Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:17]([OH:32])[C@H:18]([OH:31])[C@@H:19]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH2:20][OH:21])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].[OH-].[Na+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>>[CH2:39]([O:38][C:36]([NH:25][C@H:24]([C:23]([NH:22][C@@H:19]([CH2:20][OH:21])[C@@H:18]([OH:31])[C@@H:17]([OH:32])[C@H:2]([OH:1])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:4])=[O:30])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid (Compound 3) (2.28 g) and 0.2N aqueous sodium hydroxide solution (25 ml) were added benzyl chloroformate (0.714 ml) and 1N aqueous sodium hydroxide solution at 0° C. After stirring at room temperature for 3 hours, the mixture was washed with diethylether and acidified with 1N hydrochloric acid (20 ml). The aqueous solution was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was recrystallized from diethylether-hexane to afford the title compound(1.51 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>OS(O)(=O)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
To a solution of 2-Benzyloxy-6-nitro-phenylamine (I-107, 1.52 g, 0.0062 mol) in acetic anhydride (1.27 g, 0.0125 mol), 4 drops of conc. H2SO4 was added at room temperature and stirred for one minute and then the reaction flak was immersed in an oil bath maintained at 90° C. After 2 minutes, the solidified reaction mixture was taken in water (20 mL) and filtered the solid. Solid was further washed with water (20 mL×2) and dried under high vacuum to afford N-(2-benzyloxy-6-nitro-phenyl)acetamide, I-108 (1.59 g).
Reaction SMILES: CC(CC(O)C(C)(C)C=C=C)=C.[CH3:13][C:14](=[CH2:17])[CH2:15]Cl.[CH3:18][C:19]([CH3:27])([CH:22]=[C:23]=[C:24]([CH3:26])[CH3:25])[CH:20]=[O:21]>>[CH3:13][C:14]([CH2:15][CH:20]([OH:21])[C:19]([CH3:27])([CH3:18])[CH:22]=[C:23]=[C:24]([CH3:26])[CH3:25])=[CH2:17]
Reactant: CC(C)=C=CC(C)(C)C=O
Reactant: C=C(C)CCl
Agent: C=C=CC(C)(C)C(O)CC(=C)C
Product: C=C(C)CC(O)C(C)(C)C=C=C(C)C
Yield: 91.9 %

Procedure:
2,5,5,8-tetramethylnona-1,6,7-trien-4-ol (2b) was prepared as described for 2a from 8.72 g (0.36 mole) of Mg, 32.65 g (0.36 mole) of β-methylallyl chloride and 16.61 g (0.12 mole) of 1b. The work up resulted in 21.44 g (92%) of 2b. Bp. 61°-2° C./0.3 mm Hg, nD16 1.4810.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)[CH2:7][CH2:6]1)[CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[CH2:3]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:22])=[CH:15]3)[CH2:9][CH2:10]1)[CH3:4]
Reactant: CCN1CCC(Nc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(Nc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Yield: 60.6 %

Procedure:
A mixture of 0.15 g 5-(1-ethyl-piperidin-4-ylamino)-1H-indole-2-carboxylic acid (intermediate 3), 0.16 g O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 0.323 g DIPEA and 0.044 g morpholine in 2 ml DMF was reacted for 1 h at room temperature and evaporated to dryness. The residue was treated with ethyl acetate, water and NaHCO3 aq. The aqueous phases were further extracted with ethyl acetate and the combined organic phases were dried over Na2SO4, filtered and evaporated. The residue was further purified by chromatography and crystallization to yield 0.09 g (60%) of the title compound as light brown solid. MS (m/e): 357.4 (MH+, 100%).
Reaction SMILES: C(F)(C(F)(F)F)=C(F)F.C(F)(C(F)(F)F)=C(F)F.C(F)(C(F)(F)F)=C(F)F.[F:28][C:29]([F:54])([F:53])[C:30](F)=[C:31]([C:42]([F:51])([C:47]([F:50])([F:49])[F:48])[C:43]([F:46])([F:45])[F:44])[C:32]([F:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34].[C:55]1([Li])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CCOCC>[C:55]1([C:30](=[C:31]([C:32]([F:41])([C:37]([F:38])([F:39])[F:40])[C:33]([F:34])([F:35])[F:36])[C:42]([F:51])([C:43]([F:46])([F:45])[F:44])[C:47]([F:50])([F:49])[F:48])[C:29]([F:54])([F:53])[F:28])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: FC(=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: [Li]c1ccccc1
Agent: FC(F)=C(F)C(F)(F)F
Solvent: CCOCC
Product: FC(F)(F)C(=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, 1.0 mmol (459 mg) of hexafluoropropene trimer mixture [including 5 wt % of perfluoro-(3-ethyl-2,4-dimethyl-2-pentene)] comprising perfluoro-(4-methyl-3-isopropyl-2-pentene) as a main component was put in a 100 ml egg-plant-shaped flask with a three-way stopcock having a magnet stirrer made of Teflon (R) therein. Then, 10 ml of anhydrous ether dry-distilled on sodium was added into the mixture, and stirringly dissolved therein. 0.5 ml (1.0 mmol) of cyclohexane-ether solution containing 17% of phenyl lithium was dropped into the mixture from a dropping funnel in the interval of about 3 minutes, while maintaining the mixture at about −78° C. by cooling the reaction vessel in a dry ice-ethanol bath. After continuously stirring at about −50° C. for about 3 hours, the resulting reacted mixture became a yellow solution including a brown solid. The reaction mixture was poured into 30 ml of ice water. Then, 20 ml of ether was added therein to extract a target compound, and the extracted compound was rinsed with 30 ml of salt solution. After the reacted ether mixture was dried with magnesium sulfate for one night, the resulting mixture was subjected to reduced-pressure distillation under a vacuum of 5 mmHg to remove ether, and then subjected to reduced-pressure distillation under a vacuum of 10 mmHg. As a result, a mixture of 3 different conformational isomers of 2-phenyl-perfluoro-(4-methyl-3-isopropyl-2-pentene) was obtained. The respective structures of the obtained compounds were determined by 19F-NMR, 1H-NMR, GC-MS and others. The yields of conformational isomers A, B and C of 2-phenyl-perfluoro-(4-methyl-3-isopropyl-2-pentene) calculated from the integral ratio of the peak areas of the 19F-NMR spectrum were about 24% , 16% and 12%, respectively.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])([OH:10])=[O:8]
Reactant: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)O
Yield: 100.3 %

