Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>C(N(CC)CC)C.C(Cl)Cl>[CH2:7]([NH:9][C:10]([N:5]([O:6][C:10]([NH:9][CH2:7][CH3:8])=[O:11])[C:1](=[O:4])[CH2:2][CH3:3])=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: CCC(=O)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)ON(C(=O)CC)C(=O)NCC
Reaction time: 12 h

Procedure:
Propiohydroxamic acid (4.5 grams), ethyl isocyanate (8.0 grams), and a few drops of triethylamine were added to 100 ml of methylene chloride and allowed to stand at room temperature for about 12 hours. The solvent was then removed under vacuum leaving a residue which was recrystallized from a solution of methylene chloride and hexane leaving the desired, N-((ethylamino)carbonyl)-N-(((ethylamino)carbonyl)oxy)propionamide as white crystals, m.p. 104°-106° C.
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.[CH:8]1([CH2:14][CH2:15][Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.C(OCC)C>[S:1]1[C:5]([CH:6]([OH:7])[CH2:15][CH2:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=[CH:2]1
Reactant: Br[Mg]CCC1CCCCC1
Reactant: O=Cc1cncs1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(CCC1CCCCC1)c1cncs1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A solution of thiazole-5-carboxaldehyde (2.31 g, 20.4 mmol) in 20 mL of in THF was added to a cold (0° C.) solution of 2-cyclohexylethylmagnesium bromide (prepared from 2-bromoethylcyclohexane (7.88 g) and magnesium turnings (1.22 g)) in 30 mL of ethyl ether and the mixture stirred 30 minutes. The cold bath was removed and the mixture stirred for 2 hours more and then quenched by the addition of 3N aqueous HCl. The solution was stirred until 2 clear phases resulted and then the layers were separated. The pH of the aqueous phase was adjusted to 4 with 2M aqueous sodium carbonate and then extracted with 3 portions of ethyl acetate. All the organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (125 g, 50% ethyl acetate/hexanes) to provide 2.69 g (58%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al]>C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)nc1
Reaction time: 85 h

Procedure:
To a solution of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (2.00 g, 13.1 mmol) in 45 mL of benzene was added benzyl bromide (1.86 mL, 15.7 mmol) and silver carbonate (3.96 g, 14.4 mmol). The flask was covered with aluminum foil, and after 85 hr, the mixture was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 6-(benzyloxy)pyridine-3-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1>>[CH:12]1([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 65.2 %

Procedure:
Following general procedure A1, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.072 g, 0.48 mmol) to afford the title compound (0.095 g, 65%) as a white solid. MW=364.36. 1H NMR (DMSO-d6, 500 MHz) δ 9.97 (s, 1H), 7.69-7.57 (m, 2H), 7.42 (s, 1H), 7.25 (d, J=8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 3.34 (s, 2H), 3.20 (quin, J=8.0 Hz, 1H), 2.05-1.97 (m, 2H), 1.89-1.59 (m, 6H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 15.4 %

Procedure:
The title compound (44 mg, 15%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (240 mg, 0.714 mmol, prepared in example 1), 3-trifluoromethylbenzeneboronic acid (162 mg, 0.853 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (255 mg in 1.2 mL water), and 1,2-dimethoxyethane (4.75 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 192 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][OH:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:3]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccc3ccccc3c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-naphthalenemethanol and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28].N12CCCN=C1CCCCC2>ClCCl>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27](=[NH:28])[O:14][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[N:8]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:11]=1)[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 4 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (2.5 g, 6.94 mmol) and trichloroacetonitrile (6.95 mL, 69.4 mmol) in dichloromethane (50 mL) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.66 mmol). After stirring for 4 h, the reaction was concentrated and purified by column chromatography (12% EtOAc/Hex+0.1% Et3N) to give 3.1 g, (89%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 6.67 (q, J=6.6 Hz, 1H), 5.73 (s, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.80 (d, J=6.6 Hz, 3H), 0.93 (m, 2H), −0.05 (s, 9H). Mass spec.: 526.90 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNC(=O)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methylamide (Stage 15.1.1, 42 mg, 0.160 mmol) to give the title compound as a lightly yellow solid. (HPLC: tR 2.39 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.87-8.80 (m, 1H), 8.71-8.67 (m, 1H), 8.18-8.07 (m, 4H), 8.04-7.98 (m, 1H), 7.65 (s, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 2.83 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46]([NH:1][C@@H:2]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS )-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[N+:22]([O-])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:22][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:11]=1[CH2:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c(N)c1
Yield: 108.6 %

