Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=[C:26]2[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(CCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (1.10 g, 5.61 mmol) in DCM (20 mL) was added trimethylaluminium (5.7 mL, 11.4 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(3-(3-fluorophenyl)propanamido)but-2-enoate (1.00 g, 3.77 mmol) in DCM (8 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as an orange solid (1.10 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:7]=1[CH:8]=O)(=[O:4])=[O:3].Cl.[NH2:19][OH:20]>C(O)C>[OH:20][N:19]=[CH:8][C:7]1[CH:10]=[C:11]([CH:12]=[CH:13][C:6]=1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C=NO)c1
Yield: 88.9 %

Procedure:
A mixture of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde (2.56 g, 0.01 mol) and hydroxylamine hydrochloride (0.87 g, 0.0125 mol) in ethanol (40 mL) was heated at reflux for 2 h. The mixture was filtered hot, and the filtrate was concentrated to dryness. The residue was suspended in water. The solid was collected by filtration and recrystallized from ethyl acetate-hexane to give 2.42 g (89%) of methyl 3-[(N-hydroxyimino)methyl]-4-[(methylsulfonyl)amino]benzoate as an off-white powder, mp 160° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[C:9]2[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][C@H:16]1[C:9]2[C:8]([C:25]3[CH:26]=[CH:27][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ncnc3c2[C@H](C)CC3)cc1
Temperature: 110 °C
Yield: 74.5 %

Procedure:
A solution of Na2CO3 (1.65 mL, 1M) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (253 mg, 1.50 mmol) and 4-methoxycarbonylphenylboronic acid (297 mg, 1.65 mmol) in 1,4-dioxane (4.5 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(dppf)Cl2 (98 mg, 0.12 mmol) was added in one portion. The reaction vial was sealed and heated in microwave to 110° C. for 30 minutes. Water (20 mL) was added to the mixture and extracted with DCM (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-50% EtOAc/hexane gradient elution) to give (R)-methyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoate as an oil (300 mg, 70%). 1H NMR (CDCl3, 500 MHz) δ 9.07 (s, 1H), 8.16 (d, =8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 3.96 (s, 3H), 3.81-3.76 (m, 1H), 3.15-3.00 (m, 2H), 2.44-2.40 (m, 1H), 1.78-1.74 (m, 1H), 1.01 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:25])[CH2:13][O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Si:26]([O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=3)[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[Na+]>C(O)C>[Si:26]([O:33][CH:34]1[CH2:35][CH2:36][N:37]([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][C:49]([O:14][CH2:13][C@H:12]([OH:25])[CH2:11][CH2:10][N:3]4[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]4[Cl:1])=[CH:48][CH:47]=3)[CH2:42][CH2:41]2)[CH2:38][CH2:39]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C2CCN(c3ccc(O)cc3)CC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCN(C2CCN(c3ccc(OC[C@H](O)CCn4cc([N+](=O)[O-])nc4Cl)cc3)CC2)CC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
Toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (848 mg) and 4-[4-(tert-butyl-dimethylsilanyloxy)[1,4′]bipiperidinyl-1′-yl]phenol (850 mg) were suspended in ethanol (30 ml). Tripotassium phosphate (1.02 g) and sodium iodide (359 mg) were added to the suspension, and the mixture was stirred at 75° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Insoluble matter that was precipitated by adding isopropyl ether to the residue was collected by filtration to afford the title compound as a pale brown powder (470 mg).
Reaction SMILES: CN1[C:7](C)(C)[CH2:6][CH2:5][CH2:4][C:3]1(C)[CH3:10].C#CCCCC.Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20]>CN(C)C1C=CN=CC=1.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.ClCCl>[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:10]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CN1C(C)(C)CCCC1(C)C
Reactant: CCCCOC(=O)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCCCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC#CC(=O)OCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
3.25 g (2.75 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into 250 ml of dichloromethane in a 500 ml round-bottomed flask under argon. The dark brown solution is stirred at room temperature for 1 h. Then 150 mg (1.25 mmol) of 4-dimethylaminopyridine, 21.5 g (137.5 mmol) of 1,2,2,6,6-pentamethylpiperidine and 10.25 g (125 mmol) of 1-hexyne are added and heated to reflux at 40° C. Subsequently, 17 g (125 mmol) of n-butyl chloroformate are added dropwise over the course of 60 min. After a reaction time of 24 h, the reaction mixture is worked up by distillation to isolate n-butyl 2-heptynoate in 90% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([CH3:29])[CH2:12][C:13]2(O)[CH2:18][CH2:17][C:16]([N:25]([CH3:27])[CH3:26])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:2]1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.ClCCl>ClCCCl>[CH3:26][N:25]([CH3:27])[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:18][C:13]2([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][C@@H:11]([CH3:29])[CH2:12]2)[CH2:14][CH2:15]1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1Cc2c([nH]c3ccccc23)C2(CCC(c3ccccc3)(N(C)C)CC2)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of (R)-1-(3-(1H-indol-3-yl)-2-methylpropyl)-4-(dimethylamino)-4-phenylcyclohexanol (100 mg, 0.25 mmol) in anhydrous 1,2-dichloroethane (10 mL) was mixed with trifluoromethane sulphonic acid trimethylsilyl ester (222 mg, 181 μL, 1 mmol) and stirred for 4 h at 50° C. After adding dichloromethane (10 mL) the solution was washed with 1 M potassium carbonate solution (2×10 mL), water (10 mL) and saturated sodium chloride solution (10 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (90 mg) was taken up in methanol (10 mL) and stirred for 16 h at room temperature. The precipitated solid was separated from the solution by decanting, the remaining solid once again mixed with methanol, stirred and decanted, as a result of which Example No. 15 was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.CN(C)C=O.[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[NH:6]1[CH:7]=[CH:8][N:9]=[C:5]1[CH2:4][NH:3][C:17](=[O:19])[CH3:18]
Reactant: NCc1ncc[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.34 g of 2-aminomethylimidazole dihydrochloride was added to 20 ml of N,N-dimethylformamide in a nitrogen atmosphere. Under ice-cooling, 0.40 g of sodium hydride (60% oily) was added thereto and the resulting mixture was subjected to ultrasonication for 30 minutes. To the reaction mixture were added 20 ml of pyridine and 10 ml of acetic anhydride and the obtained mixture was stirred at room temperature for 2 days. After concentrating under reduced pressure, the residue was distributed into water and ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure to thereby give 0.24 g of the title compound as a pale brown solid.
Reaction SMILES: [CH:1]1([C:7](=[O:27])[CH:8]=[CH:9][CH:10]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:7](=[O:27])[CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Yield: 69.6 %

