Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:3].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:3][CH:2]([N:4]([CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:36]([CH3:35])(=[O:38])=[O:37])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((1-methylethyl)amino)methyl)-1,4-piperazinedicarboxylate (0.69 g, 1.9 mmol), DMAP (0.0358 g, 0.293 mmol), DIPEA (1.40 mL, 8.05 mmol) and CH2Cl2 (8 mL). To this mixture was added methanesulfonyl chloride (0.299 mL, 3.86 mmol) at room temperature. After 20 min at room temperature additional methanesulfonyl chloride (0.10 mL, 1.3 mmol) was added and stirring was continued at room temperature for an additional 1 h. The reaction mixture was partitioned between water (30 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (30 mL) and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford di-tert-butyl (2R)-2-(((1-methylethyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.617 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>CCCCCC.C(Cl)Cl>[C:31]([O:20][CH2:19][CH2:18][O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(=O)OCCOCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To dry methylene chloride solution (5 ml)of 200 mg (0.5 mmol)of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}ethanol (25a), 161 mg (1.60 mmol)of triethylamine was added under ice-cooling, 63 mg (0.8 mmol)of acetyl chloride was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added, neutralized, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1)to obtain 200 mg of 2-[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazol-2-ylmethoxy]ethyl acetate (Compound I-60)as oil (yield 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12](C(OC(C)(C)C)=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:15][CH:14]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1CN(C(=O)OC(C)(C)C)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1CNc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
To a solution of 7.00 g of 2-[(tert-butoxycarbonyl-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-amino)-methyl]-benzoic acid ethyl ester in 40 ml of dichloromethane was added 9.6 ml of trifluoroacetic acid and stirring was continued at 22° C. for 2.5 h. The mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, the organic layer was dried and evaporated. The residue was purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 3.14 g of the title compound as a pale yellow oil. MS: (M+H)+ 457.5.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[CH2:25](O)[CH2:26][CH2:27][OH:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:24][CH2:25][CH2:26][CH2:27][OH:28])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)OCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid (6.4 g, 19.5 mmol) in methylene chloride (225 ml) was added dropwise to a solution of 1,3-propane diol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.65 g, 20 mmol) and 4-(N,N-dimethylamino)pyridine (2.1 g, 17 mmol) in methylene chloride (225 ml) at −10° C. The reaction mixture was stirred overnight, warming up to room temperature. The reaction was filtered, concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoyloxy)-3-hydroxypropane as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([NH:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cc1ccc(CCCC(=O)O)cc1
Reaction time: 1.25 h
Yield: 96.2 %

Procedure:
Four and two-tenths g (0.015 moles) of 4-[4-[2-(Acetylamino)propyl]phenyl]-4-oxobutanoic acid was shaken under fifty lb/in2 of hydrogen pressure in 200 ml of acetic acid in the presence of one gram of 10% Pd/C in a Parr apparatus. Reduction was complete in approximately 1.25 hours. After removal of the catalyst by filtration, the solvent was distilled in the rotary evaporator leaving 3.8 g of a colorless syrup. An aliquot of the syrup was rubbed under acetonitrile whereupon it crystallized. Recrystallization from acetonitrile yielded white crystals of mp 114°-117°.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-])=O)[CH:15]=2)[N:10]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1ccc2nc(N3CC4CCC3CC4)ccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Reaction time: 6 h

