Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=[C:4]([O:16][CH3:17])[N:3]=1.Cl.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>CCO>[CH3:17][O:16][C:4]1[N:3]=[C:2]([NH:30][CH2:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(-c2cc(Cl)nc(OC)n2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cc(NCCc3ccc([N+](=O)[O-])cc3)nc(OC)n2)c1
Temperature: 170 °C
Yield: 50.9 %

Procedure:
To a solution of 4-chloro-2-methoxy-6-(3-methoxy-phenyl)-pyrimidine [80 mg, 0.32 mmol, Intermediate (53)] and 2-(4-nitro-phenyl)-ethylamine hydrochloride (77.6 mg, 0.38 mmol) in EtOH (1.1 mL) is added diisopropyl-ethylamine (0.139 mL, 0.80 mmol). The reaction mixture is heated under microwave at 170° C. for 45 minutes. Solvent is removed and residue is subjected to flash column chromatography (silica gel: 10-50% ethyl acetate/heptane) to afford [2-methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-nitro-phenyl)-ethyl]-amine [62 mg, 51%, Example 43(b)] as a solid. LC/MS: RT=2.57 minute, MS: 381 (M+H). 1H NMR (300 MHz, (CD3)2SO): □8.14 (2H, d, J=9.8 Hz), 7.53 (2H, d, J=9.8 Hz), 7.52 (3H, m), 7.38 (1H, t, J=8.6 Hz), 7.01 (1H, m), 6.58 (1H, s), 3.84 (3H, s), 3.79 (3H, s), 3.6 (2H, m), 2.99 (2H, m). IC50=0.9 nM
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:11]=[C:18]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[N:8]2[CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: CCNc1nc(Cl)ncc1N
Reactant: O=Cc1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CCn1c(-c2ccncc2)nc2cnc(Cl)nc21
Temperature: 140 °C
Yield: 15.4 %

Procedure:
To a solution of 8.6 g (50 mmol, 1.0 eq.) of 2-chloro-N4-ethylpyrimidine-4,5-diamine (I-5) in 200 mL of 2% v/v AcOH/DMA was added 6.0 mL (65 mmol, 1.3 eq.) of 4-pyridine carboxaldehyde. The mixture was heated at 140° C. for 14 h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide 2.0 g (7.7 mmol, 15%) of 2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purine (I-6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Cl.[Na].[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: COCCO
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Na]
Product: COCCOc1cc(C)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1,2-Dichloro-4-methyl-5-nitrobenzene (R.J. De Lang, et al. Tetrahedron (1998), 54(12), 2953-2966.) (860 mg; 4.17 mmol) was added to solution of sodium (115 mg; 5.01 mmol) dissolved in 2-methoxyethanol (15 ml). The brown reaction mixture was stirred at 100° C. for 1 h, poured on brine (50 ml) and extracted with TBME three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 1/9) to yield the title compound as orange crystals (640 mg; 63%)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[S:27][C:26]([C:24]2[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:25]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.3 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as an off-white solid (0.08 g, 16%). MS (ISP) 485.9 [(M+H)+]; mp 189° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:19][C:18]1[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:21])=[N:14][C:15]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:16][CH:17]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(NC1CC1)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC4CC4)n3)cc2)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-cyclopropyl-2((2,5-dichloropyrimidin-4-yl)amino)benzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 38% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.64 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.44 (m, 2H), 7.25 (d, 2H, J=8.2 Hz), 7.07 (t, 1H, J=7.5 Hz), 6.38 (bs, 1H), 3.50 (s, 2H), 2.93 (q, 1H, J=3.4 Hz), 2.55 (bs, 8H), 2.35 (s, 3H), 0.92 (m, 2H), 0.65 (m, 2H); MS (ESI): 492.1 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]([I:12])=[C:7]([I:11])[C:8]([OH:10])=[O:9].N1C=CC=CC=1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[I:11][C:7](=[C:6]([I:12])[I:5])[C:8]([O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: O=C(O)C(I)=C(I)I
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)C(I)=C(I)I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 0.3 ml of thionyl chloride in 2 ml of benzene was added dropwise to a mixture of 0.3 g of triiodoacrylic acid, 0.3 ml of pyridine and 3 ml of benzene. The mixture was then stirred at room temperature for 45 minutes, after which the solvent was distilled off under reduced pressure. 5 ml of benzene and 0.3 ml of pyridine were added to the resulting residue, and then 0.3 g of phenol was added, with ice-cooling, after which the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into an ice-cooled dilute solution of hydrochloric acid and then extracted with diethyl ether. The extract was washed, in turn, with a saturated aqueous solution of sodium bicarbonate, water and then a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulphate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography through silica gel eluted with a 100:12 by volume mixture of hexane and ethyl acetate, to give 0.18 g of the title compound, melting at 83°-84.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1.O>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCCNCCCl
Reactant: Nc1cc(Cl)cc2cccnc12
Agent: Cl
Solvent: O
Solvent: Clc1ccccc1
Product: Clc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 135 °C
Reaction time: 120 h
Yield: 29.4 %

