Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH:19]=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2nc(C=O)ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2)CC1
Reaction time: 3 h
Yield: 77.6 %

Procedure:
6-((tert-butyldimethylsilyl)oxy)quinoline-2-carbaldehyde (5.74 g, 20 mmol), AcOH (3.6 g, 60 mmol, 3 eq) and ethyl 4-piperidinecarboxylate (6.28 g, 40 mmol, 2 eq) in DCE (100 mL) were stirred at room temperature for 30 min. Then NaBH(OAc)3 (12.7 g, 60 mmol, 3 eq) was added to the mixture at room temperature and stirred for 3 h. The reaction mixture was quenched with water (300 mL), and adjusted to pH=8 with conc. aq. NH3 solution. Then the mixture was extracted with DCM (3×400 mL). The combined organic layer was washed by brine (300 mL), dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (PE:EA=4:1) to give ethyl 1-((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)piperidine-4-carboxylate as yellow oil (6.65 g, yield: 77%). ESI-MS (M+H)+: 429.3. 1H NMR (400 MHz, CDCl3) δ: 7.97 (d, J=8.4 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.27 (dd, J=9.2, 2.4 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 2.92-2.89 (m, 2H), 2.30-2.25 (m, 1H), 2.20-2.15 (m, 2H), 1.91-1.79 (m, 4H), 1.25 (t, J=7.2 Hz, 3H), 1.02 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(C)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 24 mg (0.24 mmol) 1-methylpiperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 19 mg (29.8%) product as an orange powder. MS (ESI) m/z 531.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]1=[O:21].BrN1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[NH:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH2:12][C:44]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]=3[CH3:35])[S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:3]1=[O:21]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Cc2c(C)[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 1,2,3,4-tetrahydro-3,6-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate [example 1 step a), 7.00 g) and N-bromosuccinimide (4.42 g) in chloroform (140 ml) was refluxed under illumination from a tungsten lamp for 2 hours. The solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (140 ml) and 2-methylindole (5.92 g) were added and the mixture stirred rapidly for 48 hours. The phases were separated and the aqueous phase extracted with dichloromethane (100 ml). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate/i-hexane (1:3) to give the sub-title compound as a pale brown solid (6.68 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[N:17][N:16]=[C:15]1[SH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[S:19][C:15]1[N:14]([CH3:13])[CH:18]=[N:17][N:16]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: Cn1cnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cnnc1Sc1ccnc2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A capped vial was charged with 4-chloro-6-bromoquinoline (500 mg, 2.06 mmol), 4-methyl-4H-[1,2,4]triazole-3-thiol (238 mg, 2.06 mmol), potassium carbonate (427 mg, 3.09 mmol), and DMF (5 mL). The reaction mixture was stirred at 60° C. for 18 h then at 90° C. for another 24 h, and cooled to room temperature. The reaction mixture was poured onto water (50 mL), and the resulting precipitate was filtered, washed with water and dried in a vacuum oven at 70° C. overnight to provide 600 mg of 6-bromo-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline as a white solid (91% yield): 1H NMR (DMSO-d6) δ 3.63 (s, 3H), 6.90 (d, 1H), 8.02 (m, 2H), 8.40 (d, 1H), 8.74 (d, 1H), 8.92 (s, 1H); MS (m/z) 321, 323 [M+H]+.
Reaction SMILES: [H-].[Na+].C([N:11]1[CH2:28][CH2:27][CH:15]2[N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH:14]2[CH2:13][CH2:12]1)[CH:19]([OH:26])[CH2:18][CH2:17]3)(=O)C1C=CC=CC=1.I[CH3:30]>CN(C=O)C>[CH3:30][O:26][CH:19]1[C:20]2[C:25]3=[C:24]([CH:14]4[CH2:13][CH2:12][NH:11][CH2:28][CH2:27][CH:15]4[N:16]3[CH2:17][CH2:18]1)[CH:23]=[CH:22][CH:21]=2
Reactant: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN2c3c1cccc3C1CCNCCC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
NaH (60% dispersion in mineral oil, 0.50 g, 1.2 mmol) was added to a solution of 10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-ol (0.20 g, 0.58 mmol) in DMF (5.0 mL) at 0° C. under N2. After 30 min, iodomethane (0.040 mL, 0.64 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1 h and then allowed to warm to room temperature prior to extracting with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/heptanes (2:1) to give 0.16 g (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 7.46-7.30, 6.94, 4.51, 4.22-4.03, 4.01-3.79, 3.65-3.41, 3.29, 3.12, 3.04, 2.90, 2.82, 2.34, 2.08; IR (drift) 1631, 1493, 1477, 1459, 1422, 1370, 1359, 1324, 1292, 1267, 1098, 1085, 786, 748, 706 cm−1; HRMS (FAB) calcd for C23H24N2O2+H 361.1916, found 361.1913.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:8]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CCOCC>[OH:6][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][C:1]1=[O:7]
Reactant: [Li]c1ccccc1
Reactant: O=C1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: O=C1CCCC1(O)c1ccccc1
Yield: 58.4 %

