Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of diethyl 4-(amino)benzylphosphonate (2.02 g; 8.3 mmoles) and triethylamine (1.02 g; 9 mmoles) in toluene (7 ml) cooled to 0-5° C., is added dropwise a solution of acryloyl chloride (0.91 g of 95% purity; 10 mmoles) in toluene (2 ml) for 30 min. Thereafter, more toluene (5 ml) is poured into the flask and the mixture is stirred at room temperature for two more hours. The reaction is terminated by addition of water (10 ml). The organic phase is extracted with diethyl ether, dried over MgSO4 and stripped of solvent under vacuum to afford a pale-yellow solid (2.22 g; yield 90%).
Reaction SMILES: [Mg].Br[C:3]1[CH:14]=[CH:13][C:6]([O:7]C(OCC)C)=[CH:5][CH:4]=1.[CH3:15][N:16]([CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17].[Cl-:32].[NH4+].Cl>O1CCCC1.CCOCC>[ClH:32].[CH3:17][N:16]([CH:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1([C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:13][CH:14]=1)[OH:25])[CH3:15]
Reactant: [Cl-]
Reactant: CCOC(C)Oc1ccc(Br)cc1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: Cl
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1ccc(O)cc1
Temperature: 55 °C

Procedure:
0.38 g (15.5 mmole) of magnesium turnings was stirred in 5 ml of tetrahydrofuran of analysis purity. 3.81 g (15.5 mmole) of 1-(4-bromophenoxy)-1-ethoxyethane dissolved in 5 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at 55° C. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of tetrahydrofuran, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator (500 to 10 mbar). 5.25 g of crude base were obtained, which were dissolved in 20 ml of ether followed by the addition of 10 ml of hydrochloric acid (1 N). The aqueous phase was separated and sufficient sodium bicarbonate was added to adjust the pH to ca. 8.The base was extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.96 g of crude base (46.3% of theory) were obtained, from which 1.8 g of 4-[2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl]phenol, hydrochloride were obtained (38.6% of theory) with 0.49 ml of hydrochloric acid (32 m %,) and 20 ml of acetone. The hydrochloride decomposes on heating above 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][C:13]#[N:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: N#CCCNS(=O)(=O)c1cccc(Br)c1
Yield: 55.9 %

Procedure:
Prepared by general procedure III from 3-Bromobenzenesulfonyl chloride (10.0 g, 38 mmol) and 3-aminopropanonitrile (2.96 g, 42 mmol) to give the title compound (6.14 g, 55%) of an off-white solid. MS (ISP) 308.1 [(M+NH4)+].
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46]CCCl>C(O)(=O)C.O1CCCC1>[ClH:46].[ClH:46].[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH:19]([NH:11][CH2:10][CH2:9][C:8]2[C:12]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:13]=3)[NH:6][CH:7]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(CCNC3CCC(c4ccccc4)(N(C)C)CC3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Methyltryptamine (348 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the exclusion of oxygen. Glacial acetic acid (114 μl) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated, the residue was taken up in 1M HCl (20 ml) and diethyl ether (40 ml), the phases were separated, and the aqueous phase was extracted with diethyl ether (2×20 ml) and adjusted to pH 11 with 5M NaOH. The aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried with Na2SO4 and concentrated. The residue was purified by chromatography with MeOH/NH3 (500:1). The nonpolar diastereomer (brown oil, 379 mg) was dissolved in 2-butanone (10 ml) and converted by addition of chlorotrimethylsilane (319 μl) into the corresponding dihydrochloride (white solid; 405 mg; m.p. 234-236° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([NH2:20])=O)[CH2:14][CH2:13]2)=[C:8]([F:21])[CH:7]=1)=[O:5])[CH3:2]>C1COCC1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]#[N:20])[CH2:16][CH2:17]2)=[C:8]([F:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1ccc(N2CCC(C#N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.5 %

Procedure:
To a solution of 1.50 g of 1-(4-ethoxycarbonyl-2-fluorophenyl)piperidine-4-carboxamide in 20 ml of THF, 2.0 ml of triethylamine and 0.9 ml of trifluoroacetic acid anhydride were added at −78° C., and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, EtOAc was added, and then the organic layer was washed with water and brine, and dried over sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=5:1˜4:1) to obtain 1.43 g of 4-(4-cyanopiperidino)-3-fluorobenzoic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:1][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)COC1CCCCO1
Yield: 80.8 %

