Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18]2>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH:20]3[CH2:23][CH:17]2[CH2:22][CH2:21]3)=[CH:4][CH:3]=1
Reactant: C1CC2CC1CN2
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CC3CCC2C3)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26 mmol), triethylamine (0.22 mL, 1.56 mmol) and 2-azabicyclo[2.2.1]heptane (71 mg, 0.52 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated under reduced pressure to afford the title compound (70 mg, quantitative yield) that was used in the next step without further purification. LCMS (Method B): RT=2.04 min, M+H+=266/268.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OC(C)C)(C)C>[CH2:46]([S:48][CH2:49][CH2:50][O:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH2:23][CH2:22][CH:21]3[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:2]([F:1])[CH:7]=2)=[C:31]([CH3:38])[CH:32]=1)[CH3:47]
Reactant: CCSCCO
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.00 g, 1.58 mmol), 2-(ethylthio)ethanol (0.219 mg, 2.06 mmol) and tributylphosphine (0.417 mg, 2.06 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.520 g, 2.06 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with diisopropyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (1.06 g, yield 93%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26](Cl)=[O:27])[CH:23]=[CH:24][CH:25]=1.CCN(CC)CC>O1CCOCC1>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:12][C:10]1[N:11]=[C:7]2[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1)=[O:27]
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3cccc(F)c3)nn12
Temperature: 90 °C

Procedure:
A mixture of 15 mg (0.062 mmol) 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]-pyridin-2-yl-amine, 11 mg (0.068 mmol) 3-fluorophenyl carboxylic acid chloride, and 31.5 μl (0.312 mmol) NEt3 in 1 ml dioxane was heated to 90° C. for 16 h. The mixture was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water gradient. Evaporation yielded the title compound. MS m/e (%): 281.7 ((M+CH3CN)+, 100).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>O1CCCC1.O>[CH2:16]([O:15][C:13]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[C:1]([OH:3])=[O:2])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-carboxypiperidine (50 g) in tetrahydrofuran (200 ml) and water (200 ml) was adjusted to around pH 9.5 with 20% aqueous sodium hydroxide. To the solution was added dropwise allyl chloroformate (45 ml) at 5° C., while adjusting pH to around 9.5 with 20% aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the mixture was washed with ethyl acetate. After addition of ethyl acetate (200 ml), the mixture was adjusted to around pH 2.0 with concentrated hydrochloric acid (30 ml) and 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 ml), washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil of 1-allyloxycarbonyl-2-carboxypiperidine (88.7 g), which was dissolved in methanol (440 ml). To this solution was added dropwise, sulfuric acid (6.9 ml) and the mixture was refluxed for 2 hours. To the mixture was added dropwise triethylamine (29.5 ml) at 20° C. Evaporation of the solvent gave a residue which was taken up into a mixture of ethyl acetate (400 ml) and water (100 ml). The organic layer was separated, washed with water, 1N aqueous hydrochloric acid, brine, 5% aqueous sodium hydrogen carbonate and brine successively, and dried over magnesium sulfate. Evaporation of the solvent gave 1-allyloxycarbonyl-2-methoxycarbonylpiperidine (92.5 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Na+].Cl.O>C(O)C>[F:14][C:2]([F:1])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of ethyl 2-(trifluoromethyl)-1,3-thiazole-4-carboxylate (278 mg) in ethanol (3.5 ml) was added 2M sodium hydroxide solution (2.4 ml) and the mixture stirred at RT for 1 h. The mixture was acidified by the addition of 2M hydrochloric acid solution (2.5 ml) and the mixture blown to dryness. The residue was treated with water (2 ml) and extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over sodium sulphate and evaporated to give the title compound (168 mg) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:27])[CH:22]([N:24]=[C:25]=[O:26])[CH3:23].C(N(C(C)C)CC)(C)C>>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]([NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[O:26])[CH3:23]