Procedure:
8-amino-6-chloroquinoline (Step 1, 0.49 g) and bis(chloroethyl)amine hydrochloride (0.49 g) were dissolved in chlorobenzene (13 mL) and heated with vigorous stirring at 135° C. for 5 days. The reaction was cooled to room temperature, diluted with water and extracted with Et2O. The aqueous phase was made basic by addition of solid Na2CO3 and then extracted with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give the desired compound (0.20 g) as a yellow semi-solid; MS (ES) m/z (relative intensity) 248 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:24]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-fluorobenzyl)pyrrolidine hydrochloride (12.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.3 mg). Calcd for C22H21FN2O2: 364.1587, found 364.1604.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][OH:5].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:49]=[CH:48][C:34]3[N:35]4[CH:40]=[C:39]([C:41]5[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=5)[N:38]=[C:36]4[S:37][C:33]=3[CH:32]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[OH:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:47][C:44]2[CH:43]=[CH:42][C:41]([C:39]3[N:38]=[C:36]4[N:35]([CH:40]=3)[C:34]3[CH:48]=[CH:49][C:31]([O:30][CH2:29][CH2:28][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[CH:32][C:33]=3[S:37]4)=[CH:46][CH:45]=2)=[O:21])[CH:8]=1)([CH2:2][OH:1])[CH3:6]
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Reactant: CC(CO)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(CO)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1

Procedure:
A mixture of phenyl 5-(1,3-dihydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (1 equivalent), 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (4) (1 equivalent) and 4-(dimethylamino)pyridine (0.05-0.5 equivalents) in anhydrous THF is stirred at a temperature between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 1-[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1a).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:48])[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][NH2:47])[CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH2:46][CH2:45][C:41]3[CH:40]=[C:39]([CH3:48])[CH:44]=[CH:43][CH:42]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Cc1cccc(CCN)c1
Product: Cc1cccc(CCNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-(m-tolyl)ethylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH:20]=[O:21])[CH:19]=1)[CH2:5][N:6]([CH:14]1[CH2:16][CH2:15]1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CC1(C)C(C)(C)OB(/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH:14]1([N:6]([CH2:5][C:4]2[CH:3]=[C:2](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(C=O)c1)C1CC1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C=O)cc(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl (3-bromo-5-formylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 90° C. for 6 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](F)(=[O:35])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:33]([C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)F
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/l; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)=Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(OC)cc1

Procedure:
Ethyl p-methoxy-α-methylcinnamate (39.1 g) is dissolved in 186 ml of 2B ethanol. This solution is shaken with 1.5 g of 10% palladium on carbon at an initial pressure of 60 psi until the uptake of hydrogen is 100%. The reaction mixture is removed on an evaporator leaving ethyl β-(p-methoxyphenyl)-α-methylpropionate.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][CH2:8][C@H:9]([OH:13])[C:10]([OH:12])=[O:11].[CH3:14][C:15](=[CH2:17])[CH3:16]>C(COC)OC>[NH2:6][CH2:7][CH2:8][C@H:9]([O:13][C:15]([CH3:17])([CH3:16])[CH3:14])[C:10]([O:12][C:15]([CH3:16])([CH3:14])[CH3:17])=[O:11]
Reactant: C=C(C)C
Reactant: NCC[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H](CCN)OC(C)(C)C
Temperature: -78 °C
Reaction time: 96 h

