Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (5 g, 40.28 mmol) and phenol (3.8 g, 44.42 mmol) in DMF (50 mL) was added K2CO3 (11.13 g, 80.57 mmol) and the resulting mixture was stirred at 110° C. overnight. The mixture was filtered, the filtrate was diluted with cold water and the product was extracted with EtOAc. The organic layer was washed with 5% aqueous NaOH solution, saturated brine solution and dried over sodium sulphate. The organic layer was then concentrated under reduced pressure to afford 7.7 g (96.5% yield) of 4-phenoxy benzaldehyde as a pale brown oil. 1H NMR: (CDCl3) δ 9.9 (s, 1H), 7.8 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.0 (t, 4H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:10]=[CH:11][CH:12]=[CH:13]2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-n2cccc2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-n2cccc2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridine (68 mg, 0.315 mmol) and sodium iodide (141 mg, 0.94 mmol) under a N2 atmosphere is added anhydrous acetonitrile (4 mL) followed by dropwise addition of chlorotrimethylsilane (118 μL, 0.940 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 17 hr. The reaction mixture is allowed to cool, diluted with water and extracted with three portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-6-methyl-5-(pyrrol-1-yl)-1H-pyridin-2-one (59 mg, 93% yield) as a white solid. This material (49 mg) is dissolved in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0M, 0.49 mL). The solution is stirred for 1.5 hr and then evaporated to give 3-ethyl-6-methyl-5-pyrrol-1-yl-1H-pyridin-2-one hydrochloride (54 mg) as an off-white solid. LC/MS: RT: 2.70 min, MS: m/e=203 (M+H); 1H NMR (δ ppm): 11.75 (1H, s), 7.16 (1H, s), 6.80 (2H, t), 6.16 (2H, t), 2.38 (2H, q), 1.97 (3H, s), 1.08 (3H, t).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][CH3:25])[CH2:19][C:18]([CH3:27])([CH3:26])[O:17][C:16]=2[N:15]=[C:14]([S:28][CH3:29])[N:13]=1.O>C1COCC1>[CH2:1]([O:8][C:12]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][CH3:25])[CH2:19][C:18]([CH3:26])([CH3:27])[O:17][C:16]=2[N:15]=[C:14]([S:28][CH3:29])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CC(C)(C)Oc2nc(SC)nc(Cl)c2C1=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC(C)(C)Oc2nc(SC)nc(OCc3ccccc3)c2C1=O
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
6.20 ml of benzyl alcohol (59.64 mmol) are placed in 400 ml of anhydrous THF. The solution is cooled to 4° C. in an ice bath and 2.39 g of 60% sodium hydride (59.64 mmol) are added portionwise. The reaction mixture is stirred at 4° C. for 15 minutes. 15 g of 4-chloro-6-ethyl-8,8-dimethyl-2-methylsulfanyl-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzo cyclohepten-5-one (49.70 mmol) dissolved in 400 ml of anhydrous THF are added dropwise. After stirring for 2 hours at 4° C., 400 ml of water are added and the THF is evaporated off. The aqueous phase is extracted twice with 300 ml of DCM, and the organic phases are combined and washed with 400 ml of water and then 400 ml of brine. The organic phase is dried over Na2SO4, filtered and concentrated. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 30% to 50%. 18.6 g of 4-benzyloxy-6-ethyl-8,8-dimethyl-2-methylsulfanyl-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:11](OC(=O)C(C)(C)C)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([O:36]C)=[O:35])=[N:32][CH:33]=4)[CH2:25][C:26]#[CH:27])[C:7]=3[C:8]=2C)[N:3]=1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[NH:11][C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[N:32][CH:33]=4)[CH2:25][C:26]#[CH:27])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)OC)nc1)C1CCc2cc3nc(C)n(OC(=O)C(C)(C)C)c(=O)c3c(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 5-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (1 g), sodium hydroxide (0.32 g), water (10 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. The mixture was evaporated. Water (60 ml) was added and the mixture was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid (0.68 g);
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[NH4+:9].[OH-].[Na+]>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:8])=[O:5].[NH4+:9]
Reactant: [OH-]
Reactant: O=C1C=CC(=O)O1
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of 9.8 g (0.1 mole) maleic anhydride was dissolved in 20 ml water at 80°-95° C. and stirred for 30 minutes while allowing the mixture to cool to 25° C. To this colorless solution at 25° C. was added 13 g of 30% aqueous solution of ammonium hydroxide (0.11 mol NH3) to give a colorless solution. This solution was boiled to dryness over a period of 30 minutes at approximately 100°-115°-C. to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 190°-200° C. for 4 hours to give a water insoluble, pinkish-tan brittle glasslike solid weighing 10.6 g. This solid was dissolved in 35.4 g of an aqueous solution containing 1.9 g of sodium hydroxide to form a clear red-brown solution, pH 9.0, containing 25% solids.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].S1[C:10]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:9]=2NC1.Cl[C:33]1C=CC=C(C(OO)=O)C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:3]=[S:2]1(=[O:5])[C:1]2[CH:13]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:11]=[CH:10][C:9]=2[CH2:14][CH2:33]1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)SCN2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)S(=O)(=O)CC2