Procedure:
Ethyl 4-[(3-cyanophenylamino)methyl]-3-nitrobenzoate (5.79 g) was dissolved in 50 ml of ethanol, then 50 ml of purified water, 0.96 g of ammonium chloride and 4.97 g of iron powder were added and the mixture was refluxed under heating for 40 minutes. The reaction solution was filtered through Celite and concentrated in vacuo. Ethyl acetate was added to the resulting residue. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, concentrated in vacuo and dried to give 5.71 g of ethyl 3-amino-4-[(3-cyanophenylamino)methyl]benzoate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>CO>[CH2:2]([O:9][C:10]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:12]2[C:11]=1[C:25](=[O:29])[C:26](=[O:27])[NH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CO
Product: O=C1Nc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2C1=O
Temperature: 170 °C

Procedure:
A mixture of 3,5-dibenzyloxyaniline hydrochloride (J. Org. Chem., 1975, 40, 1556; 10 g) and oxalyl chloride (15 ml) was heated to 170° C. for 3 hours. The mixture was cooled to ambient temperature, methanol (45 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with methanol and dried under vacuum to give 4,6-dibenzyloxy-2,3-dioxoindoline (8.8 g); NMR Spectrum: (DMSOd6) 5.22 (s, 2H), 5.28 (s, 2H), 6.12 (s, 1H), 6.42 (s, 1H), 7.3–7.55 (m, 10H), 10.97 (s, 1H).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)C>[N:25]([C@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Into a solution of trans-2-diphenylmethylpyran-4-yl methanesulfonate 4a (0.33 g, 0.95 mmol) in dry DMF (40 ml) was added sodium azide (0.18 g, 2.85 mmol). The mixture was heated to 100° C. and stirred for 4 hr. The mixture was diluted with ethyl ether, washed with 2M aqueous NaHCO3 and brine, and then dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (Hexane/Ethyl Acetate 9:1) afforded compound 5a (0.23 g, 82.7% yield) as a liquid.
Reaction SMILES: CSC(SC)=[N:4][C@H:5]([C:17]([OH:19])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.C[N:23]1CCOCC1.ClC(OCC)=O>CN(C=O)C>[NH2:4][C@H:5]([C:17]([NH2:23])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1
Reactant: CN1CCOCC1
Reactant: CSC(=N[C@@H](Cc1cccc(C(C)(C)C)c1)C(=O)O)SC
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(C[C@H](N)C(N)=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 492 mg (1.51 mmol) of N-[bis-(methyl-thio)methylene]-3-t-butylphenylalanine in 5 ml of DMF, 0.183 ml (1.66 mmol) of NMM and 0.159 ml (1.66 mmol) of ethyl chloroformate were added at −15° C. and the mixture was stirred for 30 minutes. The reaction mixture was stirred with bubbling of ammonia gas for another 30 minutes, left to stand at room temperature, diluted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 3 ml of 1,4-dioxane and, after adding 1 ml of 2 N hydrochloric acid, the solution was stirred at room temperature for 3 days. Under cooling with ice, the solution was neutralized with saturated aqueous NaHCO3, extracted with chloroform, and washed first with water, then with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=10:1) to give Phe(3-tBu)-NH2 in the amount of 210 mg (63%).
Reaction SMILES: [CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][C:20](=[O:26])[NH:21]2>>[CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([C:14]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][C:20](=[O:26])[NH:21]3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Reactant: CN1CCC(O)(Cc2ccccc2)CC1
Product: O=c1[nH]c2ncnc(N3CCC(O)(Cc4ccccc4)CC3)c2[nH]1

