Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([C:18]2[CH:26]=[C:25]3[C:21]([CH2:22][C:23](=[O:27])[NH:24]3)=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1>[O:27]=[C:23]1[CH2:22][C:21]2[C:25](=[CH:26][C:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:8])=[CH:29][CH:28]=3)=[O:17])=[CH:19][CH:20]=2)[NH:24]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A dry 25 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carbonyl chloride (0.820 g, 5.15 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The solids were filtered to afford the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.35 g, 3.60 mmol, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[C:12]([Si](C)(C)C)[NH:11][C:5]2=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.Cl.[OH-].[Na+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][NH:11][C:5]2=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)c1cc2cc(Br)c(C3CC3)nc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Brc1cc2cc[nH]c2nc1C1CC1
Yield: 79.3 %

Procedure:
A stirred solution of 5-bromo-6-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 4.84 mmol), tert-butanol (15 mL), 9N-hydrochloric acid (15 mL) was heated to reflux for 8 hours. Reaction mixture was cooled and basified with 50% sodium hydroxide to pH 8, extracted with ethyl acetate. Organic portion was in turn washed with brine, dried over sodium sulfate and concentrated to give 910 mg (79.13% yield) of the title compound. 1H NMR (CDCl3, 300 MHz) δ 9.43 (bs, 1H), 8.06 (s, 1H), 6.39-6.38 (m, 1H), 2.647-2.603 (m, 1H), 1.09-1 (m, 4H). LCMS: m/z=237.0 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].C([O:13][C:14](=O)[C:15]([C:24]#[N:25])=[C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])C>C(O)C>[CH3:17][C:16]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:14](=[O:13])[CH:15]1[C:24]#[N:25]
Reactant: CCOC(=O)C(C#N)=C(C)c1cccnc1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2cccnc2)C(C#N)C(=O)NC(=O)C1C#N
Reaction time: 16 h

Procedure:
Cyanoacetamide was stirred with sodium ethoxide in ethanol for 30 minutes. 2-Cyano-3-pyridin-3-yl-but-2-enoic acid ethyl ester was added and allowed to sit for 16 hours. The solution was acidified to pH 4 and partially concentrated under reduced pressure, causing precipitation of product. The product was filtered and allowed to dry. MS (ESI+) for C13H10N4O2 m/z 255.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]([NH2:8])=O)[CH2:5][CH2:4]1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C.ClCCl.[Cl-].[OH:28][NH3+:29]>O1CCCC1.C(N(CC)CC)C.O>[OH:28][N:29]=[C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)[NH2:8]
Reactant: COC1(C(N)=O)CC1
Reactant: [NH3+]O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC1(C(N)=NO)CC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
100 mg (1.03 mmol) of 1-methoxycyclopropanecarboxamide [L. N. Owen, H. M. Babatunde Somade, J. Chem. Soc. 1947, 1030-1034] in tetrahydrofuran (22.7 ml) was admixed with 1.51 g (6.08 mmol) of methyl N-(triethylammoniumsulphonyl)carbamate (Burgess reagent) and then stirred at 60° C. for 1.5 h. The reaction mixture was admixed with dichloromethane and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure (637 mg of crude product). 100 mg of the crude product were initially charged in ethanol (1.2 ml), admixed with 107 mg (1.55 mmol) of hydroxylammonium chloride and 0.17 ml (125 mg, 1.24 mg) of triethylamine and then stirred under reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue was admixed with saturated aqueous sodium chloride solution and then extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was subsequently stirred with ethyl acetate, the insoluble salts were filtered off and the filtrate was concentrated under reduced pressure. Yield: 32.3 mg (23% of theory)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]3C=CC=CC=3C(OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.SC1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:23]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[O:20]2)[CH2:2]1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Reactant: Sc1ncccn1
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2ncccn2)O[C@H]1n1cnc2c(N[C@H]3CCOC3)ncnc21

