Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].[C:19]1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>CCCCCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:19])[CH3:10]
Reactant: Cc1ccccc1
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1C(C)(C)c1ccccc1OC

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (15.6 g), toluene (35 ml) and anisole (35 ml) were combined in a flask and 35 ml of a 3.7M hexane solution of Red-Al was added. The mixture was heated to reflux with stirring whereupon it turned dark red. After 2 hours the heat was removed and the mixture was allowed to stir overnight. The excess hydride reagent was carefully quenched with 1.0N hydrochloric acid. The mixture was then diluted with ether and the ethereal solution separated, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a golden-brown oil. This was triturated with hexane to obtain 3.70 of the title compound. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)(=O)C.C[O-].[Na+].Cl>CO.O1CCOCC1>[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: CC(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
To a solution of (3S)-3-acetoxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (5.51 g, 17.8 mmol) (obtained as described in Reference Example 53(1)) in methanol (200 ml) was added a catalytic amount of sodium methoxide, and the mixture was stirred at room temperature for 4.5 hours. After checking the completion of the reaction, a solution of 4N hydrogen chloride in 1,4-dioxane (4.3 ml) was added thereto to neutralize the reaction mixture. The resulting reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over-anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3S)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.00 g, yield 84%) as white crystals.
Reaction SMILES: C(OC([N:8]([CH:17]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:28]2)[CH:22]=1)[CH3:18])[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH2:28][CH:27]([C:23]3[CH:22]=[C:21]([C:20]#[C:19][CH:17]([NH:8][OH:9])[CH3:18])[CH:26]=[CH:25][CH:24]=3)[O:31][N:30]=2)=[CH:37][CH:36]=1
Reactant: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)NO
Temperature: 0 °C
Yield: 69 %

Procedure:
To a solution of the product of Step 1, above (10, 0.5 g, 1.5 mmol), in triethylamine (4 ml) was added bis(triphenylphosphine)palladium (II) chloride (55 mg, 0.078 mmol) and N,O-bis(tert-butoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (840 mg, 2.8 mmol) in triethylamine (1 ml) under a N2 atmosphere. The reaction mixture was stirred at 75° C. for 1.5 hours, then concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 ml) and the organic layer was washed with 1N HCl (10 ml), saturated aqueous NaHCO3 (10 ml) and brine (10 ml). The combined extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate:n-hexane=1:6) to give N,O-bis(tert-butoxycarbonyl)-[4-(3-[4,5-dihydro-3-(4-fluorophenyl)isoxazol-5-yl]phenyl)-3-butyn-2-yl]hydroxylamine. To a solution of the protected hydroxylamine thus obtained, in CH2Cl2 (3 ml) cooled to 0° C., was slowly added TFA (0.72 ml, 9.3 mmol). The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into ice cold saturated aqueous NaHCO3 (20 ml) and extracted with CH2Cl2 (3×15 ml). The combined extracts were washed with water (30 ml) and brine (30 ml) and were dried over MgSO4. After evaporation of solvent, the residue was chromatographed on silica gel (ethyl acetate:n-hexane=1:1) to give the title compound (11, 178 mg, 69% yield) as orange solids.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:14]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C=CCn1c2ccccc2c2ccccc21

Procedure:
Into a 500-mL, three-necked, round-bottomed flask, equipped with a magnetic stirrer, a thermometer, and a condenser connected to a nitrogen bubbler, were placed carbazole (8.4 g, 50 mmole), allyl bromide (10 mL, 115 mmole), powdered anhydrous potassium carbonate (41 g, 300 mmole), and anhydrous acetonitrile (300 mL). The resultant mixture was stirred and heated under reflux with a heating mantle for 18 hours. Dichloromethane (300 mL) was then added, and the mixture was filtered through a pad of Celite. The clear filtrate was evaporated, and the residue was recrystallized from methanol to yield the desired product as amber-colored crystals. The product had melting point 56°-57° C., and sublimation (100° C./0.1 mm Hg) yielded white crystals (8.65 g, 83%), melting point 57°-58° C. The proton NMR spectrum in carbon tetrachloride was
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 82 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (0.45 g, 0.84 mmol), 4-(methanesulfonyl)phenylboronic acid (0.50 g, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (59 mg, 0.08 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([O-:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: COc1cc(Cl)cc(C(=O)[O-])n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylate, 411 mg (3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 μL (6.60 mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [CH3:1]N(CCN)C.CN(C)[CH2:9][CH2:10][NH:11][C:12]([CH:14]([OH:32])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])=[O:13]>>[CH2:10]([NH:11][C:12]([CH:14]([OH:32])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])=[O:13])[CH:9]=[CH2:1]
Reactant: CN(C)CCNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CN(C)CCN
Product: C=CCNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 84 %

Procedure:
with dimethylaminoethylamine: adenosine-5'-carboxylic acid N-(2-dimethylaminoethyl)-amide; m.p. 136°-138° C.; yield 84% of theory.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:5][CH2:6]2.[ClH:16]>O1CCOCC1.O>[OH:1][C@H:2]1[C@H:7]([Cl:16])[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Cl)[C@H](O)C1
Reaction time: 15 h

