Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](=[O:15])[CH2:3][CH2:2]1>O1CCCC1.[O-2].[Mn+4].[O-2]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4]([OH:15])=[CH:3][CH:2]=1
Reactant: O=C1CCNc2cc3ccccc3cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Oc1ccnc2cc3ccccc3cc12
Yield: 90 %

Procedure:
To 500 mg of 2,3-Dihydrobenzo[g]quinolin-4(IH)-one (1, 2.53 mmol) in 25 mL of dry tetrahydrofuran (0.25 M) under a nitrogen atmosphere was added 1.76 g manganese(IV) oxide (8 equivalents). The reaction mixture was heated to reflux and monitored by TLC until completion. The crude reaction mixture was filtered through a celite plug using 5% methanol in methylene chloride to afford 445 mg of relatively clean benzo[g]quinolin-4-ol (6) in 90% yield. Subsequently, the phenol was directly subjected to the halogenation conditions without further purification.
Reaction SMILES: [CH2:1]1C[O:4][CH2:3][CH2:2]1.Cl[C:7]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[C:9]([NH:11][CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][C:17]([OH:22])([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)=[O:10]>CCOC(C)=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH:12]2[CH:13]3[CH2:14][CH:15]4[CH2:16][C:17]([OH:22])([CH2:18][CH:19]2[CH2:20]4)[CH2:21]3)=[O:10])=[C:7]([O:4][CH2:3][CH2:2][CH3:1])[N:26]=1
Reactant: C1CCOC1
Reactant: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cl)ccc1C(=O)NC1C2CC3CC1CC(O)(C3)C2
Temperature: 150 °C
Yield: 93.5 %

Procedure:
Bis-sodium hexamethyldisilylamide 1.0M in THF (1 ml, 1 mmol) was added to 2,6-dichloro-N-(5-hydroxyadamantan-2-yl)nicotinamide (341 mg, 1 mmol) and heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-N-(5-hydroxyadamantan-2-yl)-2-propoxynicotinamide (341 mgs, 93%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[N:12]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Reactant: O=c1cc(I)c(F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Cesium carbonate (2.01 g, 6.16 mmol) was added to a solution of the 5-fluoro-4-iodopyridin-2(1H)-one (491 mg, 2.06 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (767 mg, 2.67 mmol in THF (30 mL). The resulting suspension was heated to reflux and stirred at this temperature overnight. The reaction was filtered through celite (˜1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-12g column and an eluant of ethyl acetate in heptane (30-100%) to afford the title compound as a white gum (319 mg, 34.9%). LC-MS m/z 446.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3H) 1.75 (s, 3H) 2.40-2.58 (m, 2H) 3.10 (s, 3H) 3.87-3.99 (m, 1H) 4.16-4.25 (m, 1H) 4.29 (q, J=7.22 Hz, 2H) 7.15 (d, J=5.85 Hz, 1H) 7.20 (d, J=3.32 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[CH2:10][C:11]#[N:12]>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]#[N:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: N#CCBr
Product: CCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-Ethyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a orange oil; ES-MS: M+=154.1: 1HNMR(DMSO-d6) 3.70 (s, 2H), 2.40-2.20 (m, 10H), 0.95 (t, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH2:11][CH:12]([OH:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[C:1]([O:14][CH:12]([CH3:13])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)OC(C)Cc1ccccc1