Procedure:
Compound 27 was prepared in the manner of compound 23 substituting 2-mercaptopyrimidine for 2-carbomethoxythiophenol [MS 432.4 (M+1)].
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)[CH2:14][CH3:15].OS(O)(=O)=O>CCO.C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([C:22]([CH:19]1[CH2:20][CH2:21][CH:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1)=[O:23])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCCC1CCC(C(=O)Cl)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCCC1CCC(C(=O)C(C(=O)OCC)C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To 2.5 mL of anhydrous EtOH and 0.25 mL carbon tetrachloride was added 1.2 g (50 mmol) magnesium turnings. 8.0 g (50 mmol) diethyl malonate was dissolved in a mixture of 5 mL anhydrous EtOH and 20 mL anhydrous toluene and added in small portions to the magnesium turnings over the course of 1.5 hr so as to maintain a gentle reflux. The reaction was stirred at room temperature for 1 hr, and then cooled to 0° C. in ice. 4-Propyl-cyclohexanecarbonyl chloride (50 mmol) was added dropwise and the reaction was allowed to warm to room temperature over night. The reaction was then heated to 55° C. for 4 hr with stirring, allowed to cool to ambient temperature, and was poured into a slurry of crushed ice and 10% H2SO4. The solution was diluted with brine and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated to afford 10.71 g (34.28 mmol) 2-(4-propyl-cyclohexanecarbonyl)-malonic acid diethyl ester as a clear, near colorless oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(=O)(OCC)OCC.O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O=[C:37]1[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]1.[Cl-].[NH4+]>CCOC(C)=O>[F:11][C:10](=[C:37]1[CH2:38][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40]1)[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=C(F)S(=O)(=O)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of fluoromethyl phenyl sulfone (0.50 g, 2.9 mmol) and phosphorochloridic acid, diethyl ester (0.415 mL, 2.87 mmol) in tetrahydrofuran (6 mL, 70 mmol) was added 1.000 M of lithium hexamethyldisilazide in tetrahydrofuran (6.2 mL, 6.2 mmol) dropwise at −78° C. After the mixture was stirred at −78° C. for 1 h, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.378 g, 2.21 mmol) in tetrahydrofuran (1.3 mL, 16 mmol) was added. The reaction was allowed to warm to ambient temperature and stirred for 2 h at rt. The reaction was poured into an ice-cold mixture of EtOAc and sat. ammonium chloride. The organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the desired product (560 mg, 77.5%). LCMS calculated for C15H18FNO4SNa(M+Na)+: m/z=350.1; Found (M+Na) 350.3.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[O:7][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: OCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a mixture of pentane-1,5-diol(5.2 g, 0.05 mol) and p-toluenesulfonic acid (0.1 g, 0.53 mmol) in CH2Cl2 (120 mL) was added slowly dihydro-2H-pyran (4.6 g, 0.055 mol) in CH2Cl2 (30 mL) at 0° C. After stirring for 2 h at 0° C. and for another 1 h at room temperature, saturated NaHCO3 (50 mL) was added to the reaction mixture. The CH2Cl2 layer was washed with saturated NaHCO3 (50 mL), water (50 mL), and dried (MgSO4). The residue was purified by column chromatography on silica gel with EtOAc:hexane (1:1, v/v) and subsequent Kugelrohr distillation to give the title product (4, 5.1 g, 54%); bp 80° C.-85° C./0.1 torr; IR(neat): 3450 (broad) and 1135 cm-1 :1H NMR: 1.3-1.9 (m, 12H), 2.4 (b s, lH), 3.3-3.9 (m, 6H), and 4.58 ppm (m, IH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:17][OH:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O>[O:18]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:17]1
Reactant: ON=C(Nc1ccc(Br)cc1)c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(Nc2noc3ccccc23)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
To a solution of N1-(4-bromophenyl)-2-fluoro-1-benzeneamidoxime (1.51 g, 0.00489 mol) in N-methylpyrrolidinone (25 mL), potassium tert-butoxide (0.54 g, 0.00513 mol) was added and the resulting solution was heated at 100° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield N-benzo[d]isoxazol-3-yl-N-(4-bromophenyl)amine (0.95 g, 0.00329 mol) as a white solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH3:28][NH:29][CH3:30]>CN(C)C(=O)C>[CH3:28][N:29]([CH3:30])[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1
Reactant: CNC
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)C/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with dimethyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{2-[4-(3-dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 433 (MH+).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([Cl:16])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OC

