Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[C:16]([Cl:25])=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH2:20][CH2:19][CH2:18]3)[C:3]=1[CH:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29]C)=[O:28].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[C:16]([Cl:25])=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH2:20][CH2:19][CH2:18]3)[C:3]=1[CH:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([OH:29])=[O:28]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1Cl)CCCO2)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc3c(c2c(-c2ccc4c(c2Cl)CCCO4)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 18.9 %

Procedure:
To a solution of Methyl 2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.027 g; 0.053 mmol) in methanol (0.9 mL) was added a solution of sodium hydroxide 10 N (0.090 mL; 0.90 mmol) and the mixture was heated to 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 1N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.005 g (18%) of the title compound as a white solid.
Reaction SMILES: [CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7](OC)[O:8]C)/[CH3:2].CC(C)=O>O>[CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7]=[O:8])/[CH3:2]
Reactant: C=CC(Br)=N/C(=C\C)C(=O)CCC(OC)OC
Solvent: O
Solvent: CC(C)=O
Product: C=CC(Br)=N/C(=C\C)C(=O)CCC=O
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]acrylimidoyl bromide (7.0 g, 28.9 mmol) in a solution of acetone (30 mL) and water (1.5 mL) at room temperature, is added Amberlyse-15 (20 g). After mechanical shacking for 3 hr at room temperature, the reaction mixture is filtered. The resin beads were washed with acetone (contain 10% of Et3N). The combined organic layers were concentrated and purified by chromatography (Hexane/EtOAc: 70/30) to yield N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (5.18 g, 88.1%) as light yellow liquid. M/Z=421, 243.9 [M+1]
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(C(NC(=O)Nc2cc(OC)cc(C(F)(F)F)c2)c2ccccc2C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(NC(=O)NC(c2ccc(C(=O)O)cc2)c2ccccc2C2CCCCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
4-[1-(Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid methyl ester (3.0 g) was dissolved in absolute ethanol (50 mL), sodium hydroxide (4 N, 15 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo, and additional water (50 mL) was added, pH was adjusted with hydrochloric acid (4 N) to acidic reaction and then ethyl acetate (200 mL) was added. The organic phase was washed with water (5×50 mL), dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was recrystallised from acetonitrile (25 mL) to afford 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid (1.83 g) as crystals.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1([Mg]Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.O1CCCC1.CN1CCCC1=O>[C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCCCCCCCl
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCCc1ccccc1

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 0.027 g (0.12 mmol) of palladium (II) acetate and 7 ml of N-methylpyrrolidinone were weighed in the flask, followed by stirring. Further, 0.079 g (0.12 mmol) of tricyclohexylphosphonium tetra-para-tolylborate obtained in Example B-16 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 30 minutes. 0.404 g (3 mmol) of n-heptyl chloride was added, followed by stirring at 25° C. for 30 minutes. 2 ml (4.4 mmol) of 2.2M tetrahydrofuran solution of phenylmagnesium chloride was added dropwise at 25° C. over a period of 10 minutes, followed by stirring at 25° C. for 19 hours. After the completion of the reaction, 6 ml of tetrahydrofuran and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.434 g of 1-phenylheptane (yield: 82 mol % based on n-heptyl chloride). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:19](=[N:25]/O)/[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:19]\[C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: O/N=C\c1ccco1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 15 h
Yield: 40.5 %

Procedure:
In 450 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 131 g (0.5 mol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 66.5 g (0.6 mol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 15 hours. The solvent was evaporated under reduced pressure, and the residual oily material was poured into 3 l of ice-cooled water, and crystals precipitated were collected by filtration. The crystals were washed with water (500 ml×2), dried under reduced pressure and recrystallized from ethanol and then from ethyl acetate-hexane (7:3) to yield 63.5 g of ethyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5carboxylate. m.p. 152°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28]1(=[O:37])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: COc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 12 from 3-methoxyphenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the crude product was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.070 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.54-7.45 (m, 2H), 7.45 (m, 3H), 7.18 (t, 1H), 6.53 (dd, 1H), 6.48-6.42 (m, 2H), 5.79 (t, 1H), 3.89 (t, 2H), 3.82 (s, 3H), 3.12-3.06 (m, 2H), 1.86-1.82 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 161.1, 159.8, 159.7, 135.3, 131.8, 130.2, 129.7, 128.8, 125.3, 107.2, 107.1, 106.6, 101.2, 66.2, 61.7, 55.5, 42.6, 28.9, 27.8; Mass Spectrum M+H+ 445.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20]>>[CH2:22]([N:21]([CH2:19][CH3:20])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCc1ccccc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.7 mg). Calcd for C20H17F3N2O2: 374.1242, found 374.1243.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].CN(C1C=CC=CN=1)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 4.0 mL, 40.0 mmol) in methylene chloride (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and dimethylaminopyridine (0.20 g, 1.64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography 3% methanol in methylene chloride to give a white solid (59, 8.0 g, 85%). MS(ESI) [M−H+]+=234.0.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][N:34]=[C:33]([C:42]([F:45])([F:44])[F:43])[N:32]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[C:36]([C:37]([OH:39])=[O:38])=[CH:35][N:34]=[C:33]([C:42]([F:43])([F:44])[F:45])[N:32]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylate (194 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→7:3) to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylic acid (165 mg). MS (m/z): 755 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.Cl.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)#[N:21].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 18 h
Yield: 14.1 %