Procedure:
A solution of 1-hydroxy-propan-2-one (95%, 78 g, 1.0 mol), 3,4-dihydro-2H-pyrane (95%, 88.5 g, 1.0 mol) and pyridinium p-toluenesulfonate (25.1 g, 0.1 mol) in THF (1.2 l) is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and repeatedly washed with brine. The organic phase is dried, filtered evaporated to afford 1-(tetrahydropyran-2-yloxy)-propan-2-one (127.8 g, 80.8%) as a liquid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=2)[CH:22]=[O:23])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+].O.Cl>CO>[F:1][C:2]([F:33])([F:34])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:22][OH:23])[CH:24]=2)=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(CO)c1
Yield: 99.7 %

Procedure:
To a solution of 5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzaldehyde (576 mg, 1.16 mmol) in methanol (5.8 mL), sodium borohydride (46 mg, 1.22 mmol) was added under ice-cold conditions, and the resultant mixture was stirred under ice-cold conditions for 20 minutes. The reaction solution was added with water and 5% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. (5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrophenyl) methanol (575 mg, yield 99%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][C@H:12]1OC1N=CC(=S(=O)=O)N=1.[FH:46].F.F.C(N(CC)CC)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][C@@H:12]1[F:46]
Reactant: F
Reactant: O=S(=O)=C1C=NC(O[C@@H]2C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2n2cnc3c(Cl)ncnc32)=N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: F[C@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
113 mg (0.176 mmols) of 6-chloro-9-[2-O-(sulfurylimidazolyl)-3-deoxy-5-O-(triphenylmethyl)-β-D-erythro-pentofuranosyl]-9H-purine was dissolved in 1.80 ml of toluene, to which was added 0.18 ml (1.06 mmols) of triethylamine trihydrofluoride, and stirred overnight at 50° C. After having been cooled, 10.0 ml of ethyl acetate and 8.0 ml of an aqueous saturated solution of sodium hydrogencarbonate were added to this, to separate it into layers. The organic layer was dried with anhydrous sodium sulfate, and filtered. Then, the solvent was evaporated from the filtrate. The residue was dissolved in acetonitrile and analyzed through liquid chromatography. The intended product was obtained at an yield of 41.9%.
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: OC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOCC1
Reactant: CI
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOCC1
Yield: 81 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[5-(naphth-2-ylthio)thien-2-yl]tetrahydropyran was reacted with methyl iodide to give 4-methoxy-4-[5-(naphth-2-ylthio)thien-2-yl]tetrahydropyran in 81% yield, m.p. 70° C.
Reaction SMILES: CO[C:3]1[CH2:4][C:5]2[CH2:6][C@@H:7]([CH3:24])[C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@:9]23[CH2:23][C@@H:10]2[CH2:11][C@H:12]1[CH2:21]O.C(O)(=O)[C:26](O)=[O:27].C(=O)([O-])[OH:32].[Na+]>CO.O1CCCC1.O>[OH:27][CH2:26][CH2:21][C@@H:12]1[CH2:11][C@H:10]2[CH2:23][C@@:9]32[C@H:8]2[C@H:17]([CH2:16][CH2:15][C@:13]13[CH3:14])[C:18]1[CH2:19][CH2:20][C:3](=[O:32])[CH2:4][C:5]=1[CH2:6][C@H:7]2[CH3:24]
Reactant: O=C(O)C(=O)O
Reactant: COC1=CCC2=C(C1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@H](CO)C[C@H]3C[C@@]312
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=C(CCC(=O)C2)[C@H]2CC[C@]3(C)[C@H](CCO)C[C@H]4C[C@]43[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanol (Example 1, step vi; 7.38 g) in a mixture of methanol (68 ml) and tetrahydrofuran (48 ml) was treated with a solution of oxalic acid (2.38 g) in water (40 ml). After 1 h stirring at room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (7α,14β,15β,17α)-17-(hydroxyethyl)-7-methyl-14,15-methyleneestr-5(10)-en-3-one (4.27 g). 1H NMR (CDCl3) δ3.69 (m, 1H), 3.51 (t, 1H, J=9.0 Hz), 2.72 (bs, 2H), 2.46 (bs, 2H), 1.04 (s, 3H), 0.69 (d, 3H, J=7.1 Hz), 0.48(dd, 1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H, J=5.1 and 3.1 Hz).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCO.C([O-])(O)=O.[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(Cl)c(OCc3ccccc3)c2)OC1(C)C
Reactant: COC(=O)c1c[nH]c(=O)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1c[nH]c(=O)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Temperature: 90 °C