Procedure:
Acetyl chloride (16.7 g) in dry ether (50 ml) was added dropwise to a stirred solution of 1-phenylpropan-2-ol (26.4 g) in dry ether (250 ml). The mixture was refluxed for 2 h, washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to a colourless oil (27.5 g).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([Cl:16])([Cl:15])[Cl:14])[O:10][CH:9]([C:17]([Cl:20])([Cl:19])[Cl:18])[C:8]=2[CH:21]=1.[CH3:22]I>C(O)C>[CH3:22][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([Cl:14])([Cl:15])[Cl:16])[O:10][CH:9]([C:17]([Cl:20])([Cl:19])[Cl:18])[C:8]=2[CH:21]=1
Reactant: CI
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.52 g.) in ethanol (50 ml.) was added dropwise to a stirred solution of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (5 g.) in ethanol (100 ml.) and the resulting solution was stirred for 15 minutes. Methyl iodide (1.7 ml.) was then added, the reaction mixture was warmed on a steam bath for 1 hour, and evaporated to dryness under reduced pressure, and the oily residue was triturated with diethyl ether and filtered to remove sodium iodide. The filtrate was chromatographed on silica (Kieselgel 60; 200 g.) and the product was crystallised from ethanol to give 6-methoxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][CH:14]=3)=[N:24][NH:25][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COCc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Reactant: NN
Solvent: O
Product: COCc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(4-methoxymethylbenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:57]=[C:58]([NH2:65])[C:59]4[CH:60]=[N:61][NH:62][C:63]=4[CH:64]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1>CN(C=O)C>[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:64]=[C:63]4[C:59]([CH:60]=[N:61][NH:62]4)=[C:58]([NH:65][C:11]([C:6]4[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=[CH:8][N:7]=4)=[O:13])[CH:57]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CS(=O)(=O)c1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
To 3-(methylsulfonyl)-2-pyridinecarboxylic acid (which may be prepared as described by Blank, Benjamin; DiTullio, Nicholas W.; Owings, Franklin F.; Deviney, Linda; Miao, Clara K.; Saunders, Harry L. Journal of Medicinal Chemistry (1977), 20(4), 572-576.) (89 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (29 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:7]=3[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>CO.CN(C)C=O.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150 mL)-N,N-dimethylformamide (600 mL), 10% palladium on charcoal (5.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature overnight. After the unsoluble materials were filtered out, the methanol was removed under reduced pressure. Water (2 L) was added to the residue. The precipitated solid was filtered off and dried at 90° C. under reduced pressure to give the titled reference compound (44.02 g) as a pale yellow solid. (Yield 96%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10](OCC)=[O:11])[CH3:2].CC(C)([O-])C.[K+].O1CCCC1.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][O:8][CH2:9][C:10]1=[O:11])=[O:15])[CH3:2]
Reactant: CCOC(=O)CCCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
A solution of 4-ethoxycarbonylmethoxybutyric acid ethyl ester (90%, 15.0 g, 61.9 mmol) in toluene (300 mL) was stirred at room temperature and treated over 5 min with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 74.2 mL, 74.2 mmol). The mixture was stirred at room temperature for 24 h , then was poured into 1 N hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ether. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (5% ethyl acetate/hexanes) to provide the product as a pale yellow liquid (5.06 g, 48%). 1H NMR (300 mHz, CDCl3) δ11.85 (s, 1H), 4.24 (q, J=7.3 Hz, 2H), 4.14 (t, J=1.7 Hz, 2H), 3.79 (t, J=5.5 Hz, 2H), 2.35 (tt, J=5.5, 1.7 Hz, 2H), 1.32 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=3)[CH:12]=2)[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: COC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), methyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 11) (32.9 g, 0.1 mol), n-butanol (280 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 8 h. Cooled down to room temperature and crystals precipitated overnight. After air pump filtration the cake was rinsed by n-butanol and dried to give target Compound 6 (31.7 g, yield: 83.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(O)=O.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenyl}-propionaldehyde (94 mg, 0.22 mmol) in 1,2-dichloroethane (2.2 mL) and add pyrrolidine (20 μL, 0.24 mmol), AcOH (19 μL, 0.33 mmol), and NaHB(OAc)3 (70 mg, 0.33 mmol). Stir the yellow solution at room temperature for 1 h, then add 1N NaOH (5 mL), and extract the mixture with CH2Cl2 (2×10 mL). Combine the organic portions, then dry, filter, and concentrate. Purify the crude material by flash chromatography, using 8% 2N NH3 in MeOH/CHCl3 as eluent, to give the title compound (75 mg, 71%). MS (ES+) 480.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 2H, J=8.3 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.43 (d, 1H, J=7.5 Hz), 7.25 (t, 1H, J=3.7 Hz), 6.97 (d, 1H, J=7.5 Hz), 6.93-6.88 (m, 2H), 3.83 (s, 3H), 2.70 (t, 2H, J=7.7 Hz), 2.60 (br s, 6H), 1.96-1.79 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([O:9]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:5].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:33])([F:24])[F:34])=[CH:31][N:30]=1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
A solution is made in an inert organic solvent of 2-chloro-6-fluorobenzamidocarboxylic acid, 4-nitrophenyl ester, and 5-trifluoromethyl-2-aminopyridine. The temperature of the reaction mixture is raised, and the mixture is stirred for a period of time. The mixture is then evaporated under vacuum, and the product named in the heading above, identical to the product of Example 4, is isolated and purified by recrystallization.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22](=[O:41])[C:23]([C:37](OC)=[O:38])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:37]([C:23]1[C:22](=[O:41])[C:21]([O:20][CH3:19])=[CH:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[N:24]=1)=[O:38]
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added AlMe3 (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (2.95 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (2.15 g, 67% yield) as off-white crystals: mp 170-171° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.63-7.71 (2H, m), 7.80-7.86 (1H, m), 7.88 (1H, s), 7.98 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.48; H, 4.07; N, 11.66.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH2:21]([NH:25][C:26]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: ClCCl
Product: CCCCNC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (198 mg, 714 μmol, Example 87, Step 3) in DCM (2.0 mL) was added n-butyl isocyanate (88 μL, 785 μmol). The resulting mixture was then stirred at RT for overnight. Then, the solvent was removed and the residue was mixed with silica gel. The solid mixture was the purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0%-400% EtOAc/hexane) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 377 (M+H).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[BH4-].[Na+]>CO.ClCCl>[OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14]
Reactant: O=CC[C@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1N[C@H](CCO)[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 51.5 %

