Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([O:14]C)=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16].Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([OH:14])=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(c2ccccc2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 175 °C

Procedure:
A stirred mixture of 2-methyl-2-phenyl-4,5-dichloro-6-methoxyindan-1,3-dione (5.01 g., 0.015 mole) and pyridine hydrochloride (50 g.) is heated at 175°C. for 1 hour, then poured into water (500 ml.) to give 2-methyl-2-phenyl-4,5-dichloro-6-hydroxyindan-1,3-dione.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:34][CH2:35][CH3:36])=[C:28]([O:31][CH2:32][CH3:33])[CH:29]=3)[CH:24]=[C:23]([C:37](OC)=[O:38])[C:22]=2[C:41](OC)=[O:42])=[CH:17][CH:16]=1.[OH-].[Na+].O>C1(C)C=CC=CC=1.O1CCCC1.C(Cl)Cl>[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:34][CH2:35][CH3:36])=[C:28]([O:31][CH2:32][CH3:33])[CH:29]=3)[CH:24]=[C:23]([CH2:37][OH:38])[C:22]=2[CH2:41][OH:42])=[CH:17][CH:16]=1
Reactant: CCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OCC
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cc2cc(CO)c(CO)c(-c3ccncc3)c2cc1OCC
Temperature: -10 °C
Yield: 91.4 %

Procedure:
To tetrahydrofuran (25 ml) is added a 3.4M solution of sodium bis(methoxyethoxy)aluminumhydride in toluene (18.0 ml), and the mixture is cooled to -10° C. To the mixture is added dropwise a suspension of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-diethoxynaphthalene (10.0 g) in tetrahydrofuran (25 ml) over a period of time for 15 minutes. The reaction solution is warmed, and stirred under ice-cooling for 1.5 hour, and thereto is added 15% aqueous sodium hydroxide solution (3.7 ml). To the reaction mixture are added water and methylene chloride, and the insoluble materials are removed by filtration. The filtrate is extracted with methylene chloride, and the extract is washed, dried, and concentrated to give 1-(4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-diethoxynaphthalene (7.89 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O.CO>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c(Cl)ccnc12
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NCc1cccc2c(Cl)ccnc12
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To 4-chloroquinoline-8-carbonitrile (Preparation 88) (422 mg 2.24 mmol) in toluene (20 mL) at −78° C. was added dropwise DIBAL-H (6.73 mL/1M solution in toluene, 6.73 mmol). After 20 min at −78° C. the mixture was allowed to warm to −40° C. The reaction mixture was then re-cooled to −78° C. and DIBAL-H (2.0 mL/1M solution in toluene, 2.0 mmol) was added. After 1 h water (1 mL), MeOH (5 mL) and then NH4Cl(aq) (10 mL) were added. After addition of EtOAc (20 mL) the mixture was stirred vigorously for 14 h at rt. The mixture was extracted with EtOAc (3×20 mL) and the combined organic phase washed with brine (20 mL) and dried (MgSO4). Solvent removed in vacuo to give the title compound: RT=2.10 min; m/z (ES+)=193.0 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][N:16]=1.CCN(CC)CC.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.CCO.[O-]S([O-])(=O)=O.[Cu+2].C(O)(=O)C>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:21]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)nc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To a suspension of 308 mg (1.75 mmol) of 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and 240 mg (1.75 mmol) of 2-chloro-5-ethynylpyridine in 1 mL of water and 2 mL of EtOH was added 243 μL (1.75 mmol) of Et3N. To this solution was added 1.75 mL of 1M aqueous sodium ascorbate followed by 1.75 mL of 0.1 M aqueous of CuSO4 and the resulting yellow suspension was stirred for two days. A 1 M solution of acetic acid in water (1.75 mL) was added along with an additional 2 mL of water. The suspension was stirred for 1 h, then was filtered, washed with water (2×2 mL) and hexanes (2×10 mL), and dried under suction to provide 470 mg of 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[O:1][N:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C(=N)NO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOC(=O)c1noc(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 mL) is added CDI (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction is quenched with 1N HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC retention time=0.72 minutes (condition B); MS 159.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:13])[CH:2]=C.[O:14]=[O+][O-]>ClCCl.CO>[OH:13][C:5]1[C:6]([Br:12])=[CH:7][C:8]([F:11])=[C:9]([F:10])[C:4]=1[CH2:1][CH:2]=[O:14]
Reactant: C=CCc1c(O)c(Br)cc(F)c1F
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CCc1c(O)c(Br)cc(F)c1F
Temperature: 25 °C

