Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](OCC)=[O:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(CO)cc12
Temperature: -50 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a cooled (-50° C.) and stirred solution of the product from Step 3 (17.4 g, 52.4 mmol) in anhydrous tetrahydrofuran (650 ml) was added dropwise via cannula diisobutylaluminium hydride (1M in toluene; 168 ml) over 23 minutes, under a nitrogen atmosphere. After being stirred at -25° C. for 1 hour, additional diisobutylaluminium hydride (1M in toluene; 40 ml) was added dropwise over 15 minutes and stirring was continued at -25° C. for further 30 minutes. Methanol (65 ml) was added dropwise (CAUTION! H2 evolution) at -35° C. followed by aqueous citric acid (10%; 450 ml) and the organic phase was decanted off. The aqueous solution was extracted with ethyl acetate (500 ml) and the combined organic phases were washed with brine (1×200 ml), dried (Na2SO4) and concentrated. Flash chromatography (silica gel, dichloromethane-methanol, 97:3) of the remaining residue gave 13.8 g (90.8%) of the title compound as a white solid. A sample recrystallised from dichloromethane showed: mp 129°-130° C.; δH (360 MHz, DMSO-d6) 10.70 (1H, br s, indole N--H), 7.44 (1H, s, Ar--H), 7.26 (1H, d, J=8.3 Hz, Ar--H), 7.10 (1H, s, Ar--H), 7.03 (1H, d, J=8.3 Hz, Ar--H), 6.86 (1H, br t, --NH--), 4.95 (1H, t, J=5.6 Hz, --OH), 4.54 (2H, d, J=5.6 Hz, --CH2OH), 3.18 (2H, m, --CH2N--), 2.78 (2H, t, J=7.2 Hz, --CH2 --), 1.38 (9H, s, t-Bu); m/z (EI) 290 (M+). (Found: C, 65.95; H, 7.82; N, 9.37. C16H22N2O3 requires: C, 66.18; H, 7.64; N, 9.65%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Br.[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH:22]=[C:21]([OH:31])[CH:20]=1>>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([CH3:29])[CH3:30])[CH:22]=[C:21]([O:31][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[Cl:7])[CH:20]=1
Reactant: COC(=O)c1cc(O)cc(OCC=C(C)C)c1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(OCC=C(C)C)cc(OCc2ccccc2Cl)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from potassium carbonate (1.25 g, 9.06 mmol), 2-chloro benzyl bromide (0.59 mL, 4.53 mmol), and 3-hydroxy-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester (374a) (1.07 g, 4.53 mmol). Purification by flash column chromatography eluting with 5% EtOAc in hexanes gave a colorless oil (1.60 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.61 (m, 1 H) 7.37-7.45 (m, 1 H) 7.30 (dd, J=3.92, 2.40 Hz, 2 H) 7.27-7.29 (m, 1 H) 7.24 (dd, J=2.27, 1.26 Hz, 1 H) 6.76 (t, J=2.40 Hz, 1 H) 5.49 (tt, J=6.82, 1.39 Hz, 1 H) 5.15-5.23 (m, 3 H) 4.54 (d, J=6.82 Hz, 2 H) 3.92 (s, 3 H) 1.81 (s, 3 H) 1.73-1.79 (m, 3 H); LCMS for C20H21ClO4 m/z 383.00 (M+Na)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[S:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:38]=1)(C(C)(C)C)(C)C>C1COCC1.[Cl-].[Na+].O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:37]2[N:38]=[C:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[S:35][CH:36]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(-c2csc(CCCCCCCO[Si](C)(C)C(C)(C)C)n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2csc(CCCCCCCO)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Add a solution of 1 N tetra-n-butylammonium fluoride (25.0 mmol, 25 mL, 1 M solution in THF) dropwise over 10 minutes to a solution of 2-[7-(tert-butyldimethylsilanyloxy)heptyl]-4-(4-methoxyphenyl)thiazole (6.27 g, 14.9 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen and stir the mixture for 30 minutes at 0° C. and then stir at room temperature for 3 hours. Dilute the mixture with brine (150 mL) and extract with ethyl acetate (100 mL×3). Dry the combined organic extracts over magnesium sulfate and remove the solvent under reduced pressure. Purify the crude product by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to give 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptan-1-ol (4.07 g, 89%): APCI mass spectrum m/z 306 [C17H23NO2S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[Cl:25]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[Cl:25][CH2:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CCl
Reaction time: 5 h
Yield: 88 %

Procedure:
N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g), dichloromethane (250.0 mL), and triethylamine (47.3 mL) were added to a reactor and then the reaction mixture was cooled to 0˜5° C. Methanesulfonyl chloride (13.2 mL) was slowly added to the reaction mixture, which was then stirred at 20˜25° C. for 5 hours. Water (100.0 mL) was added to the reaction mixture. The separated organic layer was sequentially washed with 0.5N hydrochloric acid solution (100.0 mL) and then water (100.0 mL). The organic layer was concentrated under reduced pressure to remove the solvent. n-Hexane (150.0 mL) was added to the resulting residue under stirring. The resulting suspension was filtered under reduced pressure. The resulting white solid was dried to obtain N-[5-chloromethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (45.5 g, yield 88%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.22 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.21 g, 51% yield), mp=118–120° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=−23.7° (c=1, EtOH).