Procedure:
The product from Example 54 is treated with two equivalents of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(C(C)=O)C>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])=[O:27])[CH3:30]
Reactant: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(OC2CCCCO2)cccc1[N+](=O)[O-]

Procedure:
A mixture of 38.4 g of 2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene, 22.2 g of potassium carbonate and 27.0 g of ethyl bromoacetate in 400 ml of methyl ethyl ketone is heated to the reflux temperature for 16 hours, whilst stirring, and then filtered; the filter residue is rinsed with 100 ml of methyl ethyl ketone. The combied filtrates are evaporated under reduced pressure. The residual yellowish oil is taken up in 400 ml of diethyl ether, the solution is clarified by filtration, with the addition of 2 g of an active charcoal formulation and the filtrate is evaporated under reduced pressure. The residual oil solidifies after some time to give a mass of crystals and gives 2-ethoxycarbonylmethoxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene; melting point 65°-66°.
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[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[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[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][C@@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (37 mg, yield 81%).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O[C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[S:35]([C:38]1[N:42]2[C@:43]([CH3:68])([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:58][CH:57]=3)[C:44](=[O:54])[N:45]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[C:48]([Cl:53])[CH:47]=3)[C:41]2=[N:40][CH:39]=1)(=[O:37])=[O:36])=[O:29])(C)(C)C.C[O:70][C:71](=O)[CH2:72][CH2:73][NH2:74].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[C:71]([CH2:72][CH2:73][NH:74][C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[S:35]([C:38]1[N:42]2[C@:43]([CH3:68])([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:60][CH:61]=3)[C:44](=[O:54])[N:45]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[C:48]([Cl:53])[CH:47]=3)[C:41]2=[N:40][CH:39]=1)(=[O:37])=[O:36])=[O:29])(=[O:70])[NH2:2]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NCCC(N)=O)n21
Temperature: 50 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
TBTU (0.15 g), (S)-1-[(R)-7-(3,5-dichlorophenyl)-5-methyl-6 oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.20 g), β-alanine methyl ester (0.067 g) and DIPEA (0.14 mL) were combined in 1% DMF—CH2Cl2 (10.1 mL) at room temperature and the solution was stirred for 1 h. The reaction was diluted with CH2Cl2, poured into 1N HCl, a nd extracted with CH2Cl2. The organic layers were combined and washed with saturated aqueous NaHCO3 followed by H2O. The combined organic phase was dried (Na2SO4), filtered and concentrated. The resultant residue was re-dissolved in 2N NH3—CH3OH (10 mL) and heated to 40-60° C. for 48 h. The volatiles were removed and the residue was purified by silica gel chromatography to afford the title compound (0.021 g) as a foam (697.2, M+1).
Reaction SMILES: [C:1]1(C)C(C(N)=O)=CC=CC=1.C(OC(=O)[NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(C)(C)C>C(O)(C(F)(F)F)=O.O.ClCCl>[NH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:33])[CH3:34])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:1].[NH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1C(N)=O
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Product: Cc1ccccc1C(=O)N(CCCN)C(c1nc2nccnc2c(=O)n1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Formula I where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 is 3-Amino-propyl-; R8 is —C(O)—R9 where R9 is p-Methyl-phenyl-; X and Y are —C═; and W and Z are —N═: The toluamide, {3-[[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, was then dissolved in TFA/H2O (95/5) (50 mL) and stirred at room temperature for 1 hour, after which it was diluted with dichloromethane, washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. Concentration of the dichloromethane solution gave the title product (±)-N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]4-methyl-benzamide as a white solid (150 mg, 98.0%). MS (Cl) M/E: 485.2.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([C:10](=[O:12])[CH3:11])=[C:7]([CH3:9])[N:8]=1.[C:13](=O)([O:21]C1C=CC=CC=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.CN(C)C=O.C(Cl)(Cl)Cl>[C:15]1([O:14][C:13](=[O:21])[NH:3][C:4]2[S:5][C:6]([C:10](=[O:12])[CH3:11])=[C:7]([CH3:9])[N:8]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Yield: 84.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.07 g, 77 mmol) was washed twice with hexane and suspended in N,N-dimethylformamide. 2-Amino-5-acetyl-4-methylthiazole (10.0 g, 64 mmol) was added with stirring and cooling on an ice bath. Stirring was continued until the sodium hydride was consumed. Diphenyl carbonate (34 g, 160 mmol) was added and the mixture was stirred for 30 minutes at room temperature. The solvent was removed under vacuum to yield a brown residue, which was dissolved in chloroform and washed successively with 0.5N aqueous hydrochloric acid, twice with water and finally with saturated aqueous sodium chloride. The aqueous phases were back extracted twice with chloroform. The combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give a white solid. This was chromatographed on silica gel, eluting with 15%-70% ethyl acetate in hexane, to give a white solid (15.0 g, 85%). 1H NMR (300 MHz, CDCl3) δ11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). Mass spec (ES+) m/z 277.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>O1CCCC1.C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:37])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Yield: 70.9 %