Procedure:
A solution of 7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (2.0 g.) in ethanol (50 ml.) was catalytically reduced with hydrogen at a pressure of 7 kg/cm2 and in the presence of a 5% palladium on charcoal catalyst (0.5 g.) at room temperature for 3 hours. The catalyst was then filtered off and the ethanol evaporated off from the filtrate, to give 7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (1.4 g.), νmax 3450 cm-1, 1700 cm-1, 1040 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2Cl.[NH:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: Fc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
6-Bromo-4-chloro-2-(2-fluoro-phenyl)-quinazoline from Step D (1 g, 2.9 mmol) was dissolved in N,N-dimethyl formamide (3 ml) and to it was added 1H-Pyrrolo[3,2-c]pyridine (0.346 g, 2.9 mmol) followed by cesium carbonate (0.961 g, 2.9 mmol). The mixture was magnetically stirred at room temperature for 1 hr. Water was added and the product filtered to yield title compound (1.236 g, 98%). MS (ES) 420 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[C:13]([Mg]Cl)[CH:12]=1>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:19])[CH:12]=1)[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: Cc1cccc([Mg]Cl)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(C)(O)c2cccc(O)c2)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of m-tolylmagnesium chloride in tetrahydrofuran (4.4 ml) as starting materials, the title compound (329.0 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([OH:18])=O)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O.C1C(N=NC2C=CC(N)=C(S([O-])(=O)=O)C=2)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([Cl:21])=[O:18])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CN1c2ccccc2C(C(=O)O)c2ccccc21
Agent: Nc1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2ccccc2C(C(=O)Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Into a 50 mL round bottom flask equipped with magnetic stirrer and under an argon atmosphere was charged a solution of 0.305 parts of 10-methylacridan-9-carboxylic acid (77) in 15 mL of dichloromethane and cooled to 5° C. (ice-water). Then, 1.05 parts of thionyl chloride was added to the cold yellow acid solution and stirred for 1.5 hr at a temperature below 15° C. The light red brown solution was concentrated under reduced pressure and the residue was dried for 15 min to give acid chloride (78).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([C:26]2[O:30][C:29]([CH:31]([OH:55])[C@@H:32]([NH:35][C:36]([C@@H:38]([NH:46][C:47]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:48])[CH2:39][C:40]([F:45])([F:44])[CH2:41][CH2:42][CH3:43])=[O:37])[CH2:33][CH3:34])=[N:28][N:27]=2)[CH2:25][CH2:24]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:23]1([C:26]2[O:30][C:29]([C:31]([C@@H:32]([NH:35][C:36]([C@@H:38]([NH:46][C:47]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:48])[CH2:39][C:40]([F:45])([F:44])[CH2:41][CH2:42][CH3:43])=[O:37])[CH2:33][CH3:34])=[O:55])=[N:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(C2CC2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(=O)c1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.7 %

