Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N/[CH:2]=[N:3]/[C:4](/[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:5](\[C:11]#[N:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7].[ClH:23]>O>[Cl:23][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=[CH:2][N:12]=1
Reactant: CCOC(=O)/C(C#N)=C(/N=C/N)NCc1ccc(OC)cc1
Reactant: Cl
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
(E)-Ethyl 3-((E)-(aminomethylene)amino)-2-cyano-3-((4-methoxybenzyl)amino)acrylate (1.24 g, 3.49 mmol) was dissolved in 23 mL hydrochloride acid (4M in dioxane, 90.64 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured into 400 mL water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified using SP1® Purification System (0% to 25%, hexane-ethyl acetate) to give 376 mg (34% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9](OC1C=CC([N+]([O-])=O)=CC=1)=[O:10].C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>C(Cl)Cl.CO>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 3-aminopyridine (114 mg, 1.21 mmol), 4-nitrophenyl chloroformate (244 mg, 1.21 mmol), diisopropyl(ethyl)amine (650 mg, 5.05 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[OH-].[NH4+:16]>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][S:5]([NH2:16])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)Cc1c(Cl)cccc1Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)Cc1c(Cl)cccc1Cl
Yield: 64 %

Procedure:
The 2,6-dichlorobenzylsulfonylchloride (27 g, 103.6 mmol) in ammonium hydroxide (270 ml) was stirred at room temperature for 3 hours. On acidification with cooled concentrated hydrochloric acid a precipitate separated and was filtered to give desired product (16 g, 64%) MS(EI) m/e 239 (M−).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[C:6](Cl)[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.[NH4+:24].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:11])[NH:24][C:6]=2[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)CCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Temperature: 75 °C
Yield: 21 %

Procedure:
To a solution of ethyl 3-{4,6-dichloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (0.42 g, 1.19 mmol) in 1,4-dioxane (5 mL) was added conc. NH4OH (3.5 mL). The reaction was heated at 75° C. in a sealed tube for 16 h. The solution was concentrated under vacuum, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) to yield the desired compound as a yellow solid (0.072 g, 21%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=2)[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]1=[O:25]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[F:21][C:15]1[CH:14]=[C:13]([CH2:12][C:10]2[N:9]3[CH:22]=[CH:23][CH:24]=[C:8]3[C:7](=[O:25])[NH:6][CH:11]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: COc1ccc(Cn2cc(Cc3ccc(C#N)c(F)c3)n3cccc3c2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(Cc2c[nH]c(=O)c3cccn23)cc1F
Temperature: 120 °C

Procedure:
A solution of A3 (1 eq) in a mixture of DCM and TFA (2:1) was heated in a microwave oven at 120° C. for 10 min. The reaction mixture was diluted with DCM and toluene and concentrated under reduced pressure. The resulting crude was diluted with DCM and washed with sat. aq. NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C15H10FN3O requires: 267, found: 268 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, d, J=5.3 Hz), 7.97 (1H, dd, J=6.3, 2.0 Hz), 7.79-7.72 (1H, m), 7.47 (1H, t, J=9.0 Hz), 7.34-7.30 (1H, m), 6.92-6.88 (1H, m), 6.54-6.49 (2H, m), 4.08 (2H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.BrCCC(Br)CC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1.COC1C=C(CC#[N:36])C=CC=1OC>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[N:23]=[C:22]([NH2:36])[C:21]12[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CC#N)c1
Reactant: BrCCCBr
Reactant: COc1ccc(CC#N)cc1OC
Agent: CCC(Br)CCBr
Product: COc1ccc2c(c1)C1(CCC1)C(N)=N2

Procedure:
5′-Methoxyspiro[cyclobutane-1,3′-indol]-2′-amine was prepared according to the procedure outlined in Example 2 substituting 1,3-dibromopropane for 1,3-dibromopentane and 2-(3-methoxyphenyl)acetonitrile for 2-(3,4-dimethoxyphenyl)acetonitrile in Step 1 of the three-step sequence. 1H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 10.02 (s, 1H), 9.83 (s, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 3.80 (s, 3H), 2.40-2.24 (m, 1H), 2.24-2.04 (m, 3H). MS (APCI) m/z 203 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].S([O-])([O-])(=O)=O.[Mg+2].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[N+:37]([CH3:40])([O-:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:40][N+:37]([O-:39])=[O:38])[CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-chloro-benzaldehyde (20 g, 0.142 mol) in nitromethane (100 mL) were added magnesium sulfate (37.6 g, 0.312 mol) and phosphazene base P1-t-bu-tris(tetramethylene) (4.43 g, 0.014 mol). The reaction mixture was stirred at room temperature for 2 h. After concentration in vacuo, the residue was purified by flash chromatography (25% EtOAc/hexane) to yield the title compound (26.4 g, 100%) as a green-yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (1H, s), 7.35–7.42 (3H, m), 6.23 (1H, broad s), 5.32–5.33 (1H, m), 4.90 (1H, dd, J=3.2, 12.4 Hz), 4.60 (1H, dd, J=1.2, 12.4 Hz).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: CCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogen carbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C. for 30 min, 4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.2 g, 51%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C=O)c(O)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
A mixture of 2,4-Dihydroxybenzaldehyde (5.52 g), potassium carbonate (6.08 g) and octyl bromide (7.73 g) in acetonitrile (55 ml) was stirred for 16 hours at 60° C. The solvent of reaction mixture was removed under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane:ethyl acetate=9:1) to give 2-Hydroxy-4-octyloxybenzaldehyde (6.73 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:14]2[CH:15]=[C:16]([C:27](=[O:29])[NH2:28])[C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[C:14]2[CH:15]=[C:16]([C:27]([NH2:28])=[O:29])[C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)CCCCC2N
Reaction time: 1 h