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: COC(=O)C(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 2-isocyanato-propanic acid-methyl ester, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 392 (M++1). 1H NMR (DMSO-d6) δ 1.30 (d, 3H), 2.96 (br.s, 4H), 3.55 (m, 4H), 3.61 (s, 3H), 4.16 (m, 1H), 6.26 (s, 1H), 6.45 (br.s, 2H), 6.90 (d, 1H), 7.10 (dd, 1H), 7.38 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (1 g, 2.53 mmol), (R)-pyrrolidin-3-ol (0.331 g, 3.80 mmol), TEA (0.706 mL, 5.07 mmol) and DMSO (2.53 mL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (50 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 1% to 4.5% EtOAc). The fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated under cyclohexane to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.15 min, m/z=462.9 [M+H]+, m/z=460.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.90 (m, 1H) 1.92-2.03 (m, 1H) 3.27 (dd, J=10.39, 1.10 Hz, 1H) 3.36-3.44 (m, 1H) 3.62-3.71 (m, 1H) 3.81 (dd, J=10.45, 4.71 Hz, 1H) 4.32-4.40 (m, 1H) 4.99 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.91 (m, 3H) 8.14 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.37 g, 10.17 mmol) was dissolved in DMF (100 mL). The solution was then heated to 80° C. N-Chlorosuccinimide (1.49 g, 11.1 mmol) was added at 80° C. under Argon gas. After two hours of continuous stirring, the reaction was checked by TLC and LCMS, and found to be incomplete. An additional aliquot of NCS (0.5 g, 3.7 mmol) was added, bringing the reaction to completion after 1.5 hours. While stirring, a portion of water (200 mL) was added to force the product to precipitate out of solution. After the precipitation was complete, the flask containing the solid was cooled in an ice water bath for 10 minutes. The solid was then filtered under vacuum and rinsed with water, yielding 2.4 g (89%) of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. This material was used in the next step without purification. LCMS m/z (%)=267 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J=12 Hz, 1H), 3.97 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:48]([CH:44]3[CH2:47][CH2:46][CH2:45]3)=[O:49])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing Example 22) (100 mg, 0.2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, mmol) and cyclobutanecarboxylic acid chloride (0.023 ml, 0.2 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA): water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA) water (0.1% TFA) (100:0 by volume) to afford the title compound (Slmg). LCMS (electrospray): m/z [MH+] 547.26. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.25(m, 8H), 7.20-7.15(m, 2H), 4.70(m, 1H), 4.50(m, 2H), 4.20(m, 2H), 3.95(m, 1H), 2.85(m, 1H), 2.30(m, 2H), 2.20(m, 2H), 2.05(m, 2H), 1.90(m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].N1C=CC=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1CCN
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1CCNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 2-(2-methoxyphenyl)ethylamine (1510 mg, 10 mmol, Aldrich), pyridine (10 mL), 4-(trifluoromethyl)benzoyl chloride (2 mL, 10 mmol, Fluka). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaHCO3 (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/CH2Cl2 to give N-(2-methoxyphenethyl)-4-(trifluoromethyl)benzamide. MS (ESI pos. ion) m/z: 324 (M+1).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[O:36]1[CH2:39][C:38](=O)[CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:2]4[CH2:3][C@@H:4]5[CH2:7][C@H:1]4[CH2:6][N:5]5[CH:38]4[CH2:39][O:36][CH2:37]4)[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C3COC3)n(C)c2n1
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A solution of of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethyl-benzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol), oxetan-3-one (40 mg, 0.31 mmol) and molecular sieves (4 Å, powdered, 200 mg) in DCE (7 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (148 mg, 0.70 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, gradient from 100:0 to 90:0) to afford 598 as a white solid (125 mg, 45%). LCMS (method I): RT=2.39 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.76 (m, 1 H), 7.26 (m, 2 H), 4.72-4.65 (m, 4 H), 4.34 (m, 4 H), 4.01-3.86 (m, 10 H), 3.35 (m, 4 H), 2.99 (m, 1 H), 2.82 (m, 1 H), 2.76 (m, 2 H), 1.79 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl[NH:2][C:3]1[N:8]=[C:7]([NH:9]Cl)[N:6]=[C:5]([NH:11]Cl)[N:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C:3]1[N:8]=[C:7]([NH:9][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:6]=[C:5]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:4]=1)=[O:18]