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)(=O)C(Cl)=O.C[N:32](C)C=O.N>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([NH2:32])=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC1(CCCC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(CCCC(N)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 3 h

Procedure:
To a very fine suspension of 0.4 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-10-yl)butyric acid in 20 ml of chloroform is added, at a temperature in the region of 20° C., 0.13 g of oxalyl chloride followed by a solution of 0.5 ml of dimethylformamide in 5 ml of chloroform, and the stirring is continued for 3 hours. 2 ml of a 5.6N solution of ammonia in methanol are then added and the stirring is continued for 18 hours. The reaction mixture is concentrated on a rotary evaporator and the evaporation residue is stirred for 2 hours with 30 ml of distilled water. The solid is filtered off and purified by chromatography on a column of silica (25 g), eluting under a pressure of 0.5 bar with a mixture of dichloromethane and methanol (9/1 by volume). 0.045 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)butyramide is obtained in the form of a light-beige-coloured solid melting above 260° C. (1H NMR spectrum: (300 MHz; (CD3)2SO-d6 ; δ in ppm): 0.65 (mt, 2H: CH2); 1.53 (s, 3H: CH3); 1.80 (t, J=7.5 Hz, 2H: CH2CON); 2.10 and 2.28 (2 mts, 1H each: hetero-CH2); 6.58 and 7.10 (2 broad s, 1H each: CONH2); 7.27 and 7.33 (2 t, J=7.5 Hz, 1H each: H 7 and H 8); 7.42 and 7.92 (2 broad s, 1H each: H of the imidazole); 7.50 and 7.68 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8)).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:34])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]=1[N+:31]([O-:33])=[O:32])=O.CC(C[Al]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]([N+:31]([O-:33])=[O:32])=[C:15]([CH:20]=1)[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C@H:5]1[CH:3]=[O:2])=[O:34]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2c3ccccc3C[C@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the methyl ester 5 (4.4 g, 9.5 mmol) in anhydrous dichloromethane (11 mL) and toluene (33 mL) was added dibal-H (19 mL, 1.0 M in toluene) dropwise via a syringe pump in 30 minutes at −78° C. The mixture continued to be stirred at −78° C. for 3 hours and TLC (hexanes/AcOEt, 1:1.5) showed that the starting material was almost consumed. The reaction was quenched with methanol (0.4 mL) and 5% HCl (30 mL) at −78° C. Ethyl acetate (100 mL) was added and the dry ice/acetone bath was removed. The mixture was stirred at room temperature for 30 minutes and then transferred to a separatory funnel. The aqueous layer was extracted with AcOEt twice and the combined organic layers were washed with brine, saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. It was filtered through celite and the solvents were removed under reduced pressure (temperature <35° C.). The residue was purified by flash chromatography (Hexanes/AcOEt, 1.5:1, 1:1, 1:1.5) to give the aldehyde 6 as a yellow solid (2.85 g, y=69%). 1H NMR (400 Hz, CDCl3): the compound appears as three distinct rotomers. δ 10.02 (s, 0.3H), 9.85 (s, 0.5H), 9.45 (s, 0.2H), 8.32-8.31 (m, 0.2H), 7.93 (s, 0.3H), 7.83 (s, 0.5H), 7.79 (s, 0.2H), 7.53-7.34 (m, 5.2H), 7.26-7.14 (m, 1.3H), 7.08 (s, 0.5H), 7.01-6.94 (m, 1H), 6.91-6.82 (m, 1H), 5.78 (d, J=8.4 Hz, 0.3H), 5.71 (d, J=8.4 Hz, 0.5H), 5.52-5.48 (m, 0.5H), 5.35-5.21 (m, 2.3H), 4.53-4.50 (m, 0.2H), 4.06 (s, 1.5H), 3.98 (s, 0.6H), 3.94 (s, 0.9H), 3.63-3.17 (m, 2H); HRMS (ESI, m/z): calc. 433.1400 (M+H)+. found 433.1387.
