Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=[CH:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>C(O)CC(C)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=[CH:23][C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:30][CH2:31]1)=[O:25]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C=Cc1ccco1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccco4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 479 mg. (2 mM) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 412 mg. (2 mM) of 3-(furan-2-yl)-acryloylpiperazine in 10 ml. of isoamyl alcohol was heated under reflux for 4 hours. After ice-cooling, the crystalline substance thus separated was recovered by filtration and washed with ethanol to afford 685 mg. of the desired product as the hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[N:23]([CH2:26][CH2:27][CH3:28])=[C:24]=[O:25]>ClCCl>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([NH:15][C:24]([NH:23][CH2:26][CH2:27][CH3:28])=[O:25])[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cc(N)ccn2)CC1
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)Nc1ccnc(N2CCN(CC)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
A mixture of 20.6 mg (0.1 mmol) 2-(4-ethyl-piperazin-1-yl)-pyridin-4-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml dichloromethane was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 7.2 mg (25%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.Cl.Cl[CH2:30][CH2:31][N:32]([CH2:37][CH2:38]Cl)[C:33]([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C>[C:33]([N:32]1[CH2:37][CH2:38][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:30][CH2:31]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Reactant: CC(C)(C)N(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1
Yield: 31.7 %

Procedure:
A mixture of 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (90 mg, 0.243 mmol), N,N-bis(2-chloroethyl)-2-methylpropan-2-amine hydrochloride (114 mg, 0.486 mmol) and Na2CO3 (129 mg, 1.22 mmol) in t-BuOH (2 mL) was heated at reflux overnight. Purification by HPLC gave 7-(4-tert-butylpiperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (40 mg, 0.077 mmol, 32% yield). MS (ESI) m/z 496.2 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (1H, s), 8.60 (2H, d, J=1.53 Hz), 8.56 (1H, br. s.), 8.40 (1H, s), 8.07 (1H, d, J=8.55 Hz), 7.85 (1H, br. s.), 7.74-7.78 (2H, m), 7.20 (1H, d, J=1.83 Hz), 7.00 (1H, dd, J=8.85, 2.14 Hz), 3.23-3.28 (4H, m), 2.71 (4H, d, J=4.27 Hz), 1.08 (9H, s).
Reaction SMILES: O.C([O:5][CH2:6][C@:7]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9][CH2:8]1)(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:19][C@@:7]1([CH2:6][OH:5])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9][CH2:8]1
Reactant: CC(=O)OC[C@@]1(C)CCn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Water (4 mL) was added dropwise to a stirred mixture of (R)-acetate 158 (427 mg, 1.67 mmol) and K2CO3 (256 mg, 1.85 mmol) in MeOH (36 mL). After stirring at room temperature for 4 h, the mixture was cooled in ice and treated with 0.1M HCl (37 mL, 3.70 mmol). The solvents were removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-2.5% MeOH/CH2Cl2 gave [(7R)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (159) (343 mg, 96%) as a pale yellow solid that was used directly in the next step; 1H NMR [(CD3)2SO] δ 8.03 (s, 1H), 5.23 (br t, J=5.4 Hz, 1H), 4.13 (dt, J=13.0, 6.0 Hz, 1H), 4.05 (ddd, J=12.9, 8.1, 5.6 Hz, 1H), 3.54 (dd, J=11.6, 4.9 Hz, 1H), 3.48 (dd, J=11.6, 5.2 Hz, 1H), 2.21 (ddd, J=14.4, 8.1, 5.9 Hz, 1H), 2.00 (dt, J=14.4, 5.8 Hz, 1H), 1.32 (s, 3H); [α]D27−16.0° (c 1.00, DMF).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: [NH4+]
Reactant: c1cncc([C@H]2CO2)c1
Solvent: CO
Product: NC[C@@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2S)-oxiranyl]pyridine (which was obtained in Example 129) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2H), 2.59-2.71 (m, 2H), 4.47-4.50 (m, 1H), 5.20 (brs, 1H), 7.31-7.34 (m, 1H), 7.68-7.71 (m, 1H), 8.42-8.43 (m, 1H), 8.50-8.51 (m, 1H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:16]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=2[C:18]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:19])[CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CCC1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CCC1

