Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:13]([OH:27])[CH2:14][N:15]1[C@H:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][CH2:16]1)=O)C1C=CC=CC=1.[BrH:35]>C(O)(=O)C.C(OCC)C>[BrH:35].[BrH:35].[NH2:11][C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:13]([OH:27])[CH2:14][N:15]1[C@H:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][S:17][CH2:16]1
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g of 3-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide and 4.1 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 1 hour. The resulting solution was diluted with anhydrous diethyl ether and the precipitated, product was rapidly filtered off and washed with fresh diethyl ether. There were obtained 2.01 g of 3-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide dihydrobromide as a white solid; 1H NMR (300 MHz): δ(D2O) 1.37 (9H, s), 3.0 (2H, m), 3.09 (2H, dq), 3.29 (2H, d), 3.85 (2H, m), 4.16 (1H, m), 4.3 (2H, q) and 7.42 (5H, m) ppm.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCI
Reactant: c1ccc(CNCc2ccccn2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCN(Cc1ccccn1)Cc1ccccn1
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To 15 ml of N,N-dimethylformamide, 0.85 g potassium hydroxide, 1.0 g di(2-picolyl)amine, and 0.99 g 1-iodopentane were successively added. The mixture was stirred under nitrogen at 35 C for 2.5 hours before an additional 0.99 g 1-iodopentane were added. The mixture was then stirred for 16 hrs at 35 C under nitrogen. The reaction was quenched with 90 ml of water and extracted with two 50 ml portions of ethyl acetate. The combined organic layers were washed with two 25 ml portions of water, dried over anhydrous magnesium sulfate, and filtered. Following solvent removal, the orange oil obtained was purified by silica gel chromatography using a methanol/ethyl acetate mixed solvent system that was ramped from 0% to 10% methanol by volume during the course of the elution. An orange oil (0.98 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=Cc2ccc(N)cc2)cc1
Temperature: 60 °C

Procedure:
A portion (20.27 grams, 0.075 mole) of 4,4'-dinitrostilbene from A above, concentrated hydrochloric acid (150 milliliters) and ethanol (300 milliliters) are added to a beaker and heated to provide a 60° C. stirred solution. Over the next eight hour period, 325 mesh powdered iron is added to the reaction mixture in aliquots until a total of 33-51 grams (0.60 mole) has been added. After completion of the iron addition, the mixture is heated for 16 hours at 60° C. then diluted with ethanol (250 milliliters) and deionized water (250 milliliters). After cooling to 25° C. , the product is filtered. The resultant solution is treated with 50% aqueous sodium hydroxide sufficient to induce precipitation of a pale tan colored product which is recovered by filtration. The recovered filter cake is washed with deionized water (500 milliliters) then dried in a vacuum oven at 100° C. and 2 mm Hg to a constant weight of 11.3 grams. The product is recovered as a pale tan colored solid. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure: Disappearance of the absorbances observed for the conjugated nitro group, appearance of --NH2 stretching absorbances at 3436 (3462 shoulder) and 3356 (3376 shoulder) cm-1, a --NH2 bending absorbance at 1616 cm-1 (1603 cm-1 shoulder due to aromatic ring absorbance) , an out-of-plane C--H deformation at 970 cm-1 due to the trans substituted ethylene group and a C--H out-of-plane bending vibration at 832 cm-1 due to the paradisubstituted aromatic rings. Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].C(O)C.[H][H]>[C].[Pd].C(N(CC)CC)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:20]([CH3:22])[CH3:21])[C:3](=[O:23])[CH:2]=1
Reactant: COc1ccc(CNc2cnn(C(C)C)c(=O)c2Cl)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cnn(C(C)C)c(=O)c2)c(OC)c1

Procedure:
320 mg of 4-chloro-5-(2,4-dimethoxybenzylamino)-2-i-propyl-3(2H)pyridazinone (Compound No. 97), 50 ml of ethanol, 1 ml of triethylamine and 100 mg of palladium-carbon were stirred, and hydrogen was added to the mixture at a temperature of from 40° to 50° C. for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 230 mg of the above identified compound having a melting point of from 167 to 168° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[C:26]([F:29])([F:28])[F:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[C:20]=3[C:26]([F:27])([F:29])[F:28])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1C(F)(F)F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1cccc(-n2cnc3ccc(OCc4ccccc4)nc32)c1C(F)(F)F
Temperature: 80 °C

