Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=2)[C:29]=1[CH2:33][C:34](=[O:36])[NH2:35])=[O:13])([O-:9])=[O:8]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccccc3[N+](=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
50 Milliliters of anhydrous pyridine and 20 ml of DMF were added to 5.0 g of 2-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 4.4 g of DCC and 218.2 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. Then, the precipitate was filtered and washed with 100 ml of warm DMF. This wash liquid and the filtrate were combined, and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to 600 ml of acetone, followed by stirring for 2 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To 1/2 of the residue were added 20 ml of methanol and 1.4 ml of concentrated hydrochloric acid to suspend the residue. The suspension was added dropwise to a mixed liquid of 200 ml of ether and 200 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.42 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.hydrochloride.
Reaction SMILES: ClC1C=CC(O[C:9]([N:11]2[CH2:15][CH2:14][N:13](C)[C:12]2=[C:17]([N+:28]([O-:30])=[O:29])[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:19])=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[CH3:9][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[C:17]([N+:28]([O-:30])=[O:29])[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19]
Reactant: CN1CCN(C(=O)Oc2ccc(Cl)cc2)C1=C(C(=O)Oc1ccc(Cl)cc1)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCNC1=C(C(=O)Oc1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 3.62 g of 2A, 1.19 g of sodium carbonate, 20 ml of dimethyl sulfoxide, and 4 ml of water was kept at 100° C. for 1.5 hours. The mixture was cooled to room temperature and diluted with 10 ml of water. After ice-bath cooling, a white solid, 2, m.p.: 211°-212° (with decomposition) was isolated by filtration.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH2:35][O:36][CH3:37])[CH2:30][CH2:29]1>>[CH3:37][O:36][CH2:35][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:33][CH2:32]1)=[O:38]
Reactant: COCC(=O)N1CCC(N)CC1
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A81) and 1-(4-amino-piperidin-1-yl)-2-methoxy-ethanone (A192) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([C:15]#[CH:16])=[C:13]([O:17][C:18](=[O:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH2:15][CH3:16])=[C:13]([O:17][C:18](=[O:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: C#Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Yield: 98.7 %

Procedure:
To a solution of (4-acetoxy-3-ethynyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (50 mg) in methanol was added 10% palladium on carbon (10 mg). The resulting mixture was hydrogenated under 40 psi of hydrogen for 2 hours and filtered. The filtrate was concentrated in vacuo to afford (4-acetoxy-3-ethyl-6-fluoro-naphthalen-2-yl)acetic acid methyl ester (50 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:14]=1[Cl:23])=[CH:6][C:7]([O:9]CC)=O)[CH3:2]>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[CH3:22][O:21][C:19]([C:17]1[C:18]2[C:7](=[O:9])[CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])[NH:12][C:13]=2[C:14]([Cl:23])=[CH:15][CH:16]=1)=[O:20]
Reactant: CCOC(=O)C=C(Nc1cc(C(=O)OC)ccc1Cl)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(Cl)c2[nH]1
Temperature: 250 °C
Reaction time: 3 h

Procedure:
A suspension of 23 (9.00 g, 25.4 mmol) in biphenyl ether (100 mL) was heated to 250° C. and stirred for 3 h. Then the reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes to EtOAc) to afford a colorless oil (24, 3