Procedure:
To (3-carbamoyl-2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-carbamic acid tert-butyl ester (0.60 g, 144 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The mixture was stirred for 1 h, evaporated under a stream of N2, diluted with CH2Cl2 and washed with 1 N NaOH. The organic layer was dried over magnesium sulfate and concentrated to a tan solid (0.45 g, 99%). MS [M+H]+ 316, m.p. 170-172° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([NH:15][CH:16]=[O:17])[C:3]=12.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:15]([CH3:20])[CH:16]=[O:17])[C:3]=12
Reactant: CI
Reactant: Cc1c2n(c3ccccc13)CCCC2NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of N-(6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-yl)formamide (7.4 g, 32.4 mmol) in dimethylformamide (90 mL) was added dropwise at 25° C. to a suspension of sodium hydride (1.78 g, 37 mmol, ~50% suspension in mineral oil) in the same solvent (90 mL). The reaction mixture was stirred at 25° C. for 2 hours under exclusion of moisture. Methyl iodide (5.1 g, 35.6 mmol) was added and the mixture stirred at 25° C. overnight. The solvent was evaporated in vacuo and the residue partitioned between water (100 mL) and chloroform (150 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to afford 7.85 g (100%) of the title compound as an amber oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:8]1([O:13][CH2:14][C:15](Cl)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:13][CH2:14][C:15]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)COC1CCCC1
Reactant: O=C1CCOCC1
Product: O=C1CCOCC1C(=O)COC1CCCC1
Yield: 37.5 %

Procedure:
3-(2-(cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)-one (280 mg, 21.5%) was synthesised from dihydro-2H-pyran-4(3H)-one (0.462 ml, 5.00 mmol) and (2-(cyclopentyloxy)acetyl chloride (3.3 mmol) by the general procedure for the preparation of diketones.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=2[C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:39][C:38]1[CH:40]=[CH:41][C:35]([CH2:34][N:31]2[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]2)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:6]
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
3-Iodo-4-methylbenzoyl chloride (1.06 g, 3.8 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2, was added to a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (1.00 g, 3.6 mmol), Et3N (0.36 g 3.6 mmol), and a catalytic amount of DMAP in THF (20 mL). After stirring at rt for 2 hrs, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (eluent: 5% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to provide the desired product as an off-white solid (67.2%, 1.25 g). 1H NMR (300 MHz, CDCl3) δ: 8.29 (1H, s), 8.00 (1H, s), 7.85 ((1H, m), 7.73-7.76 ((2H, m), 7.31-7.34 ((1H, d, J=9.0 Hz), 3.64 (2H, s), 2.53 (8H, brs), 2.49 (3H, s), 2.33 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[F:18][C:19]1[CH:30]=[C:23]2[C:24](OC(=O)[NH:28][C:22]2=[CH:21][CH:20]=1)=[O:25].Cl>O.O1CCOCC1>[NH2:28][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:30][C:23]=1[C:24]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:25]
Reactant: NCCCCCCCC(=O)O
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(F)cc1C(=O)NCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
A 50% (by weight) solution of potassium carbonate (11.2 mL, 16.8 mmol, 1.02 eq), 8-aminocaprylic acid (9.5 g, 59.7 mmol, 1.00 eq), 5-fluoroisatoic anhydride (10.82 g, 59.7 mmol, 1.00 eq), dioxane (40 mL), and water (5 mL) were added to a 100 mL round bottom flask equipped with a magnetic stir bar and a condenser. The red cloudy mixture was heated to 90° C. for 2 hours (at which time the reaction was determined, by HPLC, to have finished). The deep purple solution was cooled to 25° C. and acidified to pH=4.0 with 3% (by vol.) aqueous hydrochloric acid. The dark precipitate which formed was isolated by filtration. The solid was recrystallized from 50 mL of 65% ethanol-water, recovered by filtration, and dried over 6 hours in a 50° C. vacuum oven. The N-(2-amino-5-fluorobenzoyl) -8-aminocaprylic acid was isolated as a light yellow solid (11.86 g, 67%), mp=108°-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Nc1ccc(C(=O)OC)cc1)C(=O)OCC
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of methyl 4-aminobenzoate (3.1 g, 20.5 mmol) and diethyl bromomalonate (2.45 g, 10.2 mmol) in a round bottom flask was placed in an oven at 115° C. for 16 h. The reaction mixture, which had turned into a solid cake, was suspended in 20 mL of benzene and filtered. The filtrate was diluted with 50 mL of benzene and the organic layer was washed with 2 N hydrochloric acid (3×10 mL), water (10 mL), dried (Na2SO4) and evaporated to give an oily material which solidified upon standing. The crude was recrystallized from ether/hexane to give 2.7 g (85%) of diethyl (4-methoxycarbonylphenyl)aminomalonate, mp 66-69° C. (ether/hexane).
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30](F)=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:37])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN.[CH3:42][N:43]1CCCC1=O.O>C1COCC1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([NH:43][CH3:42])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:37])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(F)c([N+](=O)[O-])c2)n1
Reactant: CN1CCCC1=O
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of give 4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (2) (600 mg; 1.13 mmol), methylamine (5 mL of a 2M solution in THF), and 1-methyl-2-pyrollidinone (10 mL) was heated at 60 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (30 mL) and filtered to give 4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide (3) as a red solid (501 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Yield: 47.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl) acetamide (0.85 g), 1-(pyridin-4-yl)piperazine (0.64 g) and potassium carbonate (0.81 g) in dimethylformamide (10 ml) was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1)to give a yellow solid(0.6 g). The obtained yellow solid was crystallized from ethyl acetate-methanol to give the title compound (0.37 g) as white crystals, m.p.=164-166° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.[OH-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]O>>[CH2:21]([C:16]1[CH:15]=[C:14]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:34][CH:33]3[O:32][CH2:31]3)=[C:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=2)([CH3:13])[CH3:12])[CH:19]=[CH:18][C:17]=1[O:20][CH2:24][CH:26]1[O:28][CH2:27]1)[CH:22]=[CH2:23]
Reactant: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O
Reactant: COCCO
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C(C)(C)c2ccc(OCC3CO3)c(CC=C)c2)ccc1OCC1CO1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 604.4 %