Procedure:
m-Cyanophenyl isocyanate (2.0 g, 13.9 mmol) and triethylamine (3.09 g, 30.5 mmol) in dimethylformamide (30 ml) was cooled to 0° C. and p-cyanobenzylamine hydrogen chloride (2.3 g, 13.9 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction was thawed to ambient temperature and was stirred for 18 h. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with 1N HCl and brine, then dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel with 1:1 hexane:ethyl acetate as an eluent; there was obtained 0.54 g of pure N-(3-cyanophenyl)-N′-((4-cyanophenyl)methyl)urea; LRMS (M+H)+ m/z 294.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:14]([CH:20]3[CH2:22][CH2:21]3)=[N:13]2)=[CH:8][CH:7]=1)=[O:4].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH:20]1([C:14]2[CH:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[N:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:7][CH:8]=3)[N:13]=2)[CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(-n2nc(C3CC3)cc2C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1)Nc1ccc(-n2nc(C3CC3)cc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 41 (150 mg, 0.475 mmol) and morpholine (40 mg, 0.475 mmol) were dissolved in DMF (3 mL) at 0° C. and Sodium Hydride (30 mg, 1.25 mmol) was added to the reaction mixture. Reaction was allowed to stir at ambient temperature overnight. Work-up (H2O:AcOEt) followed by purification on column afforded the title compound as a white solid. M.P. 178-184° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.87 (s, 1H), 7.74 (d, J 8.7, 2H), 7.49 (d, J 8.7, 2H), 5.77 (s, 1H), 3.63 (t, J 4.2, 4H), 3.13 (s, 2H), 2.48-2.45 (m, 4H), 1.89-1.69 (m, 2H), 0.92-0.81 (m, 4H), 0.69-0.60 (m, 4H). MS (m/z): 367.32 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([S:12]([CH2:15][S:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=1.C(O)C.[OH-].[Na+]>CN(C)C=O.O>[CH2:1]([CH:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:15]([S:16]([CH:19]2[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]2)(=[O:18])=[O:17])=[N+:39]=[N-:40])(=[O:14])=[O:13])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCCC)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCCC)CC2)CC1
Reaction time: 6.5 h
Yield: 11 %

Procedure:
In 22.4 g of dimethylformamide were dissolved 22.5 g (0.050 mol) of the bis(4-n-pentylcyclohexylsulfonyl)methane prepared above and 14.8 g (0.075 mol) of p-toluenesulfonylazide. To this solution were added 90.1 g of ethanol and 22.2 g of water. The solution was cooled on an ice bath, to which 2.0 g (0.050 mol) of sodium hydroxide in 23 g of water was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 6.5 hours. Filtration of the crystals gave 2.6 g of the desired bis(4-n-pentylcyclohexylsulfonyl)diazomethane. The yield was 46%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:21])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:21])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)c(C)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1nc(-c2ccccc2O)c(C)o1