Procedure:
5.0 g (0.018 mol) of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine are dissolved in 50 ml of dioxane and the solution is treated with 60 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted with 3 times 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, whereupon trans-3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-piperidine is obtained in the form of a slightly yellow oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][OH:46])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:51]([O:53][CH:54]([CH2:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH3:52]>C1COCC1.O>[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][O:46][C:64]3[CH:63]=[CH:62][C:61]([CH2:60][CH:54]([O:53][CH2:51][CH3:52])[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:66][CH:65]=3)[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: OCCC=C1c2ccccc2COc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 3-(6H-dibenzo[b,e]oxepin-11-ylidene)-1-propanol (0.252 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 18 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to an orange gum. This was then purified by column chromatography on silica gel (20% Et2O in petroleum eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow gum; 0.252 g (53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.C(N(CC)CC)C>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:30])([F:31])[F:32])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Temperature: 30 °C
Yield: 65.1 %

Procedure:
tert-Butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I28) (5.52 g, 8.84 mmol) was dissolved in DMF (250 mL) then triethylamine (1 mL) and Pd/C (2.50 g) were added and the mixture stirred at 30° C. under hydrogen. After 16 hours the mixture was filtered through celite and the celite washed with DMF (250 mL). Triethylamine (1 mL) and Pd/C (2.50 g) were added to the combined filtrates and the mixture stirred at 30° C. under hydrogen. After 18 hours the resulting mixture was filtered through celite washing with ethyl acetate (300 mL). The filtrate was divided into two lots; each was poured into water (800 mL) and the resulting mixture extracted with ethyl acetate (3×300 mL). The ethyl acetate extracts from each lot were combined, washed with water (2×500 mL) and brine, dried (sodium sulfate) and evaporated. The two workups were combined and chromatographed (120 g silica cartridge, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I21) (3.620 g, 65% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 7.91 (s, 1H), 7.29-7.18 (m, overlaps with CHCl3), 6.85 (dd. J=8.3, 1.8 Hz, 1H), 6.77 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 3.19-3.01 (m, 4H), 2.81 (t, J=12.7 Hz, 2H), 2.64 (tt, J=12.0, 3.5 Hz, 1H), 1.85 (d, J=13.3 Hz, 2H), 1.70-1.57 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.14 min; m/z 629.2 [M+H]+, 573.1 [M-tBu+2H]+; m/z 627.2 [M−H].
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][C:32]2=[O:41])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][CH2:33][C:32]4=[O:41])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN3CCC(N4C(=O)CCc5ccccc54)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.203 g) and acetic acid (0.063 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170 g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.235 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed to dryness to give the title compound (0.205 g) as pale yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.CC(C)([O-])C.[Na+].C(=[NH:48])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:48][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(-c2cccc(Br)c2)c2ccc3ccccc3c2[nH]1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.5 %

Procedure:
The mixture of 4-(3-bromophenyl)-1H-benzo[h]quinazolin-2-one (950 mg, 2.71 mmol), 1,4-dioxane (95 mg, 1.08 mmol), sodium tert-butoxide (650 mg, 6.76 mmol), benzophenone imine (681 μL, 4.06 mmol), and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (101 mg, 0.16 mmol) was heated under reflux for 16 hours under N2 atmosphere. The solvent was removed under reduced pressure. To the residue was added methanol (50 mL) and 2M hydrochloride (50 mL), and stirred at room temperature for 16 hours. The reaction mixture was filtered to give the titled compound as a yellow solid (191 mg, yield 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19]C)=O)=[CH:4][CH:3]=1.[NH3:21]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:21])=[O:19])=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Solvent: CO
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 260 mg of methyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate in 30 mL of a 7N solution of ammonia in methanol are added 5 mL of 22% aqueous ammonia solution. The reaction mixture is then stirred for 20 hours in an autoclave at 80° C. (12.6 bar) and then concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica (eluent: 9/1 dichloromethane/methanol by volume). The fractions containing the expected product are concentrated under reduced pressure. 140 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:22]1([CH:14]2[C:15]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[O:21][C:6](=[O:7])[NH:13]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccccc1)C1(O)CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Reaction time: 5 h

Procedure:
To a mixture of CDI (388 mg, 2.394 mmol) in THF (1.5 mL) was added slowly a solution of 4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol (451 mg, 2.176 mmol) in THF (3 mL). The mixture was stirred under argon for ˜5 hours. The mixture was diluted with saturated aqueous NaHCO3 solution and DCM. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with 0.5N aqueous HCl solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, 0-100% heptane/ethyl acetate] providing 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one as a white solid. Yield: 330 mg. LCMS m/z 234.1 (M+H)+; Rt 0.52 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([Cl:18])=[O:14])[CH:8]=2)[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2cccnc2)on1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g (2.63 mmol) of 5-(pyridin-3-yl)-1,2-oxazole-3-carboxylic acid (known from the literature, no reference) in 25 ml of dichloromethane was admixed with 2 drops of N,N-dimethylformamide. Subsequently, 0.97 g (7.63 mmol) of oxalyl chloride was added dropwise under argon and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was converted farther immediately.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 110 °C

Procedure:
A screw cap test tube was charged with n-heptanol (283 μL, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), ligand (0.200 mmol), Cs2CO3 (977 mg, 3.00 mmol) and toluene (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 110° C. for 39 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1cccnc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccnc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=146-157° C.). The reaction was monitored by tlc (Rf=0.1 in CHCl3/MeOH 98:2) and the product was purified by silica gel chromatography using 959:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.