Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:30][N:29]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:30][N:29]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccccc2)nn3C2CCCCO2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(CCc2ccccc2)nn3C2CCCCO2)CC1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.74 g, 1.22 mmol) in dry methanol (40 ml) was added Pd/C (150 mg). The reaction mixture was stirred under a hydrogen atmosphere for 1 hour, filtered and concentrated under reduced pressure. The crude residue was taken in dry methanol (30 ml) and Pd/C (150 mg) was added. The mixture was submitted to a hydrogen pressure of 1 bar and was stirred for 1 hour, filtered and concentrated under vacuum to yield the title compound (0.72 g, 96%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[N:14]=[CH:15]3)=[C:10]([CH3:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCCl>[F:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[C:10]([CH3:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1c(F)cncc1-c1cc2cnc(N)cc2c(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A suspension of tert-butyl 7-(5-fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-ylcarbamate (110 mg, 0.30 mmol) in 1,2-dichloroethane (2 mL) was treated with trifluoroacetic acid (0.23 mL, 3.0 mmol), and the mixture was stirred at 40° C. for 2 hours. The mixture was concentrated in vacuo and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a bright yellow solid (80 mg, 99%), which was used in the next step without further purification.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1>>[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:63][S:60]([CH:57]2[CH2:59][CH2:58]2)(=[O:62])=[O:61])=[O:38])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a white gum (0.053 g, 87%): 1H NMR (300 MHz, CDCl3) δ8.68 (d, J=14.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 6.53 (d, J=14.1 Hz, 1H), 3.98 (s, 2H), 3.14-3.06 (m, 1H), 2.08-1.99 (m, 1H), 1.95-1.92 (m, 2H), 1.87-1.71 (m, 2H), 1.49-1.43 (m, 2H), 1.40-1.25 (m, 5H), 1.17-1.13 (m, 2H), 0.98-0.91 (m, 2H), 0.71-0.66 (m, 2H); MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:19]CCO2)=[CH:11][C:10]=1[CH2:21][CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH3:20])=[CH:11][C:10]=1[CH2:21][CH2:22][O:23][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC1(c2ccc(OCc3ccccc3)c(CCO)c2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 0 °C

Procedure:
2-[2-Benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethanol (9.0 g) was dissolved in N,N-dimethylformamide (100 ml), and 60% sodium hydride in oil (1.26 g) was added to the solution under ice-cooling with stirring. After reaction for an hour at room temperature, benzyl bromide (3.75 ml) was added to the reaction mixture under ice-cooling with stirring, followed by reaction for 16 hours at room temperature. Ice (100 g) and water (100 ml) were added to the reaction mixture, and the resulting mixture was extracted with diethyl ether, then the solvent was removed in vacuo. The residue was dissolved in 1,2-dimethoxyethane (50 ml), and 1 N hydrochloric acid (10 ml) was added to the solution, then the resulting mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave 4'-benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.5 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O-:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(CC)CC)C.[C:20]([Si:24]([CH3:33])([CH3:32])[O:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)([CH3:23])([CH3:22])[CH3:21].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCOCC1.O1CCCC1.[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[C:20]([Si:24]([CH3:33])([CH3:32])[O:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:2]2[C:7]([CH:8]=[O:10])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[CH2:27]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1
Reactant: CSc1ncc(C(=O)[O-])c(Cl)n1
Agent: [Mn+4]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc(C=O)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-methylthio-5-pyrimidinecarboxylate (900 mg, 3.87 mmol) (Aldrich) and triethylamine (1.1 mL, 870 mg, 7.74 mmol) (Aldrich) in dioxane (50 mL) was treated with (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (840 mg, 3.87 mmol) (from Example 9c supra). The mixture was stirred at reflux for 1 hour, then cooled and partitioned between brine and ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by silica gel column chromatography using a 0–20% ethyl acetate in hexanes gradient. The product isolated from this purification was then dissolved in anhydrous tetrahydrofuran (80 mL) and the resulting solution was cooled to 0° C. Followed addition in-portions of lithium aluminum hydride (440 mg, 11.61 mmol) (Aldrich) and the resulting mixture was allowed to warm to room temperature. After overnight stirring the reaction mixture was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to an off white solid. This intermediate was then dissolved in dichloromethane (80 mL) and the resulting solution was treated with manganese dioxide (3.36 g, 38.70 mmol) (Aldrich). After overnight stirring the solids were filtered off, washed with tetrahydrofuran (approximately 30 mL) and the combined organic layer was concentrated to a residue that upon a silica gel column purification with 0–50% diethyl ether in hexanes gradient gave (±)-4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbaldehyde as a viscous colorless oil. (Yield 888 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:40][S:37]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=2)(=[O:39])=[O:38])=[O:27])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.6 Hz), 8.16–8.03 (1H, m), 8.08 (2H, d, J=8.7 Hz), 7.75 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.2 Hz), 7.21–7.08 (4H, m), 5.39–5.24 (1H, m), 1.57 (3H, d, J=7.4 Hz); MS (ESI) m/z 588 (M+H)+, 586 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cncc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Yield: 54.7 %