Procedure:
A solution of 73.5 g (0.75 mole) of 1,2-cyclopentanedione in 400 ml of ether was added to 1.5 moles of phenyl lithium in 1.2 liter of ether, and the mixture was stirred under N2 for one half hour. After careful addition of water, the ethereal layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was distilled under reduced pressure and gave 77.2 g of 2-hydroxy-2-phenylcyclopentanone, b.p. 122°-126° C. (1.5 mm), nD25 1.5551. The oxime was prepared by known procedures, m.p. 110°-112° C., and was reduced by hydrogenation over Raney nickel in 20% alcoholic ammonia. Removal of catalyst, evaporation of solvent and addition of HCl gave 2-hydroxy-2-phenylcyclopentylamine hydrochloride, m.p. 198°-199° C.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=[O:9].[CH2:11](I)[CH3:12]>CS(C)=O>[CH2:11]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=[O:9])[CH3:12]
Reactant: CCI
Reactant: O=C(O)c1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1cccc1C(=O)O
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Under nitrogen, a suspension of 50 g (0.9 mol) of pulverized KOH in 440 ml of anhydrous DMSO was treated with 20 g (0.18 mol) of pyrrole-2-carboxylic acid (Aldrich); this mixture was cooled in ice and treated with 28 ml (0.36 mol of ethyl iodide. The reaction was allowed to warm to ambient temperatures and stir overnight prior to concentration in vacuo. The residue was dissolved in 125 ml of water and the pH adjusted to 4 with aqueous HCl. The product was extracted with methylene chloride, dried (MgSO4), and concentrated in vacuo to give 19.6 g (78%) of colorless material: mp 77°-78° C.; NMR (DMSO-d6) δ 1.23(t, J=7 Hz, 3H), 4.29(q, J=7 Hz, 2H), 6.06(dd, J=3 and 1 Hz, 1H), 7.10 (t, J=2 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)nc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 40.5 %

Procedure:
2-(2-Hydroxyethoxy)-5-nitropyridine (obtained as described in Annalen der Chemie., 1936, 521, 286) (114 g) was added portionwise to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 24.8 g) in N,N-dimethylformamide (DMF) (600 ml), at such a rate that the temperature did not exceed 10° C. The solution was stirred at 0° C. for 10 minutes, and then tert-butylchlorodiphenylsilane (171 g) was added dropwise at such a rate that the temperature did not exceed 10° C. The solution was stirred for 72 hours and then added to water (2 l). The mixture was extracted with ethyl acetate (2 ×1 l), and the extracts were washed with water (1 l) and saturated sodium chloride solution (500 ml), and then dried (MgSO4). Volatile material was removed by evaporation, and the residue was purified by flash chromatography, eluting with hexane to give 2-[2-(t-butyldiphenylsilyl)oxyethoxy]-5-nitropyridine (B) (106 g), as an oil which solidified on standing, m.p. 63°-64° C. (from hexane); NMR (d6 -DMSO): 1.0(s,9H), 4.0(t,2H), 4.55(t,2H), 7.0(d,1H), 7.3-7.5(m,6H), 7.55-7.75(m,4H), 8.45(dd,1H), 9.0(d,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O>C1(C)C=CC=CC=1>[CH3:27][Si:26]([N:1]([Si:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Yield: 92.6 %