Procedure:
A mixture of veratric acid (1.0 g), toluene (10 ml) and thionyl chloride (2 ml) is heated under reflux for one hour, and the reaction mixture is concentrated under reduced pressure. Veratryl chloride thus obtained was dissolved in N,N-dimethylformamide (5 ml). The solution is added dropwise, while stirring under ice-cooling, to a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.96 g), triethylamine (2.2 g) and N,N-dimethylformamide (8 ml) in the course of 3 minutes, followed by stirring for two hours at room temperature. After addition of water (50 ml), the reaction mixture is extracted twice with ethyl acetate (40 ml each portion). The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate:acetone=2:3:1). The oily product thus obtained is dissolved in ethyl acetate (10 ml). To the solution is added a hydrogen chloride-ethanol solution (5N) (1 ml). Resultant precipitates are recrystallized from acetone to afford 1-(3,4-dimethoxybenzoyl)-4 -(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.6 g) as colorless powdery crystals, m.p. 212°-215° C.
Reaction SMILES: [CH2:1]([N:4]([C:16]1[CH:21]=[C:20]([C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:28])[C:5](=[O:15])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1Br)[CH:2]=[CH2:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CC)(CC)CC)C.CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:25]1([NH:24][C:22](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([CH3:28])=[C:16]([N:4]3[CH:1]=[C:2]([CH3:3])[C:7]4[C:6](=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=4)[C:5]3=[O:15])[CH:21]=2)[CH2:27][CH2:26]1
Reactant: C=CCN(C(=O)c1cc(OC)ccc1Br)c1cc(C(=O)NC2CC2)ccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(C)cn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 120 °C
Yield: 31.5 %

Procedure:
N-allyl-2-bromo-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-methoxybenzamide (1.03 g), tri-o-tolylphosphine (283 mg), tetraethylammonium bromide (977 mg) and potassium carbonate (1.3 g) were suspended in DMF (36 ml) under argon. Pd(OAc)2 (104 mg) was added and the mixture was heated at 120° C. for 17 hours and then allowed to cool. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using a gradient of 50% ethyl acetate/iso-hexane to 100% ethyl acetate/iso-hexane to yield N-cyclopropyl-3-(7-methoxy-4-methyl-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a pale yellow foam (265 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.11 (s, 3H), 2.27 (s, 3H), 2.86 (m, 1H), 3.89 (s, 3H), 7.10 (s, 1H), 7.46-7.51 (m, 2H), 7.71-7.76 (m, 3H), 7.87 (d, 1H), 8.46 (d, 1H); Mass Spectrum: M+H+ 363.
Reaction SMILES: C(C1C(C)=C([N+]([O-])=O)C=CC=1C)C.[CH2:14]([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-])=O)[C:17]=1[CH2:26][C:27](=O)[C:28]([OH:30])=[O:29])[CH3:15]>>[CH2:14]([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[C:17]=1[CH:26]=[C:27]([C:28]([OH:30])=[O:29])[NH:23]2)[CH3:15]
Reactant: CCc1c(C)ccc([N+](=O)[O-])c1CC(=O)C(=O)O
Agent: CCc1c(C)ccc([N+](=O)[O-])c1C
Product: CCc1c(C)ccc2[nH]c(C(=O)O)cc12