Procedure:
The (3-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (1.67 g, 7.49 mmol) and triphenylphosphine (2.61 g, 9.96 mmol) were combined and dissolved in tetrahydrofuran (40 mL). Carbon tetrabromide (3.23 g, 9.74 mmol) was dissolved in acetonitrile (20 mL) and added dropwise to the reaction while stirring. After stirring for 5 h, the reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded (3-bromomethyl-phenyl)-carbamic acid tert-butyl ester (1.52 g, 78%) as a white powder: H1-NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 4.46 (2H, s), 6.47 (1H, bs), 7.06 (1H, d, J=7.2 Hz), 7.19-7.27 (2H, m), 7.51 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4]N=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([O-:18])=[O:17].Cl[C:28]1C=CC=CC=1>>[CH3:26][C:21]1[CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:28]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: Clc1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3C)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (5.00 g) and 4-nitro-2-methylphenol (6.85 g) were suspended in monochlorobenzene (25 ml) to prepare a suspension which was then heated under reflux overnight. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate, was filtered, and was dried. Next, the resultant crystal was suspended in an aqueous sodium hydroxide solution to prepare a suspension. The suspension was then filtered, followed by drying to give 6.89 g of 4-(2-methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline. 4-(2-Methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline (1.36 g) was dissolved in ethyl acetate/N,N-dimethylformamide/triethylamine (25 ml/25 ml/5 ml). Palladium hydroxide (0.4 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give the title compound (1.31 g, yield 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][CH2:35][CH3:36]>>[CH2:35]([NH:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:24])[CH3:36]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CCNc1cc(F)ccc1CN
Product: CCNc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 2-(aminomethyl)-N-ethyl-5-fluorobenzenamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.1 Hz, CH3), 1.63 (6H, s, 2×CH3), 3.10 (2H, q, J=7.1 Hz, CH2), 4.04 (4H, m, 2×CH2), 4.45 (2H, d, J=6.6 Hz, NCH2), 5.27 (2H, s, OCH2), 6.28 (1H, broad s, aromatic), 6.31 (1H, m, aromatic), 6.98 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics), 7.54 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN4O4 [M+H+]: 481.2251. found: 481.2254.
Reaction SMILES: CC(C1C=CC(C2CNCCC=2)=C(O)C=1)(C)CCCCCC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH3:33][C:34]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH2:49][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:51][CH2:52][CH:53]=2)=[C:44]([O:57]CC=C)[CH:43]=1)([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[CH3:41][C:34]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH2:49][N:50]([CH2:54][CH:55]=[CH2:56])[CH2:51][CH2:52][CH:53]=2)=[C:44]([OH:57])[CH:43]=1)([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C=CCOc1cc(C(C)(C)CCCCCC)ccc1C1=CCCN(CC=C)C1
Agent: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C=CCBr
Product: C=CCN1CCC=C(c2ccc(C(C)(C)CCCCCC)cc2O)C1
Yield: 22 %

Procedure:
A mixture of 1.0 g. (3.32 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 401 mg. (3.32 mmoles) of allyl bromide in 23 ml. of ethanol is heated at reflux for 23 hours. The reaction mixture is concentrated under reduced pressure and the residue dissolved in 250 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 125 g. of silica gel eluted with 5% methanol-dichloromethane to yield 372 mg. (29%) of 3-[4-(1,1-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-1,2,5,6-tetrahydropyridine as an oil and 247 mg. (22%) of the title compound, M.P. 109°-110° C. (from ether-pentane). Title Compound: PMR: αCDCl3TMS 0.85 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.23 (m, allyl methylene), 5.0-5.4 and 5.5-6.1 (m, four vinyl protons), 6.82 (m, ArH) and 6.97 (d, J=8Hz, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:20][C:21]1[O:25][CH:24]=[N:23][CH:22]=1)(C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:20][C:21]1[O:25][CH:24]=[N:23][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1cnco1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1cnco1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.5 %

Procedure:
1.5 g of diethyl 2-(tert-butoxyformamido)-2-[(5-oxazolyl)methyl]malonate were dissolved in 1.5 ml of water and 1.5 ml of ethanol. 337 mg of sodium hydroxide were added and the mixture was stirred overnight at room temperature. The mixture was then acidified to pH 5 with acetic acid and the solvent was removed by evaporation. The residue was dissolved in 5 ml of toluene and 0.64 ml of triethylamine was added. The mixture was heated at reflux for 2 hours and then the solvents were evaporated. Ethyl acetate was added and the solution was washed with saturated aqueous citric acid solution. The organic layer was dried over magnesium sulphate to give 1.224 g of crude N-(tert-butoxycarbonyl)-3(5-oxazolyl)-DL-alanine, 1H NMR (250 MHZ, d6-DMSO) δ: 1.4 (s,9H), 3.0-3.3 (m,2H), 6.95 (s,1H), 7.25 (m, 1H), 8.3 (s,1H).