Procedure:
Stir a solution of 4 g (14.35 mmol) of methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate and 6.42 g (18.64 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a mixture of 160 mL of dimethoxyethane (DME), 80 mL of EtOH and 120 mL of a saturated aqueous solution of NaHCO3 for 15 minutes under argon, then add 662 mg of Pd(PPh3)4 and heat the reaction mixture for 4 h 30 min at 90° C. After concentration under reduced pressure, distribute the residue obtained in a mixture of 200 mL of DCM and 10 mL of water. Extract the aqueous phase again with 100 mL of DCM, combine the organic phases, dry over MgSO4, filter and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 2% of methanol. After concentration under reduced pressure, solidify the residue in a 5/95 methanol/ether mixture, then filter and wash with ether. We thus obtain 1.99 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g, Reference Example 55) and p-toluene sulfonic acid (144 mg) in chloroform (30 ml) at 0° C. was treated with 3,4-dihydropyran (1.04 ml) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (40 ml) and water (3×40 ml). The combined aqueous layers were extracted with dichloromethane (3×60 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to yield 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (2.23 g) as a viscous brown oil. LC-MS (Method H): RT=2.79 minutes, 278.21 (M+H+Na)+. (b) 4-Formyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1>O1CCOCC1>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:33][C@@H:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: N[C@@H]1CCOC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCOC1

Procedure:
A solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (897 mg, 3.86 mmol) (Aldrich) and triethylamine (1.2 mL, 870 mg, 8.49 mmol) (Aldrich) in dioxane (20 mL) was treated with (R)-3-aminotetrahydrofuran p-toluene-sulfonic acid salt (1.0 g, 3.86 mmol) (Fluka). The mixture was stirred at reflux for 1 hour, then cooled and partitioned between brine and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography with a silica gel column using a 0–100% ethyl acetate in hexanes gradient to give (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester as a colorless viscous oil. (Yield 1.0 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:40]=[C:41](CO)[CH:42]=[CH:43][CH:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([O:38][CH3:37])[CH:44]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(COC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)c1
Yield: 79.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methoxyphenyl)methanol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (120 mg, yield 74%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C@@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:11]=1.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:48]Br)=[CH:43][C:42]=1[NH:58][S:59]([CH3:62])(=[O:61])=[O:60])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CS(C)=O>[NH3:1].[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([O:50][Si:51]([C:54]([CH3:55])([CH3:57])[CH3:56])([CH3:53])[CH3:52])[CH2:48][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C@@H:17]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:18][CH2:19][N:20]([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:25])[CH3:26])[CH:11]=2)=[CH:43][C:42]=1[NH:58][S:59]([CH3:62])(=[O:60])=[O:61])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCN)ccc1O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Product: N

Procedure:
4-(8-aminooctyl)-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol (Preparation 53, 170 mg, 0.39 mmol) and N-{2-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanesulfonamide (Prepared according to WO2005/080324, 191 mg, 0.37 mmol) were heated at 90° C. in dimethylsulfoxide (0.5 ml) overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added and the organics separated, washed with saturated aqueous sodium hydrogen carbonate, brine, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (99/1/0.1 to 95/5/0.5 by volume) to furnish the title compound as a yellow oil, 90 mg.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[CH:19]=[O:20])[S:13][CH:14]=1.C(OCC)(=O)C>CCOCC.C1COCC1>[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:19]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:20])[CH:21]=[CH:22][N:23]=2)[S:13][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1csc(Nc2cc(C=O)ccn2)n1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(C(O)c3ccccc3)ccn2)n1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
3.0 M Phenylmagnesium bromide (0.9982 mL, 2.995 mmol) in ether was added to THF (2 mL) at 0° C., and then 2-(4-methylthiazol-2-ylamino)isonicotinaldehyde (0.197 g, 0.8985 mmol) in THF (3 mL) was added. The reaction mixture was stirred for 30 minutes, then partitioned between saturated ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to afford (2-(4-methylthiazol-2-ylamino)pyridin-4-yl)(phenyl)methanol (0.107 g, 40.05% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.10 (s, 1H), 8.14 (d, 1H), 7.24-7.37 (m, 5H), 7.11 (s, 1H), 6.81 (d, 1H), 6.50 (s, 1H), 6.09 (d, 1H), 5.64 (d, 1H), 2.22 (s, 3H).