Procedure:
The product of Step A and palladium hydroxide on carbon (1.3 g, 20% by wt) was suspended in methanol (100 mL) and ethyl acetate (100 mL). The resulting mixture was degassed then stirred under hydrogen atmosphere (balloon) for 6 h. The reaction mixture was filtered through filter aid and the solvent removed under vacuum. The resulting oil was dissolved in ethyl acetate and the solvent removed under vacuum. The resulting oil was suspended in ether and triturated until crystallization occurred. The solids were filtered and washed with ice-cold ether then dried under vacuum to afford the product as a brown solid, MS: m/z 254 (MH+), which was used without further purification
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14]>C(OCC)C>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:2][CH3:1])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: CN
Solvent: CCOCC
Product: CNC1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2.9 g (0.093 mol) of methylamine were passed over the course of 20 minutes into a stirred solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. The mixture was stirred at 0° C. for one hour and at 22° C. overnight. Washing with water, drying and concentration yielded 9.4 g (89.5% of theory) of the title compound of melting point 143° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(C1C(F)=CN=C(Cl)C=1C(O)=O)C.[CH3:27][S:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CSc1cccc(O)c1
Agent: CCc1c(F)cnc(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of ethyl-2-chloro-5-fluoro-nicotinoate (29 g, 0.143 mol) (prepared according to the method of J. Med. Chem., 1993, 36(18), 2676–88, at page 2684, column 2, 3rd compound, Ethyl 2-chloro-5-fluoropyridine-3-carboxylic acid) and 3-methylsulphanyl-phenol (20 g, 0.143 mol) (prepared according to the method of WO 98/45268, page 68, preparation 61) in dioxane (300 mL) was treated with caesium carbonate (46.5 g, 0.143 mol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water (600 mL) and extracted with ethyl acetate (3×250 mL). The organic layers were combined, washed with brine (200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:toluene (99.75:0.25 to 99.5:0.5) to yield the title product as a yellow oil, 27.1 g.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([OH:24])=O)=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.C([Cl:32])(=O)OCC(C)C.C([N:35](CC)CC)C.N>O1CCCC1>[ClH:32].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=[O:24])[NH2:35])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Reactant: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cl
Product: NCCOc1noc2ccc(F)c(C(N)=O)c12
Temperature: 5 °C
Yield: 95.6 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31 g) in tetrahydrofuran (20 ml) was added isobutyl chlorocarbonate (0.14 g) and triethylamine (0.11 g) with stirring at 5° C., and the mixture was then stirred for 15 minutes. Ammonia-saturated tetrahydrofuran solution (saturated at room temperature, 5 ml) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with diethylether (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give title compound (0.24 g, 78% yield) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[C:29]([NH:28][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=5)[CH:50]=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(OC(F)(F)C(F)F)c1
Yield: 33.4 %

Procedure:
Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (74 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.39 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (46 mg, 34%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1.[C-]#N.[K+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.430 g (0.664 mmol) of the blocked nucleoside (102) and 0.216 g (3.317 mmol) of KCN in 13 mL of 70% EtOH was stirred at room temperature for 6 hr. The reaction mixture was diluted with 75 mL of EtOAc. The EtOAc solution was washed with H2O (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×15 cm, eluted successively with CHCl3, 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 43-60 (10 mL per fraction) and recrystallization from MeOH/MeCN gave 0.157 g (2 crops, 44%) of 103 as white crystals. MP: 168-170° C. MS: (FAB) m/e 518.7947 (28%, MH+ =518.7957). 1H NMR (DMSO-d6): d 8.76 (s, 1, 7-H), 5.87 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.0 Hz), 5.42 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.37 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.02 (m, 1, 4'-H, J4'-5" =2.5 Hz), 3.71 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 142.32 (C2), 140.94 (C3a), 132.50 (C7a), 120.62 (C5), 118.44 (C6), 117.10 (C7), 115.34 (C4), 89.58 (C1'), 86.50 (C4'), 71.93 (C2'), 69.63 (C3'), 60.89 (C5'). Anal. Calcd. for C12H10Br3ClN2O4 0.3 MeCN: C, 28.36; H, 2.06; N, 6.04. Found: C, 28.25; H, 1.84; N, 5.90. (the Content of 0.3 MeCN was also indicated by 1H NMR.)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:8][C:3]([CH3:9])([CH2:2][O:1][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)(C)CO
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of 25.0 g of methyl 3-hydroxy-2,2-dimethylpropanoate in 100 ml of pyridine, cooled to 0° C., were added 55.7 g of trityl chloride. The mixture was stirred at room temperature for 20 hours, and then the solvent was evaporated in vacuo. The residue was taken up in 200 ml of ethyl acetate, and the solution was washed successively with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was taken up in 50 ml of methylene chloride, and to the solution were added slowly, at 0° C., 300 ml of hexane. Trityl alcohol crystallized and was filtered off. The filtrate was evaporated in vacuo to yield 53.5 g of raw methyl 2,2-dimethyl-3-trityloxy-propionate.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.C[CH2:29][N:30](CC)[CH2:31]C.Cl[C:36](=[O:41])[C:37](OC)=[O:38].CNC.CO>C(Cl)Cl.CCO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:13]2[N:14]=[C:3]3[C:2]4([NH:1][C:36](=[O:41])[C:37]([N:30]([CH3:31])[CH3:29])=[O:38])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]4)[CH2:5][N:4]3[C:11](=[O:27])[C:12]=2[OH:26])=[O:16])=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: COC(=O)C(=O)Cl
Agent: CNC
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.134 mmol) in CH2Cl2 (2 mL) at 0° C. was added Et3N (0.094 mL, 0.671 mmol) followed by methyl 2-chloro-2-oxoacetate (0.1 mL, 0.671 mmol) and the resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated to give crude product which was dissolved in EtOH (2 mL), treated with 2M dimethylamine/methanol (0.7 mL) and heated in a sealed tube at 85° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a light yellow solid (9 mg, 13% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.36 (dd, 2H, J=8.55 and 5.49 Hz), 7.00-7.04 (m, 2 Hz), 4.54 (d, 2H, J=6.1 Hz), 4.16 (d, 2H, J=3.66 Hz), 3.28 (s, 3H), 2.91 (s, 3H), 2.50-2.56 (m, 3H), 2.06-2.10 (m, 2H), 1.92-1.99 (m, 2H), 1.70-1.74 (m, 2H). LCMS (M+H)=472.37. HPLC purity: >95%.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([N:10]([CH2:21][CH3:22])[C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]#[N:19])=[C:13]([NH2:20])[N:12]=1)[CH3:9].[O:23]1[CH2:27][CH2:26][CH2:25]C1>>[CH2:21]([N:10]([CH2:8][CH3:9])[C:11]1[N:12]=[C:13]([NH2:20])[C:14]([C:18]#[N:19])=[C:15]([NH:17][C:27](=[O:23])[CH:26]([CH3:1])[CH3:25])[N:16]=1)[CH3:22]
Reactant: C1CCOC1
Reactant: CCN(CC)c1nc(N)c(C#N)c(N)n1
Reactant: CCN(CC)CC
Product: CCN(CC)c1nc(N)c(C#N)c(NC(=O)C(C)C)n1