Procedure:
A solution of 7.8 gm (31.45 mMol) 2-allyl-3,4-difluoro-6-bromophenol in 100 mL dichloromethane and 20 mL methanol was cooled to −78° C. and was then saturated with ozone. After 20 minutes the reaction mixture was purged with nitrogen for 10 minutes and was then treated with 5 mL dimethylsulfide. The reaction mixture was allowed to warm gradually to room temperature. After 15 hours the reaction mixture was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][N:4]=1.[N:12](OC(C)(C)C)=[O:13].CC([O-])(C)C.[K+].Cl>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9](=[O:11])/[CH:10]=[N:12]/[OH:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)=O)cn1
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)/C=N/O)cn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Methoxy-5-acetylpyridine (12.1 g) and t-butyl nitrite (9.92 g) were dissolved in THF (120 ml). The solution was cooled at 0-5° C. To the solution was added t-BuOK (10.8 g) at 5-25° C. The reaction mixture was stirred at 25° C. for 2 hours. To the mixture was added 1N HCl (105 ml). The solution was portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with 10% aq. NaOAc and brine successively, dried over MgSO4. Evaporation of solvent in vacuo gave solid residue. The residue was pulverized with IPE (150 ml). The precipitated crystals were collected by filtration, to give (1E)-(6-methoxy-3-pyridyl)(oxo)acetaldehyde oxime as a solid (5.45 g) (anti, syn mixture (anti:syn=1:1)). Evaporation of solvent in the filtrate gave a residue. The residue was pulverized with IPE. The precipitated crystals were collected by filtration, to give (1E)-(6-methoxy-3-pyridyl)(oxo)acetaldehyde oxime as a solid (2.5 g) (anti, syn mixture (anti:syn=1:1)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:13]3[C:14]([CH3:36])=[C:15]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:38])[CH3:37])=[CH:5][CH:4]=1>CCCCCC.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:36])=[C:15]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:38])[CH3:37])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)c3c(C)c(N4CCC(c5ccc(OC)c(OC)c5)CC4)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C2c3c(C)c(N4CCC(c5ccc(OC)c(OC)c5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 82 %

Procedure:
Using 3-(4-methoxyphenyl)-5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 85, the title compound was synthesized in the same manner as in Example 46. Yield 82%. mp. 154–156° C. (hexane-methanol).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[C:14]2[N:15]([C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:32]=2)[CH:16]=[CH:17][C:18]=1[C:19]([O:22][Si](CC)(CC)CC)([CH3:21])[CH3:20]>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.C1COCC1>[F:12][C:13]1[C:14]2[N:15]([C:30]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=3)=[CH:31][N:32]=2)[CH:16]=[CH:17][C:18]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(F)c(C(C)(C)O[Si](CC)(CC)CC)ccn12
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2c1F
Reaction time: 3 h

Procedure:
2-Trifluoromethyl-4-chloropyrimidine (100 mg, 0.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) were combined with a THF solution of 8-fluoro-3-(tri-n-butylstannyl)-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (circa 0.2 M; 3 ml, circa 0.6 mmol) and heated to reflux, with stirring, for 3 h. After cooling, the solution was concentrated onto silica and purified by column chromatography (silica; 50% EtOAc/isohexane), then the silyl protection removed by treatment with an ethanolic solution of 37% hydrochloric acid (5 drops in 2 ml of ethanol), affording the title compound as a white amorphous solid: δH (360 MHz, CDCl3) 1.77 (6H, s), 7.48 (1H, m), 7.78 (1H, d, J 5.6), 8.42 (1H, s), 9.42 (1H, m), 9.71 (1H, d, J 7.6); m/z (ES+) 341 (100%, [MH]+).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:7]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=[CH:10][C:6]=2[C:5](=[O:21])[NH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C@@H:3]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:21])[NH:4]1)[CH3:2]
Reactant: CC[C@H]1NC(=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@H]1NC(=O)c2cc[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of (R)-6-ethyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505e, 3.49 g, 11.47 mmol) in MeOH (50 mL) in an ice bath was added potassium carbonate (3.17 g, 22.93 mmol) in one portion. The resulting white suspension was stirred in an ice bath for 1 h and at RT for 1 h. The suspension was filtered through a pad of Celite washing with MeOH. 10 g silica gel was added to the filtrate and concentrated in vacuo. It was purified on the ISCO Combiflash RF (40 g Grace Reveleris column, using a gradient of 0-20% 2 M NH3/MeOH in DCM) affording (R)-6-ethyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (966 mg, 6.43 mmol, 56% yield) as a tan solid. m/z (ESI, +ve) 151.1 (M+1)+. The material was further purified by chiral SFC (mobile phase CO2/15% MeOH (20 mM NH3), chiral column AS (250×30 mm), wave length 245 nm, flow rate 120 mL/min) The second eluting peak was collected and concentrated in vacuo to give (R)-6-ethyl-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (505f, 450 mg, 3.00 mmol, 26% yield) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (1H, br. s.), 7.55 (1H, s), 6.83 (1H, t, J=2.3 Hz), 6.07 (1H, dd, J=2.7, 1.6 Hz), 4.31 (1H, t, J=5.9 Hz), 1.50-1.74 (2H, m), 0.85 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 151.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:2]2[N:3]=[N:4][C:5]([N:8]3[CH:12]=[CH:11][CH:10]=[N:9]3)=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-n2cccn2)nn1
Reactant: CC(C)(CN)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNc1ccc(-n2cccn2)nn1)c1ccc(F)cc1
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 10.9 %