Reactant: ClNc1nc(NCl)nc(NCl)n1
Reactant: O=C(Cl)CCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 2.3 g N,N',N"-trichloromelamine, 20 ml carbon tetrachloride, 8.46 g 4-chlorobutyryl chloride and 30 mg N,N-dimethylaminopyridine was placed in a 100 ml flask fitted with a magnetic stirring bar, a reflux condenser and argon inlet. The reaction mixture was slowly heated in an oil bath to about 60° C. and was stirred at about 60° C. for 5 hours. It was allowed to cool down to room temperature and then diluted with 50 ml hexanes. The contents were stirred at room temperature for 30 minutes and then filtered. The residue was washed with hexane and dried under reduced pressure. It was characterized to be N,N',N"-tris(4-chlorobutyryl)melamine on the basis of NMR and mass spectroscopy (4.2 g; 95% yield):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9]N1C(=O)CCC1=O.O>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 96 ml of 3-fluoroaniline in 1000 ml of dichloromethane, 147 g of N-chlorosuccinimide was added at 0° C. and stirred for 12 hours at room temperature. Water was added to the reaction solution which then was extracted with chloroform. The extract was washed with saturated brine, dried on anhydrous sodium sulfate and distilled. The residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 21 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>COCCO>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccccc2)ccc1O

Procedure:
To a stirred solution of t-butyl hydroquinone (1.0 Kg) in 2-methoxy ethanol (2.0 L), was charged K2CO3 (2.0 Kg) portionwise under nitrogen atmosphere and the mixture refluxed. Benzyl chloride (0.762 L) was added dropwise at reflux temperature and heated further for 1.5 hr. The progress of the reaction was monitored on TLC. The reaction mixture was cooled and added DM Water (6.0 L). The uppermost oily layer was separated, dissolved in ethyl acetate (3.4 L), and washed with DM water (3.4 L×3). The uppermost oily layer was separated, dried over sodium sulfate and evaporated to dryness to give the crude title compound (1.5 Kg). The crude product was employed in the next step without further purification,
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][CH:31]([N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH2:32][C:33]#[CH:34]>C1COCC1.[Cu]I.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>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:34]#[C:33][CH2:32][CH:31]([N:35]2[C:36](=[O:45])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]2=[O:44])[CH3:30])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCC(C)N1C(=O)c2ccccc2C1=O
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A 100 mL, round-bottom flask containing a mixture of [4-(4-iodophenyl)but-3-ynyl]carbamic acid benzyl ester 23 (2.33 g, 5.75 mmol), CuI (0.22 g, 1.15 mmol), Et3N (10 mL) and THF (anhydrous, 15 mL) was vacuumed and refilled with nitrogen. The procedure was repeated three more time. To the suspension was added Pd(PPh3)2Cl2 (0.40 g, 0.58 mmol) in one portion, followed by a solution of compound 22 (1.35 g, 6.32 mmol) dissolved in THF (anhydrous, 10 mL), which was added dropwise over 2 h. The stirring was continued overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography eluting with a mixture of ethyl acetate (0-25%) and hexanes to afford the desired product 24 (2.60 g, 92%) as an off-yellow solid. 1H NMR (500 MHz, CDCl3) δ 1.71 (d, 3H), 2.61 (t, 2H), 2.92 (m, 1H), 3.14 (m, 1H), 3.43 (t, 2H), 4.67 (m, 1H), 5.07 (br, 1H), 5.11 (s, 2H), 7.12-7.33 (m, 9H), 7.71 (dd, 2H), 7.92 (dd, 1H); m/z (ESI) 491 [C31H26N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
Under nitrogen atmosphere, a solution of 4-chloro-2-nitro-benzoic acid (4.00 g) in THF (15 mL) was cooled to 0° C., and thereto was added dropwise dimethylsulfideborane (2.51 mL), and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=2/1) to give (4-chloro-2-nitrophenyl)methanol (1.32 g, 36%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.[CH3:81][N:82]([CH3:86])[CH2:83]CN>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:81][N:82]([CH3:86])[CH3:83])=[N:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: CN(C)CCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (16A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and N,N-dimethylethane-1,2-diamine. MS (m/z) 686.00 [M+H]+.