Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.C(O)(=O)/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1>>[C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)(=[O:7])/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](Cc1ccc(O)cc1)C(=O)NCc1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 51.2 %

Procedure:
The title compound was prepared from N-(N-tert-butoxycarbonyl-L-tyrosyl)-3,4-dihydroxybenzylamine (example 56, step A) (1.4 g, 3.3 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (978 mg, 5.4 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 40-80% AcOEt/CH2Cl2 containing 1% AcOH to yield the title product as yellow crystals (784 mg, 47%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[O:25]([C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:38]([C:35]1[CH:36]=[N:37][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1)(=[O:39])=[O:40])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate (32 mg, 0.086 mmol), triethylamine (50 μL, 0.36 mmol) and DMAP (1 mg, 0.008 mmol) in anhydrous CH2Cl2 (1 mL) was added 6-phenoxypyridine-3-sulfonyl chloride is reacted with R-aminocarnitine benzyl ester (67 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was purified by preparatory HPLC. The residue was dissolved into CH2Cl2 (50 mL) and washed with 0.1 N NaOH (5 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (18 mg, 37%). MS ESI 470.2 [M+H]+, calcd for [C24H27N3O5S+H]+ 470.17.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>O.COCCOC>[NH2:14][C:15]1[CH:22]=[CH:21][C:20]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 250 ml of water and 500 ml of 1,2-dimethoxyethane, was mixed 26.5 g of 4-(trifluoromethyl)benzeneboronic acid, 25 g of 2-amino-5-bromo-benzonitrile and 57.9 g of potassium carbonate. The mixture was bobbled through with nitrogen for 10 minutes, then 1 g of bis(triphenylphosphine)palladium(II) choride was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, added 700 ml of water and extracted with 800 ml of ethyl acetate. The organic phase was washed first with 300 ml of saturated sodium chloride, then 300 ml of 2 M calcium chloride and at last with 300 ml of water. The organic phase was dried with magnesium sulfate, evaporated to an oil and trituated with ether. Yield 30.5 g (92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 85 °C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
2-Fluoronitrobenzene (10.0 g, 70.9 mmol) was added to chlorosulfonic acid (10.0 ml, 150 mmol) at 65° C. After stirring at 85° C. for 18 h, the reaction mixture was cooled to room temperature and poured onto ice chips and extracted with CH2Cl2 (2×250 ml). The combined organic extracts were washed with saturated NaHCO3 solution and dried (MgSO4). Concentration at room temperature and then at 100° C. under high vacuum produced 2.40 g (14%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 8.76 (1H, dd, J=2.4, 6.5 Hz), 8.33 (1H, ddd, J=2.4, 3.8, 9.2 Hz), 7.61 (1H, t, J=9.2 Hz). MS (EI): 239 (15, M+), 204 (100).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([OH:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14]
Reactant: BrBr
Reactant: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Reaction time: 14 h
Yield: 74.7 %

Procedure:
6-Fluoro-3-hydroxy-2-nitrobenzoic acid (22 mg, 0.11 mmol) was dissolved in acetic acid (2 mL). Sodium acetate (10 mg, 0.12 mmol) and Br2 (10 μL, 0.19 mmol) was added and the reaction mixture was left at room temperature for 14 h. The temperature was raised to 50° and the reaction was continued for another 4 h. Evaporation gave a residue which was dissolved in water, and after adjustment of the pH the aqueous phase was extracted with EtOAc. Washing of the organic phase with water and evaporation gave a crude product which was purified by flash chromatography on SiO2. Eluation with toluene-EtOAc-HOAc afforded the product (23 mg). 1NMR (CD3OD): δ8.0 (d, J=8.7, 1H); MS (EI, 70 eV): m/z (rel. int.) 279/281 (M+, 40/38)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:6]1[C:7](OC)=[O:8])=[O:4].[NH3:15]>CO>[OH:14][C@@H:11]1[CH:6]2[C:7](=[O:8])[NH:15][CH2:2][C:3](=[O:4])[N:5]2[CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Reactant: N
Solvent: CO
Product: O=C1NCC(=O)N2CC[C@H](O)C12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl (3S)-1-(chloroacetyl)-3-hydroxy-L-prolinate (D69, 1.48 g, 6.7 mmol) in 10 ml of MeOH and 60 ml of a saturated solution of NH3 in MeOH was stirred for 48 h at rt. The solvent was evaporated under reduced pressure, to afford a solid. Analysis indicated this to be the title compound as a pair of diastereoisomers. After a short chromatography column (CHCl3/MeOH 8/2 as eluent) the title compound was isolated as a foamy solid (1 g). Yield 88%. Reference: Khimiko-Farmatsevticheskii Zhurnal 1984, 18, 1445-8
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].C1COCC1.[OH-].[Na+]>CO>[CH2:22]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sccc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccsc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.8 %

