Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:26])[N:12]3[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].CS(O[CH:41]1[CH2:44][N:43]([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]1[CH3:58])(=O)=O>O>[CH:45]([N:43]1[CH2:44][CH:41]([N:20]2[CH:21]=[C:17]([C:16]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=4)=[C:8]4[C:13](=[CH:14][CH:15]=3)[N:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:11]([CH3:26])[CH2:10][CH2:9]4)[CH:18]=[N:19]2)[CH:42]1[CH3:58])([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC1C(OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(c5ccccc5)c5ccccc5)C4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-methyl 5-(4-fluorophenoxy)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.300 g, 0.79 mmol) and N,N-dimethylformamide (10 mL), and the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.047 g, 1.17 mmol) was added, and the resulting mixture stirred for 30 min at room temperature. 1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (0.286 g, 0.86 mmol) was added, and the resulting mixture stirred overnight at 50° C. The reaction mixture was cooled to room temperature and poured into water (30 mL). The aqueous phase was separated and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 21%) as yellow oil. MS (ESI, pos. ion) m/z 617 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH3:24])[N:13]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+].CO.CCOC(C)=O.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH3:24])[N:13]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C2=NN(C(=O)N(C)C)C(C)c3cc4c(cc32)OCO4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1c2cc3c(cc2C(c2ccc(N)cc2)=NN1C(=O)N(C)C)OCO3
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A solution of 4-(4-acetylaminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine (97 mg, 0.25 mmole) in 1N sodium hydroxide (3 mL) and methanol (7 mL) was heated to reflux for 72 hours, cooled to ambient temperature, diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer was washed with EtOAc and the combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 25% hexanes/EtOAc to leave a light yellow foamy solid (63 mg, 72%). 200 MHz 1H NMR (CDCl3); δ7.45 (d, 2H, J=8.6 Hz, ArH2 '), 6.84 (s, 1H, ArH), 6.76 (d, 2H, J=8.6 Hz, ArH), 6.71 (s, 1H, ArH), 6.01 (d, 2H, J=2.9 Hz, OCH2O), 5.25 (q, 1H, J=7.1 Hz, CHCH3), 3.95 (brs, 2H, NH2), 3.07 (s, 6H, N(CH3)2), 1.33 (d, 3H, J=7.1 Hz, CHCH3): FTIR (PTFE film); 3456 cm-1, 3343, 3220, 1631, 1605, 1482, 1379, 1251, 1036.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide (0.5M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroform-carbon tetrachloride (0.18 g, 76%), m.p. 111.5-113.5° C.; δH [(CD3)2SO] 1.34 (6H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3′-H), 1.74 (2H, q, J 7.2 Hz, 2′-H), 3.3-3.5 (4H, AB part of ABX, 2×4′-H), 4.06 (2H, t, J 7.3 Hz, 1′-H), 4.40 (2H, br, 2×OH), 5.49 (1H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2H, s, 2-NH2), and 7.83 (1H, s, 8-H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl>C(N(CC)CC)C>[OH:11][NH:10][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)C1CCCCC1)NO
Yield: 38 %

Procedure:
Following the procedure described in Example 18, step 2, 3, but substituting 2-cyclohexylcarbonyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 102 obtained in 38% yield. 1H NMR (300 MHz, CDCl3): δ 2.45 (t, J=6.9 Hz, 2H), 2.36 (m, 2H), 2.10 (m, 2H), 1.80-1.25 (m, 17H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 23.13, 25.00, 25.35, 25.53, 28.22, 28.50, 28.51, 32.47, 40.27, 50.61, 177.11, 215.62.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][C:23]1[CH:24]=[C:25]([OH:38])[CH:26]=[CH:27][C:28]=1[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:8]1([C:7]2[O:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]([F:21])([F:20])[F:19])[C:3]=2[CH2:2][O:38][C:25]2[CH:26]=[CH:27][C:28]([B:29]3[O:33][C:32]([CH3:34])([CH3:35])[C:31]([CH3:37])([CH3:36])[O:30]3)=[C:23]([CH3:22])[CH:24]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C2CC2)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a 5-L 3-neck round bottom flask with a mechanical stirrer, thermocouple, reflux condenser, and drying tube is added 4-bromomethyl-5-cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazole (221.7 g, 0.612 mol, 1.05 eq), acetonitrile (2 L), 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (136.5 g, 0.583 mol, 1 eq) and potassium carbonate (241.8 g, 1.749 mol, 3 eq). The reaction mixture is heated to reflux and stirred at this temperature for 1 hour. Upon completion of the reaction, as evidenced by thin layer chromatography, the reaction mixture is cooled to 0-20° C. The reaction mixture is filtered and the filter cake is washed with acetonitrile (2×100 mL). The reaction mixture is concentrated under reduced pressure to a solid which is co-evaporated with 1,4-dioxane (500 mL). The title compound is used without further purification. 1H NMR (DMSO-d6, 300 MHz): δ 7.7-7.5 (m, 5H), 6.61 (m, 2H), 4.90 (s, 2H), 2.39 (m, 1H), 2.36 (s, 3H), 1.24 (s, 12H), 1.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11])=[O:6].CO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(Cl)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A solution of 42A (340 mg, 1.1 mmol) in THF (30 mL)/MeOH (10 mL) was treated with a solution of LiOH monohydrate (223 mg, 5.3 mmol) in water (10 mL). The reaction was stirred for 24 hours at room temperature and concentrated to a yellow solid. The crude acid was dissolved in water (100 mL) and acidified with 1 N HCl to pH 4. The resulting solid was collected by vacuum filtration and washed with water (2×100 mL) to afford 42B (260 mg, 85%).
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([C:7](=[O:14])[NH:8][C:9]2=[O:13])[CH2:5]1)=[O:3].[CH2:15]([OH:17])[CH3:16]>>[C:2]([CH:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([C:7](=[O:14])[NH:8][C:9]2=[O:13])[CH2:5]1)([O:17][CH2:15][CH3:16])=[O:3]
Reactant: CCO
Reactant: O=C(Cl)C1CC2CC(C1)C(=O)NC2=O
Product: CCOC(=O)C1CC2CC(C1)C(=O)NC2=O
Reaction time: 8 h

