Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:20]=[CH:21][C:11]1=2)(=O)OCC)C.[H-].[Na+].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)=[CH:35][CH:34]=1>O1CCCC1>[ClH:32].[ClH:32].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=[CH:9][C:10]2=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH:20]=[CH:21][C:11]2=3)=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(-c3cccc(OC)c3)ccc21)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(c2)N(C)CCN=C3C=Cc2ccccc2Sc2ccc(Cl)cc2)c1
Product: Cl
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To 112 mg (0.27 mmol) of [8-(3-methoxyphenyl)-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ylidenemethyl]phosphonic acid diethyl ester (prepared as described in Example 98) in 2 ml of tetrahydrofuran was added 19 mg (0.47 mmol) of sodium hydride (60% dispersion in mineral oil). After 10 minutes 70 mg (0.28 mmol) of 2-(4-chlorophenylthio)benzaldehyde was added and the mixture was stirred for 3 hours. The product was purified by column chromatography (20 g IST pre-packed column) eluting with 1% methanol/ethyl acetate and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated to leave an orange gum which was recrystallized from ethyl acetate to give 10 mg of (E)-5-[2-(4-chlorophenylthio)styryl]-2,3-dihydro-8-(3-methoxyphenyl)-1-methyl-1H-1,4-benzodiazepine dihydrochloride as a red solid; MS: m/e 510 (M+).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[C:24]([O:34][CH3:35])[CH:23]=1>>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:27]=[CH:26][C:25]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1OC
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC)c2)cc1)c1ccccc1
Yield: 89 %

Procedure:
Compound 37 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.4 g, 1.197 mmol) and methyl 3-(4-hydroxy-2-methoxyphenyl)propanoate (0.268 g, 1.197 mmol) by following the procedure described in scheme 13 (0.2 g, yield: 89%); Purity: 99.31%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N+:21]([C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:33][CH:32]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylforrnamide (10 mL) under argon was treated with 55% sodium hydride (0. 175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-nitrophenoxy)ethanol (1.56 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 9:1) and crystallized from dichloromethane-hexane to provide 0.75 g of 4-[[2-(4-nitrophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a 4:1 molar hydrate, mp 122°-123° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:24]1([C:2]2[C:7]([C:8]([C:10]3[CH:11]=[N:12][N:13]([CH3:22])[C:14]=3[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CCC3)cnn2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (200 mg, 0.576 mmol) in acetonitrile (6.0 mL) were added azetidine (39.0 μL, 0.576 mmol) and N,N-diisopropylethylamine (151 μL, 0.867 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The product was carried to Step 7 without further purification. LCMS m/z 368.4 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:12](OCC)=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:13][CH2:12][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(CO)CCOCC1
Temperature: -25 °C
Reaction time: 8 h

Procedure:
A solution of diethyl tetrahydro-4H-pyran-4,4-dicarboxylate, the compound of Formula (7a), (12 Kg) in toluene (104 Kg) was cooled to between -30° C. to -35° C., and diisobutylaluminum hydride (69 Kg) was added at such a rate so as to maintain a reaction temperature of -25° C. After the addition was complete, the temperature was raised to 15° C. over 3 hours, and the reaction stirred until all starting material was consumed. The mixture was then recooled to -15° C. and allowed to stand overnight. The product was partitioned between ethyl acetate (54 Kg), ethanol (48 Kg), and saturated sodium sulfate solution (60 liters), and the mixture stirred overnight at 250C. The precipitated salts were filtered off, washed with tetrahydrofuran, and the filtrate washed with brine and separated. The organic layer was dried over magnesium sulfate and solvent removed under reduced pressure, to give ethyl 4-hydroxymethyltetrahydropyran-4-carboxylate (3.8 Kg), the compound of Formula (8a).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:5]=1[CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[NH:9][C:8]1=[O:15]>C(O)(=O)C>[Br:1][C:11]1[C:10](=[O:14])[NH:9][C:8](=[O:15])[N:7]([CH2:6][C:5]2[C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=[CH:19][C:4]=2[F:3])[C:12]=1[CH3:13]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 48750 %

Procedure:
Bromine (16.5 mL, 0.32 mmol) was added to 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione 4c (48.5 g, 0.16 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat.NaHCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of 4d (0.156 mol) total. 1H NMR (CDCl3) δ 2.422 (s, 3H), 5.478 (s, 2H), 7.246–7.582 (m, 3H), 8.611 (s, 1H); MS (CI) m/z 380.9 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH:25](O)([CH3:27])[CH3:26]>>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH:25]([CH3:27])[CH3:26])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 43 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of isopropanol are treated in the same manner as described in Example 13. One g of isopropyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is obtained. Yield: 43%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][C:43]2[CH:44]=[C:45]([CH2:49][NH2:50])[CH:46]=[CH:47][CH:48]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:50][CH2:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:44]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCc1cccc(CN2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), 1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (28 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.5 g, 1.45 mmol) in dichloromethane (6 ml) was added trifluoroacetic acid (3 ml). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (3×20 ml) and 1N sodium hydroxide solution (30 ml). The combined organic phases were dried over potassium carbonate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using dichloromethane/methanol/ammonia 95:5:1 as eluant to afford the title compound as a solid (0.27 g, 76%); δH (CDCl3) 2.9 (2H, t, CH2), 3.24 (2H, t, CH2), 4.1 (2H, s, CH2), and 7.04-7.55 (7H, m, ArH).
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[C:1]1([CH2:14][O:15][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC(=O)O1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h