Procedure:
To a mixture of 1.494 g (3.583 mmol) of the product of Example 5 dissolved in 15 mL of methanol and 15 mL of THF was added 15 mL of 1N NaOH solution. The reaction mixture was stirred at room temperature for 36 h and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 1.327 g (92%) of the desired carboxylic acid as a white solid. CI Mass Spec: 404 (M+H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]([C:29](=[O:50])[NH:30][C@@H:31]3[CH2:35][CH2:34][C@H:33]([CH2:36][N:37]4[CH2:42][CH2:41][CH:40]([CH2:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH2:39][CH2:38]4)[CH2:32]3)([CH3:28])[C@@H:15]2[CH2:24][C:25]([CH3:27])=[CH2:26])[C:6]1([CH3:54])[CH3:53])(=O)C.[CH2:55]1COCC1.[OH-].[Na+]>CO>[CH2:43]([CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][C@H:33]2[CH2:34][CH2:35][C@@H:31]([NH:30][C:29]([C@:14]34[CH2:28][CH2:55][C@@H:24]([C:25]([CH3:27])=[CH2:26])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:51])([CH2:12][CH2:13]4)[C@@:10]4([CH3:52])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:53])([CH3:54])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:50])[CH2:32]2)[CH2:42][CH2:41]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: C1CCOC1
Reactant: C=C(C)C[C@@H]1[C@H]2CC[C@@H]3[C@@]4(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]2(C)CC[C@]1(C)C(=O)N[C@@H]1CC[C@H](CN2CCC(Cc3ccccc3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(2S,4aR,4bR,6aR,7R,8S,10aR,10bR,12aR)-8-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentylcarbamoyl)-1,1,4a,8,10a,10b-hexamethyl-7-(2-methylallyl)octadecahydrochrysen-2-yl acetate (Example 31, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); MASS: 711 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(5-(3,4-dimethylphenyl)pyrimidin-2-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propano ate (340 mg, 0.5 mmol, 1.00 equiv) in dichloromethane (18 mL), and trifluoroacetic acid (8.9 mL). The resulting solution was stirred for ca. 5.5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by HPLC reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 25.3 mg (8%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.35 (s, 1H), 11.26 (s, 1H), 8.72 (s, 2H), 8.25 (d, J=9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.56˜7.741 (m, 3H), 7.37 (s, 1H), 7.28˜7.13 (m, 3H), 4.34 (s, 1H), 3.84 (s, 2H), 3.31 (m, 4H), 2.60˜2.55 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[CH2:44]([O:43][C:41]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:17]1[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1)=[O:42])[CH3:45]
Reactant: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)OCC)cc1
Yield: 99.4 %