Procedure:
Dess-Martin Periodinane (15 wt % in DCM, 0.79 gm, 0.28 mmol) is added to a solution of morpholine-4-carboxylic acid ((S)-1-{(S)-1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (67 mg, 0.14 mmol) in dry methylene chloride (10 mL) and stirred at room temperature for 2.5 hours. The reaction is quenched with a solution of Na2S2O3 (110.68 mg, 0.70 mmol) in aqueous NaHCO3. The organic layer is separated and the aqueous extracted with dichloromethane. The organic extracts are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid {(S)-1-[(S)-1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propylcarbamoyl]-3,3-difluoro-hexyl}-amide as a powder (48 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH2:30][CH3:31])=[C:27]([Cl:29])[N:28]=3)=[O:23])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH2:30][CH3:31])=[C:27]([Cl:29])[N:28]=3)=[O:23])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)O)c3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185e) (120 mg) was dissolved in methanol (4 ml) and THF (4 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for one hour. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/methanol/hexane solvent to obtain 90 mg of the title compound as crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH:23]2[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:22]12>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH:22]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH:23]3[CH2:24][CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC2CCN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)C2C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) and tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (190 mg, 0.9 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylate as a solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:43][CH3:44])=[C:17]([NH:20][C:21](=[O:42])[CH:22]=[CH:23][CH2:24][N:25]([CH2:34][CH:35](OCC)[O:36][CH2:37][CH3:38])[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28]CC)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.N>>[Br:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:43][CH3:44])=[C:17]([NH:20][C:21](=[O:42])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH:35]([O:36][CH2:37][CH3:38])[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(CN(CC=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OC)CC(OCC)OCC)OCC
Agent: Cl
Agent: N
Product: CCOC1CN(CC=CC(=O)Nc2cc3c(Nc4cccc(Br)c4)ncnc3cc2OC)CC(OCC)O1
Temperature: 0 °C

Procedure:
1 ml of ice-cooled concentrated hydrochloric acid is added to 340 mg of 4-[(3-bromophenyl)amino]-6-((4-[N,N-bis(2,2-diethyoxyethyl)amino]-1-oxo-2-buten-1-yl)amino)-7-methoxy-quinazoline while cooling with an ice bath. The mixture is left to stand for 3 hours before 1.5 ml of concentrated ammonia solution is added dropwise while cooling with an ice bath for working up. The precipitate formed is suction filtered and washed with water. The crude product is purified by chromatography on a silica gel column with methylene chloride/methanol (20:1) Yield: 50 mg (17% of theory) Melting point: 133-138° C. Mass spectrum (EI): m/z=585, 587 [M]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([CH:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([O:14][CH3:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
To a solution of methyl (4-fluoro-2,6-dinitrophenyl)acetate from Step B (9.51 g, 36.8 mmol) and ethyl bromoacetate (8.17 mL, 73.6 mmol) in DMF (100 mL) was added cesium carbonate (18.0 g, 55.2 mmol). The reaction mixture was stirred for 16 h and then poured onto H2O (500 mL). The aqueous layer was extracted with EtOAc (3×250 mL). The combined organic layers were washed with H2O (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=345 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]4[C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[N:37]=[C:33]4[N:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O)=CC=1.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([CH2:12][CH2:13][CH2:14][N:15]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:34]3[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]3[N:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C(=O)OC(C)(C)C)c2ccc(-c3ccnc4nc5ccccc5n34)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2ccnc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)(tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate (130 mg, 0.23 mmol) in DMF (2 mL) was added NaN3 (83 mg, 1.3 mmol). The mixture as stirred at rt for 2 h and concentrated under reduced pressure to remove volatiles. The residue was taken up to DCM (50 mL) and washed with water (2×50 mL) and dried over MgSO4 and concentrated to afford the title compound as a yellow solid. The product was used directly for the next reaction without further purification. MS (ESI) m/z [M+H]+444.