Procedure:
The title compound, light orange solid, MS: m/e=381.4 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclobutyl-4-trifluoromethyl-benzoic acid (intermediate AP).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[CH2:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([O:31][CH3:32])[CH:17]=1)(=[O:15])=[O:14])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:19]2[CH:20]=[CH:21][C:16]([S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])=[CH:17][C:18]=2[O:31][CH3:32])[CH:3]=1
Reactant: COc1ccc(Br)cc1I
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2OC)c(OC)c1
Temperature: 80 °C
Yield: 45 %

Procedure:
A solution of 4-bromo-2-iodo-1-methoxybenzene (Preparation 57, 350 mg, 1.12 mmol), 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 365 mg, 1.12 mmol) and aqueous caesium carbonate solution (1M, 2.23 mL, 2.23 mmol) in dioxane (18 mL) was degassed with nitrogen for 10 min, followed by addition of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (46.0 mg, 0.0056 mmol). The resulting mixture was heated at 80° C. for 16 hours. After cooling to room temperature and concentration in vacuo, the crude residue was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined and washed with brine (25 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptanes/EtOAc (70:30), to afford the title compound as off-white solid in 45% yield, 150 mg.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:39])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:27][C:28]([C:30]1[O:31][C:32]([O:35]C(=O)C)=[CH:33][CH:34]=1)=[O:29])[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+]>CO>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:39])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:27][C:28]([C:30]1[O:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:29])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@]1(OC(=O)c2ccc(OC(C)=O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@]1(OC(=O)c2ccc(O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C

Procedure:
The product of Step 2 (555 mg) is dissolved in methanol (10 mL) and 2M methanolic sodium hydroxide (1 mL) is added. After 1 hour the solvent is evaporated and the residue partitioned between water and ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. Purification by flash chromatography eluting with hexanes-ethyl acetate (1:1) affords 5-hydroxyfuran-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. TLC Rf 0.25 (1:1 hexane-ethyl acetate elution).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([NH:12][CH3:13])=[O:11].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][NH:12][C:10]([C:3]1[C:4]([CH3:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11]
Reactant: CNC(=O)c1c(Cl)cc(C)nc1C
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CNC(=O)c1c(N2CCNCC2)cc(C)nc1C
Temperature: 180 °C
Yield: 73.3 %

Procedure:
4-Chloro-N,2,6-trimethyl-pyridine-3-carboxamide (300 mg, 1.5 mmol) was mixed with piperazine (645 mg, 7.5 mmol) and pyridine (3 ml) and heated under microwave irridation at 180° C. for 15 minutes. The solvent was removed under reduced pressure, the residue was taken up in 0.5 M NaOH saturated with sodium chloride and extracted with dichloromethane (2×). The combined extracts were dried over sodium sulfate, the solvent was evaporated under reduced pressure to yield 280 mg of a yellow solid (1.1 mmol, 75%). NMR (1H, 300 MHz, CD3CN): 6.73 (s, 1H), 6.70 (s, 1H), 2.99-3.02 (m, 4H), 2.82-2.86 (m, 7H), 2.37 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH2:8][CH2:9][CH2:10][S:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1SCCCS1
Reactant: ClCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)SCCCS1
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of 3.0 g (15.6 mmol) of 2-ethoxycarbonyl-1,3-dithiane in 40 ml of dry tetrahydrofuran was cooled under inert atmosphere to -78° C. and treated with 7.5 ml (15.6 mmol) of n-butyllithium. The resulting solution was warmed to -25° C., stirred for 20 min, recooled to -78° C., treated with 1.8 ml (15.6 mmol) of benzyl chloride, and stirred at ambient temperature for 16 h. After quenching with aqueous ammonium chloride, the mixture was extracted with ether, washed sequentially with water, aqueous sodium thiosulfate, and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography using 5% ethyl acetate in hexane gave 3.9 g (88%) of the desired compound. 1H NMR (CDCl3) δ 1.33 (t, J=7 Hz, 3H), 1.85 (qt, J=14, 3 Hz, 1H), 2.11 (dm, J=14 Hz, 1H), 2.69 (dt, J=14, 4 Hz, 2H), 3.23 (ddd, J=14, 12, 3 Hz, 2H), 3.38 (s, 2H), 4.27 (q, J=7 Hz, 2H), 7.25-7.35 (m, 5H). Mass spectrum (M+NH4)+ =300.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:29]([O:31]CC4C=CC([N+]([O-])=O)=CC=4)=[O:30])=[C:15](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O.[Zn]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: [Zn]
Solvent: O=CO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Yield: 71.5 %