Procedure:
Fluorenylmethanol (0.90 g, 4.5 mmol) and dimethylaminopyridine (50 mg) are dissolved in 10 ml dry pyridine. Glutaric anhydride (5.0 mmol) is added and the solution stirred overnight. The solvent is removed under reduced pressure, sodium bicarbonate added (50 ml), the solution extracted with ethyl acetate (50 ml), and the organic layer discarded. The aqueous layer is acidified to pH 2, extracted with ethyl acetate (2×100 ml), washed with brine, and the solvent removed under reduced pressure. The residue is purified by flash chromatography to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH2:12][Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (10 g, 49 mmol) in diethyl ether (20 mL) at 15° C., was added drop wise at 15° C. EtMgBr (7.22 g, 54.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with cold water and NH4Cl solution. It was extracted with diethyl ether and the ether layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-(5-bromo-2-fluorophenyl)propan-1-ol (12.1 g, 98%) as a syrup. 1H NMR (CDCl3): δ 7.6-7.7 (m, 1H), 7.2-7.3 (m, 1H), 6.9 (t, 1H), 4.9 (brs, 1H), 1.8 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[Br:17]Br>ClCCl.[Fe]>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2])[CH2:9][CH2:10]2
Reactant: CCOC(=O)C(=O)N1CCc2ccccc21
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a mixture of N-ethoxalylindoline (4 g, 18.3 mmol), and iron powder (0.40 g) in dichloromethane (40 mL) was added dropwise bromine (1.43 mL, 27.7 mmol) at 0° C. The mixture was stirred for 4 h at room temperature and filtered. The filtrate was washed with aqueous sodium thiosulfate and then brine, dried over magnesium sulfate, and concentrated to give 5.24 g of 5-bromo-N-ethoxalylindoline (95%): 1H NMR (270 MHz, CDCl3) δ8.07(d, 1H, J=8 Hz), 7.35 (dd, 2H, J=8, 1 Hz), 4.38 (q, 2H, J=7 Hz), 4.27 (t, 2H, J=8 Hz), 3.20 (t, 2H, J=8 Hz), 1.41 (t, 3H, J=7 Hz).
Reaction SMILES: [O:1]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[BH4-].[Na+]>>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(Oc3ccccc3)c2)N1
Yield: 71.8 %

Procedure:
Analogous to the procedure described for Compound 1A, Step B, 5-[3-oxo-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (923.6 mg, 2.86 mmol) was reduced with NaBH4 (54 mg, 1.4 mmol). Purification by medium pressure chromatography (1:1 hexanes:EtOAc to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 5-[3-hydroxy-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (668.3 mg). 1H NMR (CDCl3) δ 7.31 (m, 2H), 7.23 (m, 1H), 7.08 (m, 1H), 6.97 (d, 2H), 6.91 (d, 1H), 6.84 (m, 2H), 3.80 (m, 1H), 3.73 (m, 1H), 2.77-2.03 (m, 2H), 2.40 (m, 2H), 2.24 (m, 1H), 1.75-1.41 (m, 5H); MS 326.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[CH:14]=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:4][CH:3]=1.[I:23]Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[C:14]([I:23])=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Reactant: ClI
Solvent: ClCCl
Product: O=C1c2c(O)c(O)c(I)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (5 g, 16.4 mmol) in methylene chloride (300 mL) at room temperature, a solution of iodine monochloride (2.8 g, 17.2 mmol) in methylene chloride (50 mL) was added. The suspension was stirred at room temperature overnight and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed subsequently with an aqueous solution of sodium metabisulfite and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, concentrated. The residual solid was stirred in diethyl ether overnight, and collected by filtration.
Reaction SMILES: [NH2:1][C:2]1([CH3:13])[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2C(=O)O[C:21](=[O:22])[C:20]=12.CN(C=O)C>O>[CH2:9]([N:6]1[C:7](=[O:8])[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=2[F:14])([CH3:13])[C:3](=[O:12])[NH:4][C:5]1=[O:11])[CH3:10]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CCN1C(=O)NC(=O)C(C)(N)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1-ethyl-5-methylbarbituric acid (0.37 g, 2 mmol), tetrafluorophthalic anhydride (0.44 g, 2 mmol) and DMF (14 mL) was stirred under reflux for 5 hours. The yellow solution was then allowed to cool down to room temperature and poured into water (50 mL). The precipitate that formed was collected by filtration and dried under reduced pressure to give 20f as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[C:8](=O)(OCC)[O:9]CC.[H-].[Na+]>>[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][O:6][C:8](=[O:9])[O:7]1
Reactant: COCC(O)CO
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: COCC1COC(=O)O1