Procedure:
A mixture of 7-chlorocarbonyl-3-azabicyclo[3.3.1]nonane-2,4-dione (2 g) and absolute ethanol (25 ml) was left overnight at room temperature and evaporated to leave the desired compound which was used in the next step without purification.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@:51]1([CH3:59])[C:56](O)=[O:57])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]([NH:32][C:56]([C@@:51]2([CH3:59])[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:57])[CH:33]([CH3:34])[CH3:35])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), #157 (53.8 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.5 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #179 (155 mg, assume quantitative yield) as a white solid. LC-MS (Protocol Q1): m/z 814.7 [M+H+], retention time=1.14 minutes.
Reaction SMILES: ClN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Li].C([Li])CCC.S1C=CC=C1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: [Li]c1cccs1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccsc1
Solvent: Cc1ccccc1
Product: Clc1ccc(Sc2cccs2)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a suspension of N-chlorosuccinimide (10.78 g) in dry toluene (45 ml) was added dropwise, a solution of 4-chlorothiophenol (9.84 g) in dry toluene (35 ml) at room temperature. After 1 hour, the suspension was filtered, the filter pad washed with toluene (100 ml) and the filtrate evaporated under reduced pressure to give an orange oil. The oil was dissolved in dry tetrahydrofuran (40 ml) and added dropwise to a solution of 2-thienyllithium (prepared by the addition of n-butyllithium (27.2 ml, 2.5M) to thiophene (5.72 g) in dry tetrahydrofuran (60 ml) at -15° C. under nitrogen and stirred for 2 hours) at -15° C. under nitrogen. The solution was stirred for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice, extracted with ether (3×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C 60-40/60H column using petroleum ether (40°-60° C.) to give a colourless oil.
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncccc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 154.2 %

Procedure:
A mixture of 3-fluoro-2-nitropyridine (1.07 g, 6.75 mmol), aniline (1.8 mL, 20.2 mmol) and Et3N (2.8 mL, 20.2 mmol) in DMF (10 mL) was stirred at 100° C. for 16 h under a nitrogen atmosphere. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% MeOH in DCM) to afford the title compound as a red oil (2.24 g, quantitative). LCMS (Method C): RT 3.03 min [M+H]+ 216.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][CH:26]1[CH2:35][CH2:34][CH2:33][C:32]2[C:31]([OH:36])=[CH:30][CH:29]=[CH:28][C:27]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH:26]([CH3:25])[C:27]=4[CH:28]=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC1CCCc2c(O)cccc21
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC1CCCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 85.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (43 mg, 0.26 mmol) to give the title compound (56 mg, 92%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:19](ON1C(=O)CCC1=O)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CCN(CC)CC.C(O)(=O)C>CN(C=O)C>[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:19]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@H](O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
D-Threonine (4.58 g, 38.5 mmol) was dissolved in 19 ml of 40% Triton B and evaporated to an oil. It was re-evaporated twice from DMF, and the salt obtained was stirred with Boc-Tyr-OSu (13.24 g, 35 mmol) in DMF (80 ml) at 0° C. for 1.5 hr and at 25° C. for 30 hr. A constant pH of 8 was maintained by dropwise addition of Et3N during reaction time. The reaction was acidified to pH 4 with acetic acid. The solvent was evaporated to a syrup, dissolved in chloroform, washed with 0.5 N H2SO4 and water, dried (Na2SO4) and evaporated to low volume. The product was obtained as an amorphous solid from petroleum ether: 9.17 g (68.5%): [α]D25 -42.9° (c 1.4, DMF).
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].[Cl-].[Mn+2:47].[Cl-].C(O)C>O>[Mn:47].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Mn+2]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: [Mn]
Reaction time: 18 h