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.10 g, 0.44 mmol) and 1,3-difluoro-2-(trifluoromethyl)benzene (0.12 g, 0.67 mmol) were dissolved in DMF (1.0 mL) and Cs2CO3 (0.29 g, 0.89 mmol) was added. The reaction mixture was heated to 80° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether. The combined organic portions were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([O:10][CH:11]([F:13])[F:12])=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH:23]O>CO>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([OH:23])=[CH:8][C:9]=2[O:10][CH:11]([F:13])[F:12])[CH2:3][CH2:2]1
Reactant: OO
Reactant: CC1(C)OB(c2cnc(C3CC3)c(OC(F)F)c2)OC1(C)C
Solvent: CO
Product: Oc1cnc(C2CC2)c(OC(F)F)c1
Temperature: 0 °C
Yield: 58 %

Procedure:
Methanol (5 mL) was added to the crude 2-cyclopropyl-3-difluoromethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 103, 450 mg, 1.5 mmol) and the resulting solution cooled to 0° C. with stirring. Hydrogen peroxide solution (35% in water, 0.70 mL) was added over 20 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 5 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (10 mL), and rapidly stirred for 15 minutes at room temperature. The mixture were evaporated in vacuo, and brine (50 mL) was added. The residue was extracted into ethyl acetate (3×50 mL) and the combined extracts were dried over magnesium sulfate, filtered and the solvent removed to leave a brown oil. The oil was purified by flash silica gel column chromatography eluting with EtOAc:heptane 1:1 to provide the title compound as a white solid (168 mg, 58% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[C:21]([BH3-])#N.[Na+]>O>[CH3:21][N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: [BH3-]C#N
Reactant: O=C(O)CCCCNCc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CN(CCCCC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of 300 mg (1.19 mmol) of N-(p-nitrobenzyl)δ-aminovaleric acid in 6 ml of water were added 450 μl of a 37% aqueous formaldehyde solution (6.1 mmol) and 123 mg of sodium cyanoborohydride (1.96 mmol). This mixture was stirred for 45 min at rt. After quenching with 6 ml of 1 M hydrochloric acid the solution was directly adsorbed on a Dowex 50 (H+ -form) ion exchange column (2×10 cm). The column was subsequently washed with 150 ml water and the product eluted with 0.7 M ammonia. After evaporation, the remaining oil was further purified by silicagel chromatography (1×15 cm, methanol:dichloromethane=1:1). The product containing fractions (Rf =0.22) were collected and the solvent removed in vacuo. 270 mg (85% of product in form of a colorless oil was isolated. Attempts at crystallization failed. 1H-NMR (200 MHz,D2O):8.10 (d,J =8.7/2H), 7.46 (d, J =8.7/2H), 3.83 (s/2H), 2.59 (m(t)/2H), 2.28 (s/3H), 2.03 (m(t)/2H), 1.49-1.39 (m/4H); 13C-NMR (50 MHz, d6 -DMSO): 175.3, 147.8, 146.4, 129.4, 123.3, 60.6, 56.6, 41.8, 34.1, 26.3, 22.5; FAB+-MS:267 (M+1)+. EA (C13H18N2O4. O.H2O) calc. C 55.26 H 7.06 N 9.91, found: C 55.34 H 6.88 N 9.89.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[O:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: ClCc1ncco1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)C(=O)N(Cc2ncco2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 94.9 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 2-chloromethyl-oxazole (0.47 g; 4 mmol) and K2CO3 (1.1 g; 7.96 mmol) at RT for 18 h. After aqueous work-up the crude material (1.30 g) is de-acetylated in MeOH (30 ml) using DBU (280 μl) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-oxazol-2-ylmethyl-1,3-dihydro-indol-2-one (1.09 g) is obtained and used without further purification.
Reaction SMILES: [CH:1]1([C:7](=[O:28])[CH2:8][CH2:9][NH:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]([O:14]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]#[C:30][OH:31]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:11]1[N:10]([CH2:9][CH2:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[C:30](=[O:31])[NH:29][C:12]1=[O:14])=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCCCCC(NCCC(=O)C1CCCCC1)C(=O)OCC
Reactant: N#CO
Product: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCC(=O)C1CCCCC1

