Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (46.4 mg, 41%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+].[Br-].[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(=O)CC>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCC
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500 ml 2-necked bottle equipped with a condenser tube, butanone (200 ml), and then 2,4-dinitrofluorobenzene (18.60 g, 0.100 mol), hydroquinone (11.32 g, 0.100 mol), and potassium carbonate (15.26 g, 0.110 mol) were introduced. The mixture were agitated at room temperature for 2 hours. Then, potassium carbonate (15.26 g, 0.110 mol), octane bromide (27.41 g, 0.110 mol), and butanone (20 ml) were added to the bottle. The mixture were stirred at room temperature for 6 hours. Thereafter, distilled water (300 ml) was added to the bottle, and the mixture was extracted by ethyl acetate (300 ml×3). The collected organic layers were dried by anhydrous sodium sulfate, filtered, and concentrated, and recrystallized by ethanol to obtain 1-[4-(2,4-dinitrophenoxy)phenoxy]octane (31.08 g, 0.080 mol). Yield: 80%. Spectrum: IR (KBr) 3096, 2938, 2854, 1604, 1526, 1504, 1476, 1348, 1273, 1240, 1188, 1116, 1069, 1001 cm−1. 1HNMR (DMSO-d6, 300 MHz). δ8.88 (d, J=2.8 Hz, 1H), 8.43 (dd, J=2.8, J=9.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.10˜7.05 (m, 3H), 3.98 (t, J=6.4 Hz, 2H), 1.73 (quintet, J=6.7 Hz, 2H), 1.4˜1.2 (m, 10H), 0.87 (t, J=6.2, 3H) 13C NMR (DMSO-d6, 75 MHz). δ57.0, 156.1, 146.6, 141.0, 139.0, 129.7, 122.1, 122.0, 118.3, 116.3, 68.1, 31.5, 29.0, 28.9, 28.8, 25.7, 22.3, 14.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:12][CH:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Br:1])[C:3]=2[O:13][CH3:14])[CH3:11])[N:19]=[CH:18][N:17]=1
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1Br
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Temperature: 100 °C
Yield: 54 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine (40 mg, 0.14 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (J & W PharmLab, #70-0156 33 mg, 0.21 mmol) and N,N-diisopropylethylamine (74 μL, 0.43 mmol) in ethanol (1.6 mL, 27 mmol) was heated at 100° C. overnight. Purification by preparative LC/MS (pH10) gave the desired compound (54% yield). LCMS calculated for C14H13BrClFN5O (M+H)+: m/z=400.0, 402.0. found: 400.0, 402.0. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.77 (m, 1H), 7.28 (br s, 2H), 5.56 (m, 1H), 3.92 (s, 1H), 1.40 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][CH:12]\1[OH:13])=[O:5])[CH3:2].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Si:33]([O:13][CH:12]1[CH2:11][CH2:10][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]/[C:7]/1=[CH:6]\[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of (E)-3-[(ethoxycarbonyl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (14.97 g) in N,N-dimethylformamide (130 ml) were added successively t-butyldimethylsilyl chloride (6.86 g), 1H-imidazole (3.34 g) and 4-dimethylaminopyridine (0.43 g) under ice-cooling, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19) as the eluent to afford the title compound (16.38 g, yield: 86%) as a colourless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CCN1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol), and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended in acetonitrile (4 mL). The reaction was stirred at 60° C. overnight. H2O (25 mL) was added and the resulting precipitate was collected by filtration. The solid was subjected to chromatography (silica gel, ethyl acetate with 10% methanol) afforded an off-white solid (0.040 g, 30%). 1H NMR (400 MHz, CDCl3) δ 7.55 (app q, J=7.92 Hz, 1H), 6.93 (app t, J=8.39 Hz, 1H), 6.84 (app t, J=9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H), 4.16 (app t, J=6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J=6.38 Hz, 2H), 2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C19H21BrF2N2O3 requires 443.0776).
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]O.C1(O)C=CC=CC=1>CO>[CH3:9][C:10]([CH3:14])([CH:11]=[CH2:12])[CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CCO
Solvent: CO
Solvent: Oc1ccccc1
Product: C=CC(C)(C)CC(=O)OC
Yield: 39.9 %

Procedure:
A mixture of trimethyl orthoacetate (120 g; 1 mole), 3-methylbut-2-enol (21.5 g; 0.25 mole) and phenol (1.4 g; 0.015 mole) was placed in a flask equipped with a stirrer and a 10 cm fractionating column packed with Fenske rings. The mixture was heated, with stirring, to a temperature of 95°-110° C. and maintained at this temperature for a period of 2 hours while the methanol formed was collected by distillation. The excess trimethyl orthoacetate was distilled from the reaction mixture over a period of 1 hour during which time the temperature of the reaction mixture was raised to 140°-145° C. The mixture was heated, with stirring, at a temperature of 140°-145° C. for a period of 20 hours and then the product was distilled to give methyl 3,3-dimethylpent-4-enoate (14.2 g; 40%), bp 95°-99° C. at 140 mm Hg.
Reaction SMILES: [C:1]1(OC)[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[CH:8][CH3:9])[OH:3].[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:22])=O>>[CH2:22]([O:3][C:2]1[CH:1]=[CH:10][C:6]([CH:7]=[CH:8][CH2:9][O:16][CH3:13])=[CH:5][CH:4]=1)[CH:20]=[CH2:19]
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Reactant: CC=Cc1ccc(O)c(OC)c1
Agent: [K+]
Product: C=CCOc1ccc(C=CCOC)cc1