Reaction SMILES: [H-].[Na+].[CH3:3]/[C:4](/[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5]/[C:6]([OH:8])=[O:7].C1OCCOCCOCCOCCOC1.FC(F)(F)S(O[C@H:34]1[CH2:39][C@@H:38]([CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[O:37][C@@:36]([O:60][CH3:61])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[CH2:35]1)(=O)=O>C1COCC1>[CH3:3]/[C:4](/[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5]/[C:6]([O:8][C@@H:34]1[CH2:39][C@@H:38]([CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[O:37][C@@:36]([O:60][CH3:61])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)[CH2:35]1)=[O:7]
Reactant: C=CCC/C(C)=C\C(=O)O
Reactant: C=CCCC[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 100 mL dry flask under a nitrogen atmosphere was charged with NaH (60% in mineral oil, 186 mg, 4.65 mmol). The NaH was washed with pentane (5 mL), THF (2 mL) was added, and the reaction was cooled to 0° C. The title compound from Example 21 (651 mg, 4.65 mmol) in THF (3 mL) was added dropwise, after which 15-crown-5 (1.41 mL, 7.12 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 10 minutes, and then was cooled to 0° C. again. A solution of the title compound from Example 22 (1.19 mmol, used directly from the previous reaction) in THF (2 mL) was added, and the reaction was stirred at room temperature overnight.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:35])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].Br[CH2:39][CH:40]=[CH:41][CH3:42]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:33])(=[O:34])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:39][CH:40]=[CH:41][CH3:42])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(=O)(=O)Nc2ccc(NC(C)=O)cc2)cc1
Reactant: CC=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC=CCNc1cc(C(=O)O)cc(S(=O)(=O)Nc2ccc(NC(C)=O)cc2)c1Nc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the solution of 2.5 g of 4-(4-acetamidophenylamino)-3-amino-5-(4-acetamidophenylsulfamoyl)-benzoic acid in 60 ml of water and 5 ml of N potassium hydroxide, 0.7 g of 1-bromo-2-butene are added dropwise while stirring. The pH of the mixture is kept at 7.4 by subsequent addition of 4 N aqueous potassium hydroxide. After about 15 minutes the mixture is filtered, the filtrate acidified with glacial acetic acid to pH = 4, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylamino)-3-but-2-enylamino-5-(4-acetamidophenylsulfamoyl)-benzoic acid melting at 265° with decomposition.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][OH:26])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[C:29]=1F>CN(C=O)C>[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][O:26][C:29]2[C:30]([N+:34]([O-:36])=[O:35])=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirring solution of sodium hydride (0.257 g, 6.43 mmol) (pre-washed in hexanes) in DMF (15.30 mL) at 0° C., tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(hydroxymethyl)morpholine-4-carboxylate (Example 1, Step 5) (1.66 g, 4.59 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour. At this point, 1,2-difluoro-3-nitrobenzene (0.494 mL, 4.50 mmol) in 0.5 mL of DMF was added dropwise and the final solution was slowly warmed toward room temperature and stirred for 1 hour. Complete by LC/MS at this time. The contents were quenched by adding saturated aqueous sodium bicarbonate and then extracted between water and EtOAc (3×75 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification on silica gel (120 g) eluting with a gradient of 0-60% EtOAc/hexanes afforded the title compound (1.68 g, 3.36 mmol, 73% yield) as a yellow oil, MS (ESI): m/z=401.11 (M+H-boc).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:15]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)[N:5]=2)=[O:17])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: COc1cccc(-n2nc(C(=O)O)cc2O)c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 150 mg of 5-Hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid and 220 mg of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 98 mg of HOBT and 122 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[CH:9].[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:28])[C:23](Br)=[N:24][C:25]=1[CH3:26])=[O:20])[CH3:17].CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:28])[C:23]([C:9]#[C:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:24][C:25]=1[CH3:26])=[O:20])[CH3:17]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(C#Cc2ccccc2)n1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
In analogy to the method as described in Chem. Pharm. Bull. 1987, 35(2), 823-828, 17.5 mg (0.025 mmol) bis-(triphenylphosphine)-palladium-II-chloride, 2.9 mg (0.015 mmol) cuprous iodide, 60.5 mg (0.6 mmol) triethylamine, 32.4 mg (0.3 mmol) ethynylbenzene and 61.8 mg (0.25 mmol) 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester are dissolved in 1 ml DMF and shaken for 3 h at 90° C. The title compound (19.3 mg, 29%, MS: m/e=269.3, [M+H+]) was isolated from the reaction mixture by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[C:26]1([C:32]2[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NC1C=CNN=1.C1(NC2C=CNN=2)C=CC=CC=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:37][C:34]3[CH:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:36][N:35]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Agent: c1ccc(Nc2cc[nH]n2)cc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=CNc1cc(-c2ccccc2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.065 gms. 5.-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0417 gms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[N:23]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[CH:26]=[C:25]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=3)[CH:24]=[N:23]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(Br)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of 5.68 g (20.0 mmol) 3-bromo-5-iodo-pyridine, 7.55 g (20.0 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1-carboxylic acid tert-butyl ester (synthesis described in WO 2007/066187) and 8.49 g (40.0 mmol) tri-potassium-phosphate-trihydrate in 40 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 421 mg (0.60 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 50 μl (0.361 mmol) triethylamine were added. The reaction mixture was stirred for 16 hours at 80° C. The reaction mixture was partitioned between THF and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. The residue was recrystallized from isopropanol yielding 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS (A): 2.41 min, [M+H] 407/409.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
To a 500 mL round-bottomed flask was added 4-(trifluoromethyl)cinnamic acid (231 mL, 116 mmol), DCM (7.44 mL, 116 mmol), thionyl chloride (17.7 mL, 243 mmol), and a few drops of DMF. The resulting mixture was stirred at reflux for about 1.5 hours and followed by LCMS (MeOH quench). Once no starting material was present, the solvents were reduced and the oil was used immediately in the next step.