Procedure:
Reaction of diethyl 2-((3-cyclohexyl-3-oxopropyl)amino)nonanedioate (20.8 g) with cyanic acid using the general procedure of Example 2d afforded 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-oxopropyl)hydantoin which was converted to the corresponding acid which crystallised from ether, m.p. 77.5°-78.5° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pt]>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(I)cc1N
Temperature: 22 °C

Procedure:
To a solution of 4-iodo-1-methyl-2-nitro-benzene (25.0 g, 107 mmol) in 300 mL of ethanol was added sulfided platinum (3.00 g) and ammonium formate (20.3 g, 321 mmol). The mixture was heated to reflux for 12 h and then cooled to 22° C., filtered through Celite® and concentrated in vacuo. The resulting residue was diluted with H2O (300 mL) and extracted with 3×200 mL CH2Cl2. The organic fractions were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give b (21.1 g, 95%): MS m/z═234 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18]>>[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxy-2-methylpropylamine to provide 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, m.p. 234°-244° C.(dec.). Analysis: Calculated for C13H15N3O3 : %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N, 16.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:24][CH2:23][CH2:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:25]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(NCCNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.8 %

Procedure:
To a stirred solution of 2-fluoro-6-nitro-benzoic acid methyl ester (0.35 g, 0.00176 mol) in DMF (8 mL) under nitrogen was added (2-amino-ethyl)-carbamic acid tertbutyl ester (0.28 g, 0.00176 mol) and potassium carbonate (0.49 g, 0.0035 mol). The reaction mixture was stirred at room temperature for 48 h. The reaction solvent was removed and the resulting oil redissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The reaction mixture was purified by ISCO chromatography on silica gel (20 g column) using 10-50% ethyl acetate-hexane to give 2-(2-tert-Butoxycarbonylamino-ethylamino)-6-nitro-benzoic acid methyl ester (0.59 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.48 (t, 1H, J=8 Hz), 7.11 (m, 2H), 7.00 (m, 1H), 6.52 (m, 1H), 3.77 (s, 3H), 3.24 (m, 2H), 3.11 (m, 2H), 1.44 (s, 9H); MS (m/e) 340 (M+1).
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]([O:16][CH3:17])(=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([O-])=[O:10])[CH:7]=1>CN(C=O)C>[CH3:17][O:16][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([Cl:3])=[O:10])[CH:7]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
SOCl2 (15 mL) and dry DMF (2 drops) were added to monomethyl isophthalate (5 g, 17.7 mmol), and the reaction mixture was refluxed at 80° C. for 6 hr. The SOCl2 was removed in vacuo, and a colorless oil was obtained and used directly in the next step.
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH:41]=O)([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:41][CH2:40][CH2:39][NH:38][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:43])[CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride (0.67 g, 1.93 mmole) was dissolved in methanol (5 ml), treated with diisopropylamine (0.34 m], 1.93 mmole) and allowed to stir at room temperature for 5 minutes. The product from Step 1 (0.50 g, 2.89 mmole) and sodium cyanoborohydride (133 mg, 2.12 mmole) were added and the mixture stirred under argon for 18 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:1) to afford the title compound (0.71 g). 1H NMR (CDCl3) δ 7.78-7.75 (2H, d), 7.59-7.56 (2H, d), 7.41-7.31 (4H, m), 4.52-4.43 (2H, d), 4.27-4.20 (1H, t), 3.51-3.42 (4H, br m), 3.25-3.15 (2H, m), 2.45-2.35 (6H, m), 1.72-1.60 (2H, m), 1.45 (9H, s).
Reaction SMILES: C(S[C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[N:10][C:8]=2[N:9]=1)C.ClC1C=C(C=CC=1)C(OO)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.O1CCOCC1>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[N:10][C:8]=3[N:9]=2)[CH2:42][CH2:41]1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: CN1CCNCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde (5-4a) (1.0 g, 2.69 mmol) in CH2Cl2 (30 mL) was added m-chloroperoxy benzoic acid (0.660 g, 3.0 mmol). The solution was stirred for 1 hr then quenched with sat. NaHCO3 and 10% Na2S2O3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2, extracted, dried with MgSO4, and filtered. A portion of the resulting sulfoxide (0.700 g, 1.81 mmol) was dissolved in dioxane (7 mL) with methyl piperazine (181 mg, 1.81 mmol) and heated to 100° C. for 20 min. in a microwave reactor. The mixture was concentrated under reduced pressure and the residue was purified by HPLC (Phenomenx Synergi column; 20-85% acetonitrile/water+0.1% TFA) to give the title compound (5-5a). 1H-NMR (500 MHz, d4-CD3OD) δ 10 (s, 1H), 9.48 (s, 1H), 8.65 (s, 1H), 7.88 (d, 2H), 7.64 (d, 2H), 7.46 (m, 6H), 7.33 (m, 3H), 7.26 (m, 3H), 3.6-3.4 (m, 8H), 3.00 (s, 3H) LRMS m/z (M+1) Calcd: 410.5, found 410.5.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].S(O)(O)(=O)=O.CS[C:21](=[NH:23])[NH2:22]>CS(C)=O>[C:21]([NH:13][NH:12][C:10]([C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)=[O:11])(=[NH:22])[NH2:23]
Reactant: CSC(=N)N
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: N=C(N)NNC(=O)c1csc(NC(=N)N)n1