Procedure:
4-allyloxy-3-methoxypropenylbenzene was prepared by refluxing a stirred mixture of isoeugenol (164 g),allybromide (133 g) and potassium carbonate (278 g) in dry acetone (700 mls) for 18 hours. Removal of the solids and solvent gave a crude product 208 g which was vacuum distilled to yield 130 g of pure 4-allyloxy-3-methoxy-prop-1-enylbenzene (b.p.. 104-118° C. at 0.1 imbar).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[C:23]([CH:24]=[O:25])=[CH:22][C:21]([O:26][CH3:27])=[N:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH:14]([N:13]1[C:9]([C:4]2[CH2:5][O:6][CH2:7][CH2:8][C:3]=2[CH2:2][O:17][C:18]2[C:23]([CH:24]=[O:25])=[CH:22][C:21]([O:26][CH3:27])=[N:20][CH:19]=2)=[CH:10][CH:11]=[N:12]1)([CH3:16])[CH3:15]
Reactant: CC(C)n1nccc1C1=C(CBr)CCOC1
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)c(OCC2=C(c3ccnn3C(C)C)COCC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (50 mg, 0.19 mmol) (see the synthesis of Compound L) and 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.23 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0.38 mmol). After stirred at room temperature for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 5-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (26 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.40 (s, 1H), 7.81 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.08 (d, J=1.6 Hz, 1H), 4.42 (s, 2H), 4.40 (m, 1H), 4.19 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 2H), 1.41 (d, J=6.8 Hz, 6H); MS (ESI) m/z 358.4 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([NH:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:26][CH:25]=1)=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
A solution of 2-benzamidoisonicotinic acid (0.18 g, 0.74 mmol) in thionyl chloride (10 mL) was refluxed for 30 minutes and concentrated in vacuo to dryness. The residue was dissolved in dichloromethane (25 mL) and added to a mixture of (4-(trifluoromethyl)phenyl)methanamine (0.13 g, 0.74 mmol) and triethylamine (0.31 mL, 2.23 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes, washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 30-45% ethyl acetate in hexanes to give 2-benzamido-N-(4-(trifluoromethyl)benzyl)-isonicotinamide as a colorless solid (0.02 g, 8%): mp 165-168° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.79 (br s, 2H), 8.66 (s, 1H), 7.89-7.86 (m, 2H), 7.59-7.44 (m, 8H), 7.05-7.03 (m, 1H), 4.69 (d, J=6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 166.0, 165.4, 152.1, 149.1, 143.7, 141.7, 133.6, 132.7, 129.0 (2 peaks), 128.1 (2 peaks), 127.2 (2 peaks), 125.8, 125.7, 118.7, 110.3, 43.7; MS (ES+) m/z 400.4 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].C[CH:14]([NH2:17])[CH:15]=[O:16].[CH:18]1C=CC=CC=1>>[CH3:18][N:17]([CH2:14][CH:15]=[O:16])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: c1ccccc1
Reactant: CC(N)C=O
Product: CN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methyl-aminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product dimethyl acetal of 2-[1-methyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5]2.Br[C:18]([Br:21])([CH3:20])C.[C:22]([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[Br:21][CH2:18][CH2:20][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](C)[C@@H]1CCc2cc(O)ccc21
Reactant: CC(C)(Br)Br
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OCCCBr)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 34 %

Procedure:
Methyl (2S)-2-[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1 yl]propanoate (Example 14) (500 mg, 2.27 mmol), dibromopropane (4.308 g, 21.34 mmol), Cs2CO3 (834 mg, 2.56 mmol), and water (5 drops) were combined in DMF (20 mL) and stirred for 7 h at rt. The reaction mixture was concentrated under reduced pressure, water was added and the aqueous solution was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:25) gave 263 mg (34%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.08 (d, 3H), 1.91 (m, 1H), 2.17 (m, 1H), 2.32 (m, 2H), 2.80 (m, 1H), 2.88 (m, 2H), 3.51 (m, 1H), 3.61 (t, 2H), 3.72 (s, 3H), 4.08 (t, 2H), 6.69 (d, 1H), 6.76 (s, 1H), 6.98 (d, 1H).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[OH:12][C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:24]=O>O.CO>[OH:12][C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:24]=[N:2][NH:3][C:4]([NH2:6])=[O:5]
Reactant: NNC(N)=O
Reactant: O=Cc1c(O)c(O)cc2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NN=Cc1c(O)c(O)cc2ccccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
86.0 g of semicarbazide hydrochloride dissolved in 500 ml of water and 103 g of sodium acetate (CH3COONa.3H2O) were placed in a 2.5 l sulfonation flask equipped with stirrer, thermometer and dropping funnel. At an internal temperature of 40°-50° C., there was added dropwise a solution of 138.4 g of 2,3-dihydroxy-naphthaldehyde in 1000 ml of methanol. The mixture was stirred at 40°-50° C. for 1 hour and then, after adding 2 l of water, cooled to 10° C. and suction filtered. The material on the suction filter was back-washed thoroughly with water and dried at 60° C. in vacuo. Recrystallization from glacial acetic acid gave 131.9 g (73.1% of theory) of 2,3-dihydroxy-naphthaldehyde semicarbazone of melting point 210°-215° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][C:6]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:3])[CH3:2].[OH-:31].[Na+].Cl.[OH2:34]>C(O)C>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:34])=[O:31])=[CH:7][C:6]=1[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 85 °C