Procedure:
A solution of di-tert-butyl 2-[[[2-(benzyl-carboxy)propyl]tert-butoxyphosphinyl]methyl]pentane-1,5-dioate (8.9 g, 16.1 mmol), palladium on carbon catalyst (10%, 1.0 g) and ethyl acetate (100 ml) was shaken under hydrogen (60 psi) for 16 hours. The reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure leaving a clear oil (7.5 g, 100%). 1H NMR (CDCl3) δ 1.3 (d, 3H), 1.4-1.5 (m, 27H), 1.8 (m, 2H), 1.9 (m, 2H), 2.2 (m, 4H), 2.7 (m, 1H), 2.9 (m, 1H).
Reaction SMILES: COC1C=C(OC)C=C(OC)C=1C[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(Cl)Cl>O>[SH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Oc1cccc(-c2ccccc2S)c1
Yield: 66.9 %

Procedure:
2′-(2,4,6-trimethoxybenzylthio)biphenyl-3-ol (0.948 g, 2.48 mmol) was treated with TFA:triethylsilane:DCM (8 ml:3 ml:80 ml). The solution was stirred 30 min. before 40 ml water was added and the mixture was extracted with DCM (2×80 ml). The organic was washed with water, brine, dried over magnesium sulfate and concentrated. The residue was purified by silica flash chromatography (hexane:ethyl acetate 80:20) to afford 0.335 g product (1.66 mmol, 67% yield).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[C:8](Cl)(=[O:10])[CH3:9]>N1C=CC=CC=1>[CH3:1][C@H:2]([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CC(=O)Cl
Reactant: C[C@H](CO)C(=O)O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 520 %