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.75 g, 8.71 mmol, prepared as in Example 15a) and 5-chloro-3-pyridinol (1.69 g, 13.10 mmol, Aldrich Chemical Co.). were allowed to react in the presence of triphenylphosphine and DEAD as described in Example 2a. The crude product was purified by chromatography over silica gel eluted with hexane/EtOAc to provide 1.49 g (60%) of the title compound as a pale yellow oil. TLC Rf 0.75 (1:1 EtOAc/Hex). MS (DCI/NH3) m/e 313 (M+H)+ with 35Cl and m/e 315 (M+H)+ with 37Cl.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.CO[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1>O1CCCC1>[Br:8][C:6]1[CH:5]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:3]=[C:2]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)[CH:7]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C#N)c1cc(Br)cc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
A solution of isopropylmagnesium chloride lithium chloride complex (1.71 ml, 1.65 mmol) in tetrahydrofuran (10 ml) was cooled down to −20° C. 2-(3,5-dibromophenyl)-2-methylpropanenitrile (500 mg, 1.65 mmol, preparation as described in Example 2 step 1) was added in one portion and the reaction stirred for 1.5 hours at −15 to −5° C. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260.7 mg, 269.9 μL, 1.65 mmol) was added and the reaction was allowed to warm up to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was partitioned between a diluted solution of ammonium chloride and ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound as a light yellow solid (551 mg, 95% yield).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:19])[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.[SH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[S:21][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:21][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH:10]=[CH:11][C:12]=3[S:21][C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[C:7](=[O:19])[C:6]=2[C:5]([S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)ccc(Cl)c2C(=O)c2c(Cl)ccc(Cl)c21
Reactant: Sc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(Sc3nc4ccccc4s3)ccc(Sc3nc4ccccc4s3)c2C(=O)c2c(Sc3nc4ccccc4s3)ccc(Sc3nc4ccccc4s3)c21
Yield: 90.2 %

Procedure:
The dyestuff used can be prepared as follows: 15 g of 1,4,5,8-tetrachloro-anthraquinone, 75 g of dimethylformamide, 35 g of 2-mercaptobenzthiazole and 30 g of potassium carbonate are heated to 125°-130° C for about 3 hours. After cooling, the dyestuff which has precipitated in attractive red prisms is filtered off and washed with methanol and water. After drying, 34 g of 1,4,5,8-tetra-(2-benzthiazolyl-thio)-anthraquinone = 90% of theory are obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(C(F)(F)F)cc2)CO3)N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.03 g, 2.75 mmole) and 4-trifluoromethylbenzylamine (1.60 ml, 11.2 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.56 g, 54%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.06 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 211°-212° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1
Reactant: C#CCN1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C#CCN1CC[C@H](O)C1
Reaction time: 1.25 h