Procedure:
A mixture of 14 g (0.132 mol) of compound 370487 (Method 2--Step 2), 31.16 g (0.264 mol) of diethyl carbonate in the presence of 0.108 g of 50% sodium hydride is heated until distillation of the alcohol formed. After completion of the reaction, the aimed product is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:5].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>O1CCCC1>[N+:27]([C:25]1[CH:26]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]3[CH2:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:15][CH2:16]3)[C:30](=[O:31])[NH:1]2)=[CH:23][CH:24]=1)([O-:29])=[O:28]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCCCN1CC=C(c2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Yield: 57.7 %

Procedure:
A mixture of 2-amino-4-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.52 g) and carbonyldiimidazole (0.43 g) in dry tetrahydrofuran (10 ml) was stirred under reflux for 2 hours. After evaporation of the solvent, the crude residue was crystallized and recrystallized from ethanol to give crystals of 7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.32 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[N:8]=1)C.C(O)(=O)C>[Pd].CCO>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:4](=[O:3])[CH2:5][O:6][C:7]=2[N:8]=1
Reactant: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNc2ccc3c(n2)OCC(=O)N3)c(OC)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
[6-(2,4-Dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (6.35 g, 16.2 mmol) and acetic acid (8 mL) were dissolved EtOH (160 mL). 10% Pd/C (635 mg) was added and the mixture was stirred under a hydrogen atmosphere for 24 hours after which time the product precipitated. The solid was collected by filtration, suspended in 1,4-dioxane (200 mL) and then heated briefly to ˜100° C. The mixture was allowed to cool and was then filtered while still luke-warm (to remove Pd/C). The filtrate was evaporated in vacuo to give 6-(2,4-dimethoxy-benzylamino)-1H-pyrido[2,3-b][1,4]oxazin-2-one (3.76 g) as a beige solid. MS: [M+H]+=316.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:29][CH2:28][CH2:27][O:26][CH3:25])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Product: COCCNCc1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Yield: 56 %

Procedure:
Following the procedure for 119, 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and 2-methoxyethylamine were reacted. After purification by flash chromatography the resulting oil was dissolved in ether and treated with 1M HCl in ether to give a solid that was filtered off and dried to give 120 as a yellow solid (129 mg, 56%). LCMS: RT=6.11 min, [M+H]+=400. 1H NMR δ (ppm) (DMSO-d6): 9.17 (2 H, s), 8.93-8.90 (1 H, m), 8.29 (1 H, d, J=8.13 Hz), 7.28 (1 H, dd, J=8.22, 1.81 Hz), 7.24 (1 H, d, J=1.76 Hz), 5.47-5.38 (1 H, m), 4.33 (2 H, t, J=4.98 Hz), 4.10 (2 H, t, J=5.38 Hz), 3.56 (2 H, t, J=5.15 Hz), 3.43-3.30 (2 H, m), 3.25 (3 H, s), 3.02 (2 H, t, J=5.63 Hz), 1.56-1.49 (6 H, m)
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3OCCO3)=[CH:7][C:5]=2[CH:6]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]=[C:20]3[S:16][C:17](=[O:22])[NH:18][C:19]3=[O:21])=[CH:7][C:5]=2[CH:6]=1
Reactant: Clc1cc2cc(C3OCCO3)ccc2o1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3oc(Cl)cc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 2-Chloro-5-[1,3]dioxolan-2-yl-benzofurane (intermediate 67) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][CH2:12][O:13][CH3:14])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH2:19].[S-2].[Na+].[Na+].Cl.C[OH:26]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10](=[O:26])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: COCC#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Product: COCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 75 °C
Yield: 13 %

Procedure:
To a solution of 2-amino-5-(3-methoxy-prop-1-ynyl)-4-trifluoromethyl-benzoic acid methyl ester (1.19 g, 4.15 mmol) in MeOH (100 mL) were added successively a solution of sodium sulfide (0.1 M, 12.4 mL, 1.24 mmol), followed by 10% aq HCl-solution (3.70 mL, 12.45 mmol). The reaction mixture was heated to 75° C. for 29 h, cooled and filtered over Celite. Evaporation of the filtrate gave a yellow oil which was purified by MPLC (oRP-C18 column (particle size 5-21 μM) with 1:1 CH3CN/water. The fractions containing the product were combined, the acetonitrile was distilled off and the residual water phase was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) and the solvent was removed in vacuo to provide the title compound (0.167 g, 13%) as a white powder, mp 89-91° C. IR (FTIR microscope in transmission): 1696 m, 1674 s cm−1.