Procedure:
To a solution of (2R)-2-methyl-3-hydroxypropionic acid (10.0 g, 100 mmol) in pyridine (30 mL) as added acetyl chloride(11.8 g, 15.0 mmol) at 0° C., and the reaction mixture was warmed to rt. After being stirried for 3 h, the reaction mixture was quenched with 1N HCl (30 mL), and the pH of the solution was adjusted to 3-4. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl at 4-5 times, dried over MgSO4, filtered, and concentrated to give the title compound (11.4 g, 95.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:42][CH2:43][C:44](=[O:56])SC1C=CC(C(F)(F)F)=CC=1)[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:44](=[O:56])[CH2:43][CH2:42][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
A solution of benzyl 2-aminoacetate hydrochloride (15.8 mg, 0.0784 mmol) and DIPEA (0.0136 ml, 0.0784 mmol) in DMF (0.0784 ml) was added to a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-((4-trifluorophenyl)thio)-5-oxopentanoate (Compound 5f-2) (30.0 mg, 0.0603 mmol) in DMF (0.541 ml) and water (0.200 ml), and the mixture was stirred at 50° C. for 45 minutes. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 5-((2-(benzyloxy)-2-oxoethyl)amino)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (Compound 5d-2) (26.4 mg, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[CH3:23][S-:24].[Na+]>C(#N)C>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH2:12][NH:11][C:10]1[C:5]2[N:6]([C:21]([CH3:22])=[C:3]([CH2:2][S:24][CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CSCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (0.2 g, 0.64 mmol) and sodium methanethiolate (0.1 g, 1.3 mmol) were added to acetonitrile (10 ml) and stirred for 4 h. at room temperature. The solvent was evaporated under reduced pressure and to the residue were added methylene chloride and water. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether (1:2) as eluent and crystallization from diethyl ether:petroleum ether (1:2) gave 0.05 g (24%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][C:23](O)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1.P(C#N)(=O)(OCC)OCC>O.C(N(CC)CC)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:22][C:23]([N:38]4[CH2:39][CH2:40][C:35]5([O:34][CH2:33][CH2:32][O:31]5)[CH2:36][CH2:37]4)=[O:24])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CC2(CCN1)OCCO2
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a mixture of 20.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid and 250 ml of dimethylformamide were added 16 ml of triethylamine, 10.4 g of 1,4-dioxa-8-azaspiro[4.5]decane and 16 ml of diethyl phosphorocyanidate, and the mixture was stirred for 20 minutes. After addition of water, the resulting crystalline precipitate was collected by filtration, washed with water and dried to give 26.4 g of crude crystals. Recrystallization from methylene chloride-ethyl acetate gave 27.1 g of colorless crystals melting at 238°-239° C.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH3:17])[C:7]2=[O:18].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[F:19][C:3]1[C:2]([C:27]2[NH:26][C:25]3[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=3[CH:28]=2)=[C:11]2[C:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]([NH:12][C:13]3([CH3:16])[CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC2(C)CC2)nc2c(Br)c(F)ccc2c1=O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C)c(NC5(C)CC5)nc34)[nH]c21
Temperature: 40 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510a, 88 mg, 0.270 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 109 mg, 0.324 mmol), X-Phos precatalyst II (10.61 mg, 0.013 mmol), and potassium phosphate (172 mg, 0.809 mmol) in 1,4-dioxane (2.2 mL)/water (0.54 mL) was sparged with nitrogen for 3 min at RT; the red solution was then heated to 40° C. for 1 h when starting bromide and product were observed via LCMS. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (120 mg) was added, and the red solution was stirred for another 1 h at 40° C. when more product was observed via LCMS. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-6% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510, 15 mg, 0.039 mmol, 14% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.89 (m, 2H) 0.96-1.05 (m, 2H) 1.38 (d, J=6.65 Hz, 3H) 1.54 (s, 3H) 3.38 (s, 3H) 4.66 (q, J=6.39 Hz, 1H) 6.80 (d, J=3.91 Hz, 1H) 7.11 (dd, J=11.93, 8.80 Hz, 1H) 7.75 (s, 1H) 7.84 (s, 1H) 7.85-7.90 (m, 1H) 13.39 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.44 (s, 1F). MS (ESI, pos. ion) m/z: 382.1 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>ClCCCl.CN(C=O)C.Cl[Ti](Cl)(Cl)Cl>[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[C:30]=3[C:6]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[O:8])=[CH:25][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1ccc(I)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
A slurry of 4-iodobenzoic acid (7.67 g, 30.9 mmol) in 300 mL of 1,2-dichloroethane and 2 drops of DMF was treated with SOCl2 (11.3 mL, 154.6 mmol). The resulting mixture was heated at reflux overnight. The clear solution was evaporated in vacuo, then the solid residue was resuspended in 1,2-dichloroethane and reconcentrated. The crude acid chloride was dissolved in 300 mL of 1,2-dichloroethane, and 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (5.0 g, 15.5 mmol) was added. The solution was cooled to 0° C. and treated with TiCl4 (8.5 mL, 77.3 mmol). After 5.5 h, the reaction mixture was carefully poured into 600 mL of saturated aqueous NaHCO3. The layers were separated, and the aqueous phase was extracted with CHCl3 (3×300 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by PrepLC (SiO2; 1% MeOH in CHCl3, saturated with NH4OH) afforded 6.79 g (12.3 mmol; 79%) of the title product as a yellow foam.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:33]1[CH:34]=[CH:35][C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M54) (250 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[NH:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH2:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:36][NH:35][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC(=O)OC(C)(C)C)ccn34)c12
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylicacid (250 mg, 0.550 mmol) in DMF (5 mL) was added tert-butyl hydrazinecarboxylate (80.0 mg, 0.605 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (116 mg, 0.605 mmol), 1H-benzo[c/][1,2,3]triazol-1-ol hydrate (92.7 mg, 0.605 mmol) and triethylamine (66.8 mg, 0.660 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided tert-butyl 2-(3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carbonyl)hydrazinecarboxylate (188 mg), to which was added TFA/DCM (2 mL/3 mL). The mixture was stirred for 30 minutes and concentrated to give the product as the TFA salt (156 mg).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6]1)=[O:4].C1(C)C=CC=CC=1.C[O-].[Na+]>COC(C)(C)C>[CH2:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H]1CC[C@H](CC(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C

Procedure:
A 2-necked round bottom flask, which had been dried and cooled under argon, was charged with cis/trans-4-isobutyl-cyclohexanecarboxylic acid methyl ester (7:3) (0.5 g, 2.5 mmol), dry toluene (10 ml) and sodium methoxide (0.41 g, 7.6 mmol). The reaction mixture was heated at reflux for 96 h. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether (100 ml) and washed with ice-cold aqueous hydrochloric acid solution (pH 1). The aqueous layer was extracted with one 50-ml portion of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a (15:85) cis/trans mixture. MS m/e: 183 ([M−H]−)