Procedure:
About 9.24 g of ethyl 4-aminobenzoate, 14.88 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 32.68 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 8 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 4-[bis(trimethylsilyl)amino]benzoate (4-BTMSAEBz) as a yellow oil (16.04 g, 93% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet, 2 H, aromatic protons), 6.76 (doublet, 2 H, aromatic protons), 4.12 (quartet, 2 H, CH2 protons), 1.00 (triplet, 3 H, CH3 protons), 0.02 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[NH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:33][CH2:32][CH2:31][NH:30][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: NCCO
Reactant: Cc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(NCCO)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1

Procedure:
A mixture of cis-4-[(4-chloro-6-methyl-1,3,5-triazin-2-yl)amino]-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (70 mgs, 0.16 mmol, 1.0 equiv), 2-aminoethanol (15 mgs, 0.25 mmol, 1.5 equiv), and potassium carbonate (34 mgs, 0.25 mmol, 1.0 equiv) in acetonitrile (3 ml) was heated to reflux for 16 h. The solvent was removed under reduced pressure, and the residue was extracted with CH2Cl2 and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 453.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Reactant: C1COCCN1
Product: O=C(c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1)N1CCOCC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using morpholine to give after working up and purification 25.0 mg (12%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CC(C)O
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCSC3)c2n1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.055 ml of aniline in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 20 hours, left to return to ambient temperature, diluted with 5 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum to a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 173 mg of expected product is thus obtained in the form of white crystals.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8](Cl)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[CH:23]1[C:28]([OH:29])=[CH:27][C:26]2[C:30]([CH2:33][CH2:34][NH2:35])=[CH:31][NH:32][C:25]=2[CH:24]=1>>[S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:35][CH2:34][CH2:33][C:30]3[C:26]4[C:25](=[CH:24][CH:23]=[C:28]([OH:29])[CH:27]=4)[NH:32][CH:31]=3)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Reactant: NCCc1c[nH]c2ccc(O)cc12
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(O)cc34)nc(-c3csc4ccccc34)nc21

Procedure:
Following the procedure of Example 15e, 2-(benzo[b]thiophen-3-yl)-6-chloro-9-isopropyl-9H-purine (b) (80 mg, 0.243 mmol) was reacted with serotonin. The reaction mixture was concentrated, then aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0 to 5% MeOH in DCM eluant) to afford the title compound as an off-white solid. MS m/z 469.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:11][C@@H:10]1[C@@H:12]([O:13][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([O:15][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:16]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][C@H:9]1[O:8][C@@H:7]1[C@@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH:2]([O:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:4][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:5]1[O:6][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lactose (1.0 g, 2.92 mmol) was dissolved in dry pyridine (20 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 58 mmol, 6.8 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 3.67 g (quantitative) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([NH:48][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and benzylamine (31 μL) according to Method A to give a material which was re-purified by reversed phase C-18 HPLC in absence of trifluoroacetic acid to give the title compound (29 mg). 1H-NMR (400 MHz, CD3OD) d 7.78 (s, 1H), 7.36 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 7.30-7.13 (m, 10H), 6.96 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.58 (t, J=6.9 Hz, 1H), 3.11-2.94 (m, 4H), 2.76 (dd, J=10 Hz, J=13.4 Hz, 1H), 1.33 (s, 9H); IR (KBr) 3304, 2979, 1694, 1640 cm−1; HRMS m/z 619.2511 (calc. of monoisotopic mass for C33H37N3O9 gives 619.2530).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1nc2cc(F)c(F)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Difluoro-benzene-1,2-diamine (4.98 g; 34.5 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.48 g; 51.9 mmoles) were suspended in 6N HCl (8 mL; 48 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a pale orange solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:13][C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]1[N:7]=[C:3]([CH2:2][NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CNCCCN2CCOCC2)n1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol) in DMF (2 mL) was added 4-(3-aminopropyl)morpholine (36.5 mg, 0.25 mmol) and KI (4.2 mg, 0.03 mmol) and the resulting mixture heated at 80° C. for 2 h. After cooling to room temperature, the mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with brine and water and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 80:20) afforded the title compound (47 mg, 74%) which was obtained as a yellow gum. MS: m/e=503.4 [M+H]+.