Procedure:
2-(4-Octyloxyphenyl)-4,5-diphenylimidazole (2.5 g) was reacted with ethyl 8-bromooctanoate (2.96 g) in a method similar to Example 9. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 1-(7-ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4, 5-diphenylimidazole (3.48 g, 94%) as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 34.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (41 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23.2 mg, 35%) as a red orange foam. 1H-NMR (CDCl3) δ 11.0 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.06 (dd, J=3.3, 6.8 Hz, 2H), 3.10-3.0 (m, 4H), 2.75 (m, 2H), 2.55 (m, 4H), 2.27 (m, 1H), 1.68 (d, J=10.1 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H); LC/MS (ESI+): 477 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([CH3:15])[C:13]#[CH:14].N1CCCCC1>CN(C)C=O.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.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:14]#[C:13][C:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)([CH3:15])[CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1nc(N)nc(N)c1C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Yield: 95.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 3, using 1.3 grams (0.005 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 1.6 grams of (0.008 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne (prepared as in Step F of Example 17), 0.3 gram of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram of copper iodide, and 8 mL of piperidine in 20 mL of N,N-dimethylformamide, yielding 1.6 grams of 2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butynyl]pyrimidine, mp 153°-157° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:16]=[C:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CC(N(C)C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17](=[O:18])[NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCCCCN=C=O
Solvent: CC(=O)N(C)C
Product: CCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
13.0g (0.10 mole) of 5-fluorouracil was suspended in 60 ml of dimethyl acetamide, then 14.0g (0.11 mole) of n-hexyl isocyanate was added thereto at room temperature and stirred at 50° C for 8 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured into 400 ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 19.3g (75.0% yield) of 5-fluoro-1-(n-hexylcarbamoyl)uracil was obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:26][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(Cl)c1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A suspension of Cs2CO3 (23.1 g, 71.0 mmol), 1-(2-chloroethyl)pyrrolidine, hydrochloride (9.0 g, 53.2 mmol) and 2-chloro-4-nitrophenol (3.0 g, 17.8 mmol) in DMF (50 mL) was heated at 80° C. for 4 days. After dilution with H2O (50 mL), the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O (30 mL), then with brine prior to drying over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 5%-10% gradient MeOH/CH2Cl2 to yield yellow brownish solid (1.5 g, 31%) MS (ESI) 271 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12)C)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12
Reactant: [H][H]
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2CCN(C)Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CNCCC1C(=O)N(c2ccccc2)c2cc(Cl)ccc2-n2c(C)nnc21

Procedure:
4 g of 4-[2-(N-benzyl-N-methylamino)ethyl]-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 0.4 of Raney nickel is hydrogenated at 50 p.s.i. hydrogen pressure until 0.0085 moles of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:21]1[C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of [(S)-1-(7-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (2.26 mmol) in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at RT for 3 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product was eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a pale orange oil (482 mg, 78%). LCMS: RT 2.11 and 2.24 min [M+H]+ 271.9
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>>[CH2:1]([NH:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1ccccc1

Procedure:
Using the method of Example 1, benzylamine and 4-chloro-3-nitroquinoline were reacted to provide 4-benzylamino-3-nitroquinoline. The structural assignment for the crude product (m.p. 178°-196° C.) was supported by infrared spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:12](O)(=[O:16])[C@@H:13]([CH3:15])[OH:14].CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][C:12](=[O:16])[C@H:13]([OH:14])[CH3:15])[NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: NC(=NO)c1cccc(Cl)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](O)C(=O)ON=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.82 g (22.4 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide and 2.00 g (22.2 mmol) of (R)-lactic acid were dissolved under Ar at 0° C. in DCM (50 mL) and DMF (15 mL). After 5 min 3.4 mL (33.2 mmol) DIC and 3.50 g (25.9 mmol) HOBt were added. After 15 min the mixture was warmed to r.t. and stirred for additional 3 h, followed by filtration and washing with DCM. The filtrate was evaporated in vacuo to near dryness, taken up in EA and washed with aq. NaHCO3, followed by water and finally 2 M aq. citric acid. The EA layer was filtered over a mixture of Na2SO4 and silica. Flash chromatography (Hep/EA=4/1 to 2/1 to 1/2) gave an oil which was triturated with Et2O to yield after drying 4 g (75%) of the title compound. 1H NMR: 7.69 (t, 1 H), 7.55-7.59 (m, 1 H), 7.44-7.49 (m, 1 H), 7.36 (t, 1 H), 5.10 (s, 2 H), 4.50 (q, 1 H), 1.54 (d, 3 H)