Procedure:
To a solution of (3R,4R)-4-(2-oxoethyl)-3-phthalimidoazetidin-2-one (52 mg) in a mixture of methanol (3 ml) and dichloromethane (1 ml) was added a solution of sodium borohydride (8 mg) in methanol (2 ml) at 0° C. during one hour. The reaction was quenched by addition of acetic acid (two drops). After evaporation in vacuo, the residue was chromatographed on silica gel (1.6 g; eluting with 3 to 5% methanol in dichloromethane) to give 32 mg of crude crystals. Crystallization from a mixture of methanol and ether afforded 27 mg (51.5%) of (3R,4R)-4-(2-hydroxyethyl)-3-phthalimidoazetidin-2-one. IR (Nujol): 3350(br), 3250, 1750, and 1705 cm-1 ; NMR (DMSO-d6) δ: 1.79 (q, J=6 Hz, 2H), 3.46 (m, 2H), 3.97 (dt, J=2.5 and 6 Hz, 1H), 4.47 (brs, 1H), 4.89 (d, J=2.5 Hz, 1H), 7.86 (s, 4H), and 8.42 (brs, 1H).
Reaction SMILES: [C:1]1([CH:7]([SeH])[CH:8]([CH2:15]C)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([C:8](=[CH2:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:1]
Reactant: CCC(CCC(=O)OC)C([SeH])c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CC)CCC(=O)OC
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of selenide XIII (1.8 g, 6.0 mmol) in methylene chloride (15 ml) at -78° C. was added m-chloroperbenzoic acid (1.28 g, 85%, 6.3 mmol). The solution was allowed to warm to room temperature over 30 min. and was then washed with water, saturated sodium carbonate and dried (MgSO4). The methylene chloride was removed in vacuo and the selenoxide was taken up in carbon tetrachloride (15 ml). Triethylamine (640 mg, 6.3 mmol) was added and the solution was refluxed under nitrogen for 2 h. The reaction was taken up in methylene chloride (25 ml), washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated on a roto-evaporator. The crude olefin XIV was distilled bp 70°-75° C. (25 mm) to give a colorless oil (630 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][S:6][CH2:7][C:8](O)=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:11]([C:8](=[O:9])[CH2:7][S:6][CH2:5]2)=[CH:12][CH:13]=1
Reactant: O=C(O)CSCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CSCc2cc(Cl)ccc21
Yield: 51.1 %

Procedure:
3-Chlorobenzylmercaptoacetic acid from Step 2 (3.35 g) was dissolved in trifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) was added and the reaction stirred at reflux, under a nitrogen atmosphere for 16 hours. The solution was carefully poured into 10% Na2CO3 solution (500 mL) which was stirring vigorously. The organics were extracted into ether (500 mL) and washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting brown solid was purified by silica gel chromatography eluting with a 0-10% gradient of ethyl acetate in hexane to yield 7-chloroisothiochroman-4-one (1.57 g, 51%): 1H NMR (CDCl3) δ=3.49p (d, 2H, J=0.8 Hz), 3.8p (s, 2H), 7.16p (m, 1H), 7.3p (dd, 1H, J=2.0, 8.4 Hz), 7.96p (d, 1H, J=8.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[C:4]([CH2:19][CH3:20])[N:3]=1.[CH3:21][NH2:22]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:22][CH3:21])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[C:4]([CH2:19][CH3:20])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CCc1nc(N)nc(N)c1-c1ccc(NC)c([N+](=O)[O-])c1
Yield: 92 %

Procedure:
A suspension of 2,4-Diamino-5-(4-chloro-3-nitro phenyl)-6-ethylpyrimidine (nitropyrimethamine) (10 g) in aqueous methylamine solution (40%; 200 ml) was refluxed for 48 hours with the further addition of methylamine solution (100 ml) after 24 hours and 36 hours. An orange colour slowly developed and the consumption of starting material was monitored by t.l.c. After cooling and dilution with water, the crystalline product was collected and recrystallized from aqueous DMF to yield orange prisms of 2,4-Diamino-5-(4-methylamino-3-nitrophenyl)-6-ethylpyrimidine (9.0 g. 92%), m.p. 262°-265° C. (Elemental analysis: C, 53.9; H, 5.9; N, 29.3%; calculated: C, 54.2; H, 5.6; N, 29.2%).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[C@H:3]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]([N:4]([CH3:5])[C@@H:3]([CH2:24][C:25]3[N:26]=[CH:27][S:28][CH:29]=3)[C:2]([OH:6])=[O:1])=[O:8])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cscn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](Cc1cscn1)C(=O)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 87.1 %

Procedure:
(S)-(9H-Fluoren-9-yl)methyl 5-oxo-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (Compound SP817) (40.0 g, 98.4 mmol), trifluoroacetic acid (245 ml, 3.18 mol) and triethylsilane (160 ml, 1.00 mol) were dissolved in dichloromethane (1 l) under a nitrogen atmosphere, and the mixture was stirred at 35° C. for two days. The reaction solution was concentrated under reduced pressure and then dissolved in diethyl ether, and the organic layer was washed with an aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 3 with a aqueous potassium bisulfate solution and extracted with dichloromethane. All organic extracts obtained were washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP811, Fmoc-MeAla(4-Thz)-OH) (35 g, 87%).