Procedure:
A mixture of 6.5 g sodium lysocellin, 2.0 g manganese chloride and 100 ml of 90% ethanol was stirred and held at ambient temperature for 18 hours. Stirring was continued and water added slowly to precipitate a tacky semi-solid. Removal of the mother liquor by decantation and trituration of the residue with fresh water gave a filterable amorphous solid which was isolated and dried (6.4 g). The product had a melting point of 112.8° C. Analysis: Calculated % Mn (4.19); Found (3.75).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[SH:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].[C:19](#N)C>>[S:12]1[CH2:19][C:13](=[O:16])[NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4]([C:3]1=2)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: Nc1ccc2ccccc2c1S
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: [K+]
Product: O=C1CSc2c(ccc3ccccc23)N1
Temperature: 25 °C

Procedure:
Under nitrogen, a mixture of 5.3 g of 2-aminonaphthalene-1-thiol, 6.2 g of trans-3-(p-methoxyphenyl)glycidate and 0.6 g of potassium carbonate in 80 mL of acetonitrile was stirred at reflux for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to a volume of about 20 mL. The crystals were separated by filtration to give 1.4 g of 2H-naphtho[1,2-b]-1,4-thiazin-3(4H)-one, mp 211°-212°. The mother liquors after removal of 1.4 g of the above compound were concentrated under reduced pressure to give 11.0 g of a mixture of (±)-threo-[(2-amino-1-naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid methyl ester, 2H-naphtho[1,2-b]-1,4-thiazin-3(4H)-one and p-methoxybenzaldehyde. The mixture was chromatographed on a column using 120 g of silica gel. The column was eluted with 75 mL portions of methylene chloride. The first six portions of which were collected and the solvent was removed under reduced pressure gave 1.1 g of an oil, whose nuclear magnetic resonance spectrum was identical with that of p-methoxybenzaldehyde. Further elution of the column with the same solvent (fractions 7-19) afforded 1.0 g of 2H-naphtho[1,2-b]-1,4-thiazin-3(4H)-one. A sample of this compound was recrystallized from ethanol, mp 211°-212°. (±)-threo-[(2-Amino-1 -naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid methyl ester was obtained from the column by further elution with methylene chloride. The methylene chloride fractions 20-35 were combined and the solvent was removed under reduced pressure to afford 1.2 g of (±)-threo-[(2-amino-1-naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid methyl ester, which was treated with hydrogen chloride (anhydrous) in ethyl acetate to afford 1.1 g (85%) of the hydrochloride of (±)-threo-[(2-amino-1-naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid methyl ester, mp 139°-140°. The hydrochloride salt (1.1 g) on treatment with dilute sodium hydroxide and extraction of the aqueous suspension with ethyl acetate gave after removal of the solvent 1.0 g of (±)-threo-[(2-amino-1-naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid methyl ester. A sample of this compound was recrystallized from ether--pet. ether, mp. 32°-34°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[CH:7]=[CH:8][C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:20]OS(OC)(=O)=O.[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:5]([N:4]([CH3:20])[C:1](=[O:3])[CH3:2])=[C:6]([CH:13]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Cl)cc1C=CC(=O)O
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
12.8 g of methyl 2-acetamido-5-chlorocinnamate are dissolved in 200 ml of dimethylformamide/toluene (1:1), and 1.6 g sodium hydride (80% in paraffin oil) are added. Stirring is effected for 30 minutes, and at 0° 7 g of dimethylsulphate are added drop by drop. After 2 hours additional stirring at room temperature, 500 ml of water and 50 ml of 2 N sodium hydroxide solution are added followed by washing with toluene. After acidification, extraction with methylene chloride, removing of the solvent and chromatografic purification one obtains 7.6 g of 5-chloro-2-(N-methyl-acetamido)-cinnamic acid as oil. This oil is stirred for 24 hours at 100° with 100 ml of 5 N hydrochloric acid; after cooling the pH is adjusted to 8.5 with dilute sodium hydroxide solution, and 10 g of sodium bicarbonate are added. 7.5 g of 3,4-dichlorobenzoyl chloride in 50 ml of toluene are added dropwise. Working up as in Example 1(a) yields 10.8 g of 5-chloro-2-(N-methyl-3,4-dichlorobenzamido)cinnamic acid, which are reacted without further purification for 2 days at room temperature with 200 ml of methanol under addition of 4 ml of concentrated sulphuric acid. Extraction with methylene chloride and working up yield 8.3 g of the corresponding methyl ester, which is reacted analogously to (a).
Reaction SMILES: Cl[C:2]1[C:3]2[O:18][CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[IH:19].[Na+].[I-]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:19])[C:3]3[O:18][CH2:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Reactant: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (80 mg, 0.28 mmol, 1 eq) in a 57% HI solution in water (2 ml) at rt. was added NaI (206 mg, 1.41 mmol, 5 eq). The reaction mixture was stirred at rt overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine that was not further purified.