Procedure:
To 3.2 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile in 15 ml ethanol was added 30 mmol 2 M aq NaOH and the mixture was heated at 85° C. for 16 h. The mixture was then cooled to RT, diluted with water and acidified to pH 1 with conc HCl, and then extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, concentrated in vacuo, and the residue purified by chromatography on silica gel (eluant: methanol/dichloromethane 5:95) to afford the title compound. MS (m/e): 435.3 ([M−H]−, 100%)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]([O:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][C:18]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(I)c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25 g (84.2 mmol) of 3-iodobenzyl bromide are added to a solution of 24.3 g (88.4 mmol) of diethyl [(tert-butoxycarbonyl)amino]malonate and 3.7 g (92.6 mmol) of sodium hydride in 300 ml of DMF while cooling in ice. After stirring the mixture at RT for 4 h, 5 ml of water are added cautiously while cooling in ice. The mixture is extracted several times with ethyl acetate, and the combined organic phases are washed with a saturated sodium chloride solution and water, dried over magnesium sulfate and concentrated in vacuo. The crude product is dried under high vacuum.
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.[O-:22][CH2:23][CH3:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)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:22][CH2:23][CH3:24])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 2-amino-6-chloro-9-(2-[2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in ethanol (1.5 ml) was added sodium ethoxide (1M in ethanol, 1.5 ml) and the mixture was stirred at 60° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 1 hour 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), the solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chlorororm-methanol (6:1) to afford 2-amino-6-ethoxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (0.24 g, 85%), m.p. 150-152° C.; λmax (H2O) 213 (24,3000), 249 (7,360), and 280 (9,270) nm; νmax (KBr) 3330, 3210, 2900, 1650, 1610, 1580 cm−1; δH [(CD3)2SO] 1.3-1.6 (4H, m, 3′-H and CH3), 1.73 (2H, q, J 7 Hz, 2′-H), 3.2-3.6 (4H, AB part of ABX, 2×4′-H) 4.04 (2H, t, J 7 Hz, 1′-H), 4.3-4.55 (4H, m, 2H D2O exchangeable, 2×OH; D2O exchange leaves 2H, q, J 7 Hz, 6-OCH2), 6.30 (2H, s, D2O exchangeable, 2-NH2), and 7.84 (1H, s, 8-H); (Found: C, 50.91; H, 7.00; N, 24.89%; C12H19N5O3 requires C, 51.23; H, 6.81; N, 24.90%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)([C:5]([OH:7])=O)O.[H][H].C(O)C>C(O)CCC>[OH:11][CH2:9][CH2:8][CH:3]1[CH2:2][CH2:1][O:13][CH2:5]1.[OH:7][CH2:5][CH:3]1[CH2:2][CH2:1][O:13][CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCCCO
Product: OCC1CCOCC1
Product: OCCC1CCOC1
Yield: 1.5 %
Yield: 52 %

Procedure:
400 g of citric acid were dissolved in 1000 ml of n-butanol and hydrogenated at 250° C. and 200 bar together with 60 g of catalyst A (4-mm pellets) until the take-up of hydrogen had ceased. The reaction product was freed from n-butanol and ethanol and distilled under reduced pressure, giving 99 g (52%) of 3-(2'-hydroxyethyl)tetrahydrofuran and 2.9 g (1.5%) of 4-hydroxymethyltetrahydropyran.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:32][C:33]([NH2:35])=[NH:34].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:34]=[C:33]([NH2:35])[N:32]=[CH:4][C:5]=4[CH2:6]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:24]=1
Reactant: N=C(N)N
Reactant: COc1ccc(COc2ncccc2N2CCC(=O)C(=CN(C)C)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ncccc2N2CCc3nc(N)ncc3C2)cc1

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (673 mg, 1.83 mmol) in ethanol (100 ml) was treated with guanidine carbonate (1.32 g, 7.33 mmol), followed by addition of sodium acetate trihydrate (1.99 g, 14.64 mmol) and the reaction mixture was refluxed for 21 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The separated organic layer was dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 6% methanol in EtOAc) gave the title compound as a light yellow, amorphous solid (477 mg, 72%).