Procedure:
To a solution of (R)-3-hydroxy-1-prop-2-ynyl-pyrrolidine (200 mg, 1.59 mmol) (see Example 92A), benzoic acid (230 mg, 1.91 mmol) (Aldrich) and triphenyl phosphine (628 mg, 2.39 mmol) (Aldrich) in 25 mL of THF, was added diisopropyl azodicarboxylate (485 mg, 2.39 mmol) (Aldrich) at 0° C. The mixture was stirred for 1.25 hr and then partitioned between EtOAc and aqueous saturated Na2CO3. The organic layer was dried over Na2SO4, concentrated, and the residue was passed through a silica gel column with a 0-50% EtOAc in hexanes gradient. The resulting intermediate benzoate ester promptly was dissolved in 15 mL of MeOH, and K2CO3 (439 mg, 3.18 mmol) was added. After stirring for 36 hr, the reaction mixture was filtered and concentrated. (S)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine was obtained after silica gel column chromatography with neat THF and triturating with pentane. (Yield 102 mg, 51%).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[C:38]([O:40]CC)=[O:39]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH:37]([CH2:36][CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:54])[C:50]([F:51])([F:52])[F:53])[C:38]([OH:40])=[O:39])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([Sn](C)(C)C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:15].[Br:16]Br.S([O-])([O-])(=O)=S>C(Cl)Cl>[Br:16][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:15])[O:5][CH2:4]2
Reactant: BrBr
Reactant: Cc1c([Sn](C)(C)C)ccc2c1COC2=O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1COC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-5-(trimethylstannyl)isobenzofuran-1(3H)-one (4.37 g, 14.05 mmol) in DCM (20 mL) was added bromine (0.796 ml, 15.46 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Saturated thiosulfate solution was added and the mixture was extracted with methylene chloride (2×100 mL), the combined organic phase was dried over sodium sulfate, concentrated to give 5-bromo-4-methylisobenzofuran-1(3H)-one. LC/MS: (M+1)+: 226.89; 228.89.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([NH:13][C:14]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4C3CCCCO3)=[CH:18][C:17]([CH:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH3:37])=[CH:16][N:15]=2)=[CH:4][N:3]=1.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+]>[OH-].[Na+].C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([NH:13][C:14]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][NH:24]4)=[CH:18][C:17]([CH:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[CH3:37])=[CH:16][N:15]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a 20 mL scintillation vial, N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (0.165 g, 0.263 mmol) and 5N hydrochloric acid (0.5 mL, 2.5 mmol) were mixed into THF (3 mL). The solution was stirred at room temperature for 30 min. 10 mL of buffer (pH 5, citric acid/NaOH) was added and the pH was further adjusted to about 5 by adding a few drops of 6N NaOH. The aqueous phase was extracted with 10% isopropanol in chloroform (3×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The corresponding fractions were collected and concentrated down to dryness. The residue was treated with about 5 mL of pH 5 buffer and pH 7 buffer were added to adjust pH to about 6. The aqueous phase was extracted with 10% isopropanol in chloroform (3×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.101 g of yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.65 (br. s., 1H) 13.11 (br. s., 1H) 9.82 (br. s., 1H) 9.68 (br. s., 1H) 8.71 (d, J=1.96 Hz, 1H) 8.66 (s, 1H) 8.53 (s, 1H) 8.34 (d, J=1.17 Hz, 1H) 3.50-3.67 (m, 5H) 3.15 (s, 3H) 2.88 (s, 3H) 2.35-2.46 (m, 2H) 1.42 (d, J=6.65 Hz, 3H). Note: 2 protons were buried under DMSO peak and could not be integrated. m/z (ESI, positive ion): 544.0 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=O)(=[S:3])[CH3:2].[NH2:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13]>>[C:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13])=[O:7])(=[S:3])[CH3:2]
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: CC(=S)C(C(=O)O)C(C)C
Product: CC(=S)C(C(=O)N[C@@H](C)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O)C(C)C

Procedure:
Following General Procedure D above using 2-thioacetyl-3-methyl butanoic acid (Coric et al., J. Med. Chem. 39, 1210 (1996)) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B, the title compound was prepared.