Procedure:
17.9 g (0.089 mol) of 2 guanidino-4-thiazole carboxylic acid hydrazide was combined with 24.9 g of 2-methyl-2-thiopseudourea sulfate (0.089 mol) and heated rapidly to reflux in 125 ml dimethylsulfoxide. The reactants dissolved and within 5 minutes reflux a heavy precipitate formed. Reflux was continued for a total of 30 minutes. The reaction was cooled and the resulting heavy precipitate was isolated by filtration and washed with a small portion of dimethylsulfoxide followed by washing with isopropyl alcohol and ether. The resulting solid was dried in vacuo to give 34.6 g of 2-guanidino-4-thiazole carboxylic acid 2-amidinohydrazide containing some occluded dimethylsulfoxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:17][C:18]1[CH:19]=[C:20]([C:30](=[O:32])[CH3:31])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([N:27]1[CH2:26][CH2:25][N:24]([C:23]2[CH:22]=[CH:21][C:20]([C:30](=[O:32])[CH3:31])=[CH:19][C:18]=2[F:17])[CH2:29][CH2:28]1)=[O:8]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)c1cc(Br)ccc1N1CCOCC1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(Br)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 5-Bromo-2-morpholin-4-yl-benzoyl chloride and 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (94%, yellow foam, MS (m/e): 490.3 (M+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24](=O)[O:25]N2C(=O)CCC2=O)=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Reactant: COc1nccnc1NCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A)(118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S.(M+1): 371.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1>O1CCCC1>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
N,N'-Carbonyldiimidazole (12.9 g) is added to a solution of 2-chlorobenzoic acid (12.5 g) in anhydrous tetrahydrofuran (250 cc). The mixture is stirred for 2 hours at a temperature in the region of 20° C., until the evolution of gas has ceased. 2-Amino-7-chloro-1,8-naphthyridine (8.9 g) is then added and the mixture is heated under reflux for 22 hours. The reaction mixture is poured into distilled water (2000 cc), and the precipitate formed is separated by filtration, washed with water and dried in the air. On recrystallization from ethanol (180 cc) of the product thereby obtained, N-(7-chloro-1,8-naphthyridin-2-yl)-2-chlorobenzamide (6.9 g), m.p. 180° C., is obtained.