Procedure:
4-Benzyl-1-methyl-piperidin-4-ol was reacted with 6-chloro-7,9-dihydro-purin-8-one under conditions analogous to those set out in Example 3A to give the title compound LC/MS: (LCT) Rt 5.68 [M+H]+ 326.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.Br[CH2:19][CH2:20][F:21].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN1C(=O)CCC1>[F:21][CH2:20][CH2:19][NH:17][C:14]1[S:15][CH:16]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[N:13]=1
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FCCNc1nc(-c2ccc3ccccc3c2)cs1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A mixture of 4-(naphthalen-2-yl)thiazol-2-amine hydrochloride (113 mg, 0.5 mmol), 1-bromo-2-fluoroethane (127 mg, 1 mmol), Cs2CO3 (326 mg, 1 mmol), and 15 mg KI in 2 mL of NMP was heated at 80 C for 20 min in a microwave reactor. After cooling to rt, the mixture was taken up to 50 mL EtOAc and washed with water (3×80 mL) and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford N-(2-fluoroethyl)-4-(naphthalen-2-yl)thiazol-2-amine as a white solid (10 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1 H), 8.29 (d, J=1.6 Hz, 1 H), 7.95-7.91 (m, 2 H), 7.86-7.83 (m, 1 H), 7.67 (dd, J=8.4, 2.0 Hz, 1 H), 7.57-7.54 (m, 2 H), 6.70 (s, 1 H), 4.79 (t, J=4.8 Hz, 1 H), 4.67 (t, J=4.8 Hz, 1 H), 3.71 (m, 1 H), 3.65 (m, 1 H); MS (ESI) m/z 273 (M+H+).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:39])=[O:38]
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) and Hunig's base (0.31 mL, 1.8 mmol) is cooled in an ice bath and methanesulfonyl chloride (0.068 mL, 0.88 mmol) is added dropwise. The reaction is stirred cold for 45 minutes and washed with 0.1 N HCl (2×) and H2O. The organic phase is dried (Na2SO4), and concentrated to a white foam. The crude material is purified over silica (1.5% MeOH/dichloromethane) to afford 161 mg (48% yield) of the desired compound. 1H NMR (CDCl3) δ 7.17 (d, J=8.1 Hz, 1H), 7.07 (m, 2H), 7.00 (m, 2H), 6.85 (m, 3H), 4.45 (t, J=8.1 Hz, 1H), 3.96 (t, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.33 (t, J=8.4 Hz, 1H), 3.06 (s, 3H), 2.97 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 2.30 (s, 6H).). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [F:1][C:2]([F:44])([C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=2[N+:41]([O-:43])=[O:42])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[CH2:45](Br)[CH:46]=[CH2:47].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:47]([N:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]([F:44])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:26]=1)[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42])[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCN(c1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine (5.4 g), allyl bromide (1.5 mL), potassium carbonate (2.6 g) and N-methyl pyrrolidone (15 mL) was heated to 60-70° C. for 5.5 hr. Extraction in the normal fashion gave 5.6 g of N-allyl-N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=O)C.[ClH:39]>CO.C(Cl)Cl>[ClH:39].[OH:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 37 %

Procedure:
2M Aqueous sodium hydroxide solution (900 μl) was added to a solution of 4-(3 -acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline (290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml) and the mixture stirred for 25 minutes at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 and 95/5). The purified white solid was suspended in methanol (20 ml) and a solution of 7.5M hydrochloric acid in methanol (2 equivalents) was added. The solid was collected by filtration, washed with methanol and then pentane and dried under vacuum at 50° C. to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline hydrochloride (106 mg, 37%).