Procedure:
Zinc powder (2.0 g.) was added portionwise to a stirred solution of 4-nitrobenzyl 7-(2-phenylacetamido)-3-tosyloxy-3-cephem-4-carboxylate (2.0 g.) in 90% formic acid (40 ml.) over 6 minutes under ice-cooling. The mixture was stirred at room temperature for an hour and then filtered. The remaining insoluble substances were washed with ethyl acetate. The filtrate and the washings were combined together and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water, diluted hydrochloric acid and water in turn, dried over magnesium sulfate and then evaporated to dryness in vacuo. The oily residue was pulverized by trituration with diisopropyl ether and the solidified precipitates were collected by filtration to give 7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (0.73 g.), Yield 71.5%.
Reaction SMILES: C1COCC1.C[O:7][C:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:20]3[CH:21]=[CH:22][N:23]=[C:24]([NH2:25])[C:19]3=[C:18]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][C:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[N:33]4)=[CH:28][CH:27]=3)[N:17]=2)[CH2:12][CH2:11]1)=[O:9].[OH-].[Na+]>CO>[NH2:25][C:24]1[C:19]2[N:20]([C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([C:8]([OH:9])=[O:7])[CH2:15][CH2:14]3)=[N:17][C:18]=2[C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:33]3)=[CH:28][CH:27]=2)[CH:21]=[CH:22][N:23]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
A THF solution (2 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester was charged with 10M NaOH (0.31 mL, 3.1 mmol); a minimal amount of methanol was added to homogenize the reaction mixture. The reaction stirred at rt for 2 h. The reaction mixture was concentrated to solids and acidified to pH 5 with 2M HCl. The aqueous layer was extracted with CHCl3 (5×) and combined organic layers were dried over Na2SO4, filtered, and concentrated to the desired compound as a orange solid; 1H NMR (CDCl3, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H), 5.25 (s, 2H), 6.91 (d, 1H, J=6.0 Hz), 7.29-7.33 (m, 1H), 7.51-7.59 (m, 3H), 7.81 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.00-8.05 (m, 2H), 8.21-8.23 (m, 2H), 8.32 (d, 1H, J=9.2 Hz), 8.41-8.42 (m, 1H); MS (ES+): m/z 464.0 [MH+]; HPLC: tR=2.3 min (Micromass Platform II, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16]>ClCCl.O=[Mn]=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[O:16]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c2ccccc12
Yield: 79.1 %

Procedure:
The title compound was prepared by treating (1,4-dimethoxy-naphthalen-2-yl)-methanol (6.5 g, 29.8 mmol, 1.0 equiv, prepared according to C. Flader, J. Liu and R. F. Borch J. Med. Chem. 2000, 43, 3157-3167) with activated MnO2 (25.9 g, 297.8 mmol, 10.0 equiv) in dichloromethane for 4 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated by evaporation of the solvent under reduced pressure affording 5.1 g (81%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.02 (s, 3H), 4.10 (s, 3H), 7.14 (s, 1H), 7.61-7.65 (m, 2H), 8.18-8.30 (m, 2H), 10.58 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][NH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(=O)[nH]cnc12
Product: Cc1cccc2c(Cl)ncnc12
Temperature: 120 °C
Yield: 90 %

