise. The resulting mixture was filtered hot (~80° C.) and the collected solids were slurried in 300 ml of boiling methanol for 15 min. and then vacuum filtered. The slurrying and vacuum filtration process was repeated first with 300 ml of warm (65° C.) water and then again with 300 ml of boiling methanol. Air-drying of the collected solids gave 12.51 g (20.5% yield) of purified 4-(((4-(1-methylethyl)phenyl)methyl)amino)benzenesulfonic acid as a white powder, having a melting point greater than 275° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.Cl[C:14]1[S:15][C:16]([C@@:19]2([OH:26])[CH2:24][CH2:23][O:22][C@@H:21]([CH3:25])[CH2:20]2)=[CH:17][N:18]=1>CN1C(=O)CCC1>[OH:26][C@:19]1([C:16]2[S:15][C:14]([S:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]4)=[N:18][CH:17]=2)[CH2:24][CH2:23][O:22][C@@H:21]([CH3:25])[CH2:20]1
Reactant: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Reactant: CN1C(=O)Cc2cc(S)ccc21
Solvent: CN1CCCC1=O
Product: C[C@H]1C[C@@](O)(c2cnc(Sc3ccc4c(c3)CC(=O)N4C)s2)CCO1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 26 except that NMP was used in place of DMF as reaction solvent, 5-mercapto-1-methylindolin-2-one was reacted with (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1-methyl-2-oxoindolin-5-ylthio)thiazol-5-yl]tetrahydropyran in 27% yield, m.p. 140° C.;
Reaction SMILES: Br[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7].[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C=O)C.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:52]([O:51][C:47](=[O:50])/[CH:48]=[CH:49]/[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:42][CH2:43][CH2:44][CH3:45])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7])([CH3:55])([CH3:54])[CH3:53]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1/C=C/C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 47.8 %

Procedure:
To a solution of benzyl 4-(4-bromo-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 164A, 80 mg, 0.12 mmol) in DMF (580 μL) and Et3N (580 μL) was added (PPh3)2PdCl2 (8 mg, 0.012 mmol) followed by tert-butyl acrylate (58 μL, 0.40 mmol). The reaction mixture was purged with N2 for 5 min and then heated at 140° C. overnight. The reaction mixture was poured into a separatory funnel containing 1N aq. HCl solution and EtOAc. The organic layer was washed 1N aq. HCl solution (2×) and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 0% to 35% EtOAc/hexanes) to provide the title compound (42 mg, 50%) as a colorless oil. MS(ESI+) m/z 733.5 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12](Cl)([Cl:14])=[O:13].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:12]([Cl:14])(=[O:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)Nc1ccc(OC(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 4-acetominophenol (75.0 g), phosgene solution (450 mL, 20% in toluene), and ethyl acetate (1875 mL) was cooled to 0° C. N,N-Diethylaniline (94.7 mL) was added dropwise and the reaction was stirred at 0° C. for two hours. The reaction was then allowed to warm to room temperature. An aliquot for NMR analysis was taken four hours post addition. The reaction remained incomplete and was stirred at room temperature overnight. An-aliquot for NMR analysis after overnight stirring indicated no change had occurred in the reaction since the previous aliquot. The reaction was heated to 40° C. until phosgene gas evolution ceased (approximately 30 minutes). The reaction was cooled to room temperature and was then filtered. The filter cake was washed with ethyl acetate. NMR analysis of the filtered solid indicated it was N,N-diethylaniline related material. The filtrate was washed was washed with 0.1N HCl (375 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a pale yellow solid. The solid was triturated using ether (375 mL) for twenty minutes at room temperature. The solid was filtered and washed with ether. NMR analysis indicated product with residual ether remaining. The solid was dried overnight in a vacuum oven at ambient temperature to afford 77.55 g (73.3% yield). NMR and MS analysis indicated product. 1H NMR (300 MHz, CDCl3+DMSO-d6): δ 9.18 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s, 3H); MS m/z: 214 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH:38](O)[CH3:39])[C:33]#[N:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:38]([C:37]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[Cl:29])[CH3:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc(C#N)cc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(C#N)cc1Cl

Procedure:
In a similar manner as described for example B31, 1.42 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.8 g of 3-chloro-4-(1-hydroxyethyl)benzonitrile, 2.26 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.56 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[N:20]=[C:19]([C:21]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=2[C:23]#[N:24])[CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=4[C:23]#[N:24])[CH:18]=[CH:17][CH:16]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(F)ccc1-c1cccc(Br)n1
Reactant: CC(C)(C)c1ccn2ccnc2n1
Product: CC(C)(C)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Yield: 63 %

Procedure:
7-tert-Butylimidazo[1,2-α]pyrimidine was coupled with 2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile as described in Example 27 to give 2-[6-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile (0.235 g, 63%) as a white powder: δH (360 MHz, CDCl3) 1.43 (9H, s), 7.05 (1H, d, J 7), 7.37-7.73 (6H, m), 7.81 (1H, s), 7.85 (1H, dd, J 8 and 1), 8.75 (1H, d, J 7); m/z (ES+) 371 (M++H).