Procedure:
7 g of triethylamine are added to a solution of 10.3 g of 2-diethylamino-4,6-diamino-5-cyanopyrimidine (prepared in accordance with Example 2) in 90 ml of tetrahydrofuran. Then 8.5 g of isobutyryl anhydride are added dropwise to this solution at 60° C. The reaction mixture is heated for 48 hours under reflux, concentrated by evaporation, and the residue is washed with diethyl ether, affording the title compound of formula ##STR24## with a melting point of 151°-152° C. (compound 1.3).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.[NH2:15][C@H:16]1[CH2:21][C:20]2[C:22]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:22]2[C:20]3[CH2:21][C@H:16]([NH:15][C:8](=[O:10])[C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:12][CH:11]=4)[CH2:17][O:18][C:19]=3[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OC(F)(F)F)cc2)CO3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
A mixture of 4-trifluoromethoxybenzoic acid (254 mg, 1.23 mmol) in thionyl chloride (5 mL) was heated at 60° C. for 25 min. The excess of thionyl chloride was removed under reduced pressure, and the remains were evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (277 mg, 1.12 mmol) and triethylamine (234 μL, 1.68 mmol) in methylene chloride (10 mL). The reaction mixture was stirred for 2 h at room temperature and was washed with a saturated solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The product was purified by column chromatography on silica (eluent: chloroform/ethanol, 92:8+0.5% conc. NH3) affording 248 mg (51% yield) of the title compound as a white solid: mp 192-193° C.; [α]21D−75° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 435 (6, M30 ).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH2:40][CH3:41]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH2:40][CH3:41])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CCC=O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CCCN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using propionaldehyde. The final product was obtained in 40% yield.
Reaction SMILES: [CH2:1]([OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:1]([O:27][S:42]([C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Yield: 21.9 %

Procedure:
A solution of hexacosanol (250 mgs, 0.654 mmol), triethylamine (125 1, 0.900 mmol) and 4-chlorobenzenesulphonyl chloride (150 mgs, 0.711 mmol) in methylene chloride (30 ml) is stirred at room temperature for 120 h. The reaction mixture is then diluted with methylene chloride (20 ml) and washed with water (2×50 ml). The organic phase is dried over magnesium sulphate, filtered and concentrated to give a crude product. Flash column chromatography on silica gel (10:1 hexane:ethyl acetate) followed by recrystallization from methanol gives n-hexacosanyl-4-chlorobenzenesulphonate (80 mgs, 22%).