Procedure:
POCl3 (300 mL) was taken in a 2 L round bottom flask under nitrogen. To this was added 8-Methylquinazolin-4(3H)-one (45 g) in portions. The reaction mixture refluxed at 120° C. for 12 h. Reaction completion was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The resulted residue was dissolved in DCM (500 mL) and quenched slowly into an ice cold solution of saturated K2CO3 with constant stirring. Then the organic layer was separated and washed with brine solution, dried over sodium sulphate and concentrated under vacuum to afford (45 g, 90% yield) of the titled compound as yellow solid. This was taken for next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 8.08-8.06 (dd, J=8.9, 8.4 Hz, 1H), 7.77-7.76 (d, J=7.1 Hz, 1H), 7.59-7.56 (d, J=15.5 Hz, 1H), 2.75 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][O:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[N:4]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2nc(CCl)cs2)cc1
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: O=C(COCc1csc(-c2ccc(F)cc2)n1)c1ccccc1
Yield: 74.1 %

Procedure:
11.2 g (0.05 mol) of 4-chloromethyl-2-(4-fluorophenyl) thiazole (see Example 4), 5.4 g (0.04 mol) of 2-hydroxyacetophenone, 7.5 g (0.055 mol) of potassium carbonate and 0.5 g of potassium iodide in 20 ml ethanol are refluxed for 24 hours. The mixture is filtered, the filtrate is concentrated, the residue is taken up in dichloromethane, the solution is extracted with dilute sodium hydroxide solution and then with water, and the organic phase is dried over MgSO4. Removal of the solvent by distillation under reduced pressure results in a solid residue which is washed with diisopropyl ether to give 9.7 g (59% yield) of 2-[2-(4-fluorophenyl)-4-thiazolylmethyloxy]acetophenone as yellowish crystals of melting point 104°-106° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(CCc2ncccc2C)cc1
Yield: 95.8 %

Procedure:
A solution of 3-methyl-2-[2-(4-aminophenyl)ethyl]pyridine (14.2 g) and acetic anhydride (13.65 g) in ethyl acetate (150 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of diethyl ether and ethyl acetate to give 3-methyl-2-[2-(4-acetamidophenyl)ethyl]pyridine (16.3 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][S:12][CH2:13][CH2:14][CH2:15]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:15][CH2:14][CH2:13][S:12][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: CSCCCO
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CSCCCOc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (4.02 g, 20.0 mmol), 3-(methylthio)-1-propanol (2.12 g, 20.0 mmol) and tributylphosphine (7.97 mL, 32.0 mmol) in toluene (320 mL) was added 1,1′-(azodicarbonyl)dipiperidine (8.07 g, 32.0 mmol), and the mixture was stirred at room temperature for 18 hr under nitrogen atmosphere. Hexane (160 mL) was added to the reaction mixture, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (5.03 g, yield 87%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:16][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: COc1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: COc1ccc(COc2cc(N)ccn2)cc1
Temperature: 160 °C
Yield: 73.7 %

Procedure:
A solution of 4-amino-2-chloropyridine (Aldrich) (1.000 g, 7.78 mmol) in 4-methoxybenzyl alcohol (Fluka) (9.66 mL, 78 mmol) was treated with sodium hydroxide (J. T. Baker) (0.584 mL, 31.1 mmol) and tetrabutylammonium iodide (Aldrich) (0.287 g, 0.778 mmol). The resulting mixture was heated at 160° C. under N2 for 2 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 20% to 30% acetone in hexanes) to give the product as a white solid (1.32 g). m/z (ESI, +ve ion) 231.1 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=5.70 Hz, 1H); 7.38 (d, J=8.18 Hz, 2H); 6.91 (d, J=8.48 Hz, 2H); 6.22 (d, J=7.02 Hz, 1H); 5.99 (s, 1H); 5.27 (s, 2H); 4.04 (br. s., 2H); 3.82 (s, 3H).
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[P:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCSP(=O)(Cl)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-methyl S-ethyl chlorothiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 4-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product O-methyl S-ethyl O-(4-formylphenyl) thiophosphate.