Procedure:
The following reaction was carried out in a Fischer-Porter tube. Dimethoxyethane (76 ml) and 3.2 ml of concentrated sulfuric acid were added in that order to 4.0 g of 4-amino-(2S)-hydroxybutyric acid (AHBA), and the mixture was then cooled to −78° C. Isobutylene (38 ml) was added thereto, and the tube was sealed, followed by stirring at room temperature for 96 hr. The tube was then slowly opened, and isobutylene was removed by distillation at room temperature. The reaction mixture was then added dropwise to 128 ml of ice water, and the mixture was washed twice with 250 ml of ether, was cooled to 0° C., and was then neutralized with a 6 N aqueous sodium hydroxide solution. Further, solid sodium chloride was added to prepare a saturated solution, and the mixture was extracted four times with 100 ml of chloroform. The chloroform layers were combined, and the combined chloroform layers were dried over anhydrous sodium sulfate and were then concentrated under the reduced pressure to give 250 mg of a yellow oil. The yellow oil was purified by column chromatography on silica gel (30 g, chloroform-methanol-concentrated aqueous ammonia=20:1:0.05→9:2:0.1) to give 37.9 mg of intermediate 3 and 161 mg of intermediate 4.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CCOCC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
A solution of 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (3.64 g, 23 mmol) in tetrahydrofuran (136 ml) was treated with a solution of lithium hydroxide (4.83 g, 115 mmol) in deionized water (27 ml). The reaction mixture was heated to 50° C. for overnight and then partitioned between EtOAc/water. The aqueous phase was collected and then partitioned between EtOAc/ice cold 1N HCl. The organic layers were dried over MgSO4, filtered, and concentrated providing 3 grams (90%) of 4-methyl-tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:28][S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:31])=[O:30])[C:6]([OH:38])=[O:5])=[O:27])=[CH:16][CH:15]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2cccc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CCOc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1

Procedure:
Ester 30-6 (120 mg, 0.22 mmol) was dissolved in 1 mL CH2Cl2, and 1 mL TFA was added. After 1 h the reaction was concentrated azeotroped with toluene, chromatographed (silica, 18:1:1→9:1:1→CH2Cl2 /MeOH/HOAc) and purified by prep HPLC (C18, 0.1% TFA in H2O/CH3CN) providing 30-7 as a white solid.
Reaction SMILES: [CH:1]1([CH2:8][NH:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1N(CC2CCCC2)C(=O)N(CC2CCCC2)[C:24](=[O:41])[CH:23]=1>>[NH2:21][C:22]1[N:9]([CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:10](=[O:11])[N:12]([CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:24](=[O:41])[CH:23]=1
Reactant: Nc1cc(=O)n(CC2CCCC2)c(=O)n1CC1CCCC1
Reactant: O=C(NCC1CCCCCC1)NCC1CCCCCC1
Product: Nc1cc(=O)n(CC2CCCCCC2)c(=O)n1CC1CCCCCC1

Procedure:
In the manner of step (b) of Example 1, 1,3-bis(cycloheptylmethyl)urea (from step (a), 3.99 g, 14.23 mmol) was converted to 6-amino-1,3-bis(cyclopentylmethyl)uracil (3.22 g, 65%), m.p. 194°-197° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][C@H:48](Cl)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:48]([CH3:47])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@H](C)Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Putting 4-benzyloxyphenol (5 g) and triphenyl phosphine (23.58 g) into a two-neck bottle (500 mL), and then vacuuming for 1 hour. Under the protection of nitrogen, adding dichloromethane (150 mL) followed by stirring to dissolve. Adding diethyl azodicarboxylate (22.73 g) into the bottle on ice bath followed by stirring. Adding (s)-2-octylchloride (13.36 g), reacting 24 hours under room temperature. Extracting by water and dichloromethane, drying with anhydrous magnesium sulfate, removing the solvent by a rotary vacuum evaporator, column chromatography of the crude product is carried out to gain a pure target compound (19.41 g). The yield is about 83%.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]([Br:18])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2c1nc(Br)n2Cc1ccccc1

Procedure:
To a stirred solution of 9-benzylpurine (6) (15.0 g, 66.5 mmol) in chloroform (750 mL) was added N-bromosuccinimide (59.26 p. 332.9 mmol) and the reaction mixture vas stirred under an atmosphere of nitrogen at reflux temperature for 3 h. The reaction mixture was then transferred to a separatory funnel and washed with saturated aqueous sodium sulfite (2×250 mL) followed by brine solution (2×250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated to give a reddish oil, which was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 9.72 g. (48%). Mp 199-201° C. 1H NMR (CDCl3) δ 5.39 (s, 2H, benzylic CH2), 7.29-7.33 (m, 5H, Ar—H), 8.29 (s, 1H, purine C2—H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH2:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Yield: 98 %

Procedure:
Preparation from 1-(t-butyloxycarbonylamino)-3,6-dioxa-8-octanamine) (5 g, 20.16 mmol) and succinic anhydride (2.218 g, 22.18 mmol) gave a thick yellow oil which crystallised on standing (6.5 g, yield 98%). LCMS (Method 6): Rt 2.99 min; m/z (M+1) 349; Calcd.: 349.