Procedure:
The compound was prepared via 3-ethyl-2,4-dimethylnitrobenzene (b.p. 141°-145° C/11mm Hg) and 3-(2-ethyl-3-methyl-6-nitrophenyl)-pyruvic acid (m.p. 135° C (decomp.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:29](=[O:45])[CH:30]([NH:37]C(OC(C)(C)C)=O)[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:29](=[O:45])[CH:30]([NH2:37])[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1)C1CCCCC1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution containing 121 (370 mg, 0.51 mmol) in DCM (10 mL) at 0° C. was added TFA (4 mL). After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM and the organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 210 mg of 122 which was used without further purification. Mass spectrum, m/z [523.3] (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23](O)=[O:24])[C:12]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]([O:37][CH3:38])=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23](=[O:24])[NH:33][C:32]2[CH:34]=[C:28]([Cl:27])[C:29]([O:37][CH3:38])=[CH:30][C:31]=2[O:35][CH3:36])[C:12]1=[O:26])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)c2ccccc2n(CC(=O)O)c1=O
Reactant: COc1cc(OC)c(Cl)cc1N
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)c3ccccc32)cc1Cl

Procedure:
This compound is made analogously to Example 1-2 by replacing Intermediate A with [3-(2-tert-butoxycarbonylamino-ethyl)-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl]-acetic acid and by replacing cyclopentylamine with 5-chloro-2,4-dimethoxyaniline to afford the title compound. The reaction is carried out in DCM.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)[C:18](=O)[CH3:19].C(Cl)(=O)C>O>[CH3:18][C:19]1[O:11][C:10]([CH2:9][O:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:12][N:13]=1
Reactant: CC(=O)N(C)C
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)Cl
Product: Cc1nnc(COc2ccc([N+](=O)[O-])cc2)o1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of 2-(4-nitrophenoxy)acetohydrazide (1.57 g) and N,N-dimethylacetamide (50 mL) was added dropwise acetyl chloride (0.70 g) at room temperature. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, diphosphorus pentaoxide (1.76 g), hexamethyldisiloxane (4.03 g) and 1,2-dichlorobenzene (10 mL) was stirred at 140° C. for 3 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole as colorless crystals (0.41 g, yield 56%) from a fraction eluted with hexane-ethyl acetate (3:2-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCNC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate (0.8 g, 1.7 mmol) in dichloromethane (25 ml) at 0° C. was added trifluoroacetic acid (5 ml). The reaction mixture was warmed to room temperature and stirred at room temperature for 20 hr. The solvent was evaporated and dilute NaOH added (5N, 10 ml). The resulting residue solution was extracted with EtOAc (3×50 ml) and the combined organics were washed with brine (1×75 ml). The organic solution was dried (sodium sulphate), filtered and evaporated in vacuo to leave 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as a white solid (0.5 g, 79%) m.pt. 182-184° C. Rf in 1:1 EtOAc : MeOH=0.15. 1H NMR (d6 DMSO, 250 MHz): 8.14 (1H, s), 7.37-7.50 (5H, m), 7.05-7.18 (5H, m), 6.14 (2H, bs), 5.23 (1H, m), 3.09-3.27 (2H, m), 2.83-2.98 (2H, m), 2.19-2.33 (1H, m), 1.88-2.01 (1H, m). Mass spec. 371.1758 (C22H2 ON5). IR (KBr disc): 3106, 1585, 1489, 1232 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH3:8])[CH:9]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CNCC1c1ccccc1
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a stirred solution of ((3RS,4SR)-1-Benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester (2.03 g, 5.56 mmol) in MeOH (20 ml) at RT, was added ammonium formate (1.60 g, 25.4 mmol) and palladium on charcoal (0.40 g, 10%) The reaction mixture was stirred for 2 hours, filtrate on celite and concentrated under vacuo. The residue was purified by column chromatography (CH2Cl2/MeOH, 9/1) to give 0.57 g (41%) of the title product as a waxy solid.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.Cl>CO.[Pd]>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](C)NC(=O)c1cccc2c1NC1CCCC21
Yield: 55.1 %

Procedure:
Following the procedure of method 7C, methyl (2R)-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (4.9 mmol, 1.4 g) was hydrogenated using 5% Pd/C (1.5 g) and concentrated HCl (7 mL) in methanol (25 mL) to yield an oil (2.7 mmol, 0.77 g, 55%).