Procedure:
To a 5 mL microwave vial was added 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (320 mg, 1.8 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (386 mg, 2.3 mmol, 1.3 equiv), diisopropylethylamine (620 μL, 3.6 mmol, 2.0 equiv), and NMP (4 mL). The reaction was heated in a microwave reactor to 250° C. and stirred for 15 min. A portion (roughly a third) of the reaction was purified by reverse phase chromatography and then silica gel chromatography (10% MeOH/DCM) to give 61 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(1H-pyrazol-1-yl)pyridazin-3-amine, m/z=312.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(O)C.[I:12]I>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[C:7]([I:12])=[CH:6][C:5]([F:8])=[CH:4][N:3]=1
Reactant: II
Reactant: Nc1ccc(F)cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ncc(F)cc1I
Reaction time: 24 h
Yield: 25.2 %

Procedure:
5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulfate and 400 ml of ethanol are placed in a 500 ml two-necked flask equipped with a magnetic stirrer. 11.31 g (44.6 mmol) of iodine powder are then added portionwise. Stirring is continued at room temperature for 24 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 ml) and sodium carbonate solution (200 ml). After separation, the organic phase is successively washed with aqueous 25% sodium thiosulfate solution, with saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 2.67 g (11.22 mmol) of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3([CH3:29])OCC[O:25]3)=[CH:20][C:19]=2[O:30][CH2:31][O:32][CH3:33])=[N:6][CH:7]=1.Cl>C1COCC1>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:35])=[O:34])=[C:19]([O:30][CH2:31][O:32][CH3:33])[CH:20]=1)(=[O:25])[CH3:29]
Reactant: COCOc1cc(C2(C)OCCO2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1cc(C(C)=O)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.9 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[2-(methoxymethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)benzoylamino]benzamide (4.37 g, 8.78 mmol) in THF (150 mL) at 0° C. was added 5 N HCl (28 mL, 140 mmol). The resulting solution was stirred at room temperature for 6 h. The solution was concentrated to the half of its original volume, diluted with H2O (300 mL) and basified with 2 N NaOH (˜pH 9). The solid obtained was filtered, washed with H2O (3×50 mL), and dried to give the expected product (3.82 g, 96%),
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][OH:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.C1COCC1>[Si:20]([O:14][CH2:13][C@H:2]([NH2:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CO)Cc1c[nH]c2ccccc12
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of D-Tryptophanol (1.024 g) and imidazole (403 mg) in DCM (40 ml) and THF (8 ml) was added a solution of tert-butyldimethylsilyl chloride (0.852 g) in DCM (5 ml) dropwise. The reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and the reaction mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and methyl 2-bromo-2-methylpropanoate (1.25 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.97 g, 79%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:112][C:113]([CH3:133])=[CH:114][CH2:115][CH2:116]/[C:117](/[CH3:132])=[CH:118]/[CH2:119][CH2:120]/[C:121](/[CH3:131])=[CH:122]/[CH2:123][S:124][CH2:125][C@H:126]([NH2:130])[C:127]([OH:129])=[O:128]>C(Cl)Cl>[CH3:4][C:2]([CH3:1])([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:130][C@H:126]([C:127]([OH:129])=[O:128])[CH2:125][S:124][CH2:123]/[CH:122]=[C:121](\[CH3:131])/[CH2:120][CH2:119]/[CH:118]=[C:117](\[CH3:132])/[CH2:116][CH2:115][CH:114]=[C:113]([CH3:133])[CH3:112])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-glycine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (78 mg, 18%) to yield Compound N-4. 1H-NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 1.60 (bs, 6H), 1.67 (s, 3H), 1.68 (s, 3H), 1.97 (t, J=7.5 Hz, 2H), 2.01-2.15 (m, 6H), 2.85 (bd, J=13 Hz, 1H), 3.01 (bd, J=13 Hz, 1H), 3.14-3.23 (m, 2H), 3.81 (d, J=16.5 Hz), 4.01 (d, J=12 Hz, 1H), 4.77 (m, 1H), 5.09 (m, 2H), 5.30 (1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.1, 17.7, 25.7, 26.5, 26.7, 28.4, 30.0, 32.9, 39.7, 39.7, 43.8, 51.7, 80.7, 119.5, 123.8, 124.3, 131.4, 135.4, 140.1, 156.3, 169.8, 172.9; ES-MS: mass calcd for Chemical Formula: C25H42N2O5S 482.3. Found (M+Na) m/z 505.1.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[F:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:43]([C:41]3[CH:40]=[CH:39][C:38]([F:46])=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[N:42]=3)=[O:44])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.7 mg, 0.018 mmol), HATU (15.0 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 1 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18, 30×10 mm 5 μm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the sub-title compound as a colorless gum (4.0 mg, 42%). LCMS calc. for C32H35F3N5O5 (M+H)+: m/z=626.3. Found: 626.1.