Procedure:
Dissolve 5-[4-(2-methoxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (3.5 g, 11.5 mmol) in CH2Cl2 (50 mL) under nitrogen at RT. Add boron tribromide (1M in CH2Cl2, 29 mL) and stir at RT until the reaction is complete. Quench the mixture into ice/water and extract with CH2Cl2. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to allow for isolation of 5-[4-(2-hydroxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (2.61 g, 78%). MS (ES): (M+1)+ 290.2 m/z.
Reaction SMILES: IC.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[C:14]([C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH3:19])[NH:16][C:17]=2[CH3:18])=[O:12])=[CH:6][C:5]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25].[C:34](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[C:14]([C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH3:19])[N:16]([CH3:34])[C:17]=2[CH3:18])=[O:12])=[CH:6][C:5]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C(=O)Cc2ccc(F)c(C(=O)N3CCC(OC)CC3)c2)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Iodomethane (0.029 mL, 0.46 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (57) (0.100 g, 0.23 mmol) and potassium carbonate (0.048 g, 0.35 mmol) in DMF (5 mL). The resulting suspension was stirred at room temperature for 16 hours. The reaction was incomplete and further iodomethane (0.029 mL, 0.46 mmol) was added and the suspension was stirred at room temperature for a further 4 hours. The reaction was incomplete so the temperature was increased to 50° C. and the reaction mixture was stirred for a further 3 hours. The reaction mixture was poured into water (75 mL), extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.082 g, 79% yield); m/z (LC-MS, ESI+), RT=2.06 min (M+H=445.30).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17]>O>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([NH:14][CH2:15][CH2:16][OH:17])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: NCCO
Solvent: O
Product: OCCN[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
40 g (0.22 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated under reflux with 42 g (0.68 mol) of 2-aminoethanol in 450 ml of water overnight. The solution is extracted once with tert.-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([P:25]([CH2:29][CH3:30])([CH2:27][CH3:28])=[O:26])[P:19]([CH2:23][CH3:24])([CH2:21][CH3:22])=[O:20])=[C:8]([CH3:31])[C:7]=1[CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])(=[O:4])[CH2:2][CH3:3]>CO.[Pd]>[C:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([P:25]([CH2:29][CH3:30])([CH2:27][CH3:28])=[O:26])[P:19]([CH2:23][CH3:24])([CH2:21][CH3:22])=[O:20])=[C:8]([CH3:31])[C:7]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)O
Yield: 102 %

Procedure:
Compound 133 (815 mg, 1.17 mmol) was dissolved in MeOH (10 mL) and stirred with Pd/C (400 mg, 49%) under H2 (1 atm) for 8 hr. The catalyst was filtered off and the solvent removed under reduced pressure resulting in the crude colourless liquid 134 (650 mg, 92%), which was used without purification: 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J=7.5, 3H), 1.33 (t, J=7.2, 6H), 1.34 (t, J=7.2, 6H), 1.73-1.79 (m, 4H), 1.92-2.06 (m, 2H), 2.22 (s, 3H), 2.24 (s, 3H), 2.36 (tt, J=6.2, 24.3, 1H), 2.44-2.48 (m, 2H), 2.59 (q, J=7.7, 2H), 2.80-2.83 (m, 2H), 3.73 (t, J=6.1, 2H), 4.13-4.22 (m, 8H), 6.69 (s, 1H): 31P (162 MHz, CDCl3) δ 25.03 (s, 2P).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][CH3:25])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Clc1nc(Nc2ccccc2)c2[nH]cnc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A one liter flask is charged with 25.5 g of 2chloro-6-(phenyl-amino)-purine (104 mmol), 16.7 g of K2CO3 (121 mmoles) and 500 ml of DMF. The mixture is stirred for one hour to solubilize K2CO3, followed by addition of ethyliodid (16.1 ml, 200 mmoles). The flask is stirred at RT for 2 hours under argon. Upon completion, the solvent is removed by evaporation under reduced pressure, and the remaining powder is extracted with 150 ml of ethyl acetate, washed with water (3×30 ml) and with 30 ml of a saturated NaCl soln. The aqueous layers are extracted with ethyl acetate (2×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The crude product is stirred with 100 ml of diethyl ether to give a crude yellow powder, which is filtered and dried at 50° C. under HV. 23.08 g (84 mmol, 81% yield) of 2-chloro-9-ethyl-6-(phenyl-amino)-9H-purine are obtained as a white crystalline powder. Rf=0.65 (CH2Cl2/MeOH (95/5); m.p. 158° C.; ESI-MS: 274 (M+H)+; 1H-NMR (d6-DMSO, 200 MHz, TMS): 1.4 ppm (t, 3H, J1=7 Hz, H1), 4.2 ppm (q, 2H, J1=7 Hz, H2), 7.1 ppm (t, 1H, J2=8 Hz, H7), 7.4 ppm (t, 2H, J2=8 Hz, H6), 7.85 ppm (d, 2H, J2=8 Hz, H5), 8.3 ppm (s, 1H, H3), 10.3 ppm (s, 1H, H4).