Procedure:
2,2-Bis(3-allyl-4-hydroxyphenyl)propane (308 g) was mixed with 2-methoxyethanol (10 g) and epichlorohydrin (740 g) and heated to 60° C. Sodium hydroxide flake (80 g) was added portionwise over 3 hours, and the mixture was stirred for a further 1/2 hour, also at 60° C. The mixture was filtered, the residue being washed with toluene, and the filtrate was evaporated to remove the solvents and the excess of epichlorohydrin. The concentrated product was filtered once more to give 334 g of 2,2-bis(3-allyl-4-(glycidyloxy)phenyl)propane, having an epoxide content of 4.03 equiv./kg and 4.5 allyl double bond equiv./kg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:26][N:12]1[CH2:11][C@@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1CNC(=O)OC(C)(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1C[C@@H](CNC(=O)OC(C)(C)C)[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 145 mg (0.44 mmol) of trans-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine synthesized by the process described above in acetonitrile (1.5 ml) were added 0.20 ml (2.7 mmol) of a 37% aqueous solution of formaldehyde and 46.9 mg (0.75 mmol) of sodium cyanoboro-hydride. The mixture was stirred for 20 minutes at room temperature. Acetic acid was then added to the resultant solution to adjust its pH to about 5. The solution was stirred for an additional 30 minutes at room temperature. A 1N aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH of the reaction mixture to about 10, and extraction was then conducted with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 90.1 mg (yield: 60%) of crude crystals of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][N:12](C=O)[CH3:13].[OH:16]N1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CC(O)=O>[NH:6]1[C:11]2=[N:12][CH:13]=[C:10]([CH2:9][C:8]([NH2:7])=[O:16])[CH:2]=[C:3]2[CH:4]=[CH:5]1
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cnc2[nH]ccc2c1
Yield: 95 %

Procedure:
Into a solution of 5-aminoazaindole (0.6 g, 4.5 mmol) in dry DMF (11 mL) N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (TBTU, 1.45 g, 9 mmol), 1-hydroxybenzotriazole (HOBt, 0.69 g, 9 mmol) and glacial AcOH (260 micro), diisopropylethylamine (DIPEA, 3.12 mL, 18 mmol) was slowly dropped in ca. 30′ under stirring. The reaction mixture was stirred at room temperature for 18 h, concentrated and the residue was purified by flash chromatography eluting with dichloromethane/MeOH 10:1. The desired 1H-pyrrolo[2,3-b]pyridin-5-ylacetamide (title compound) was obtained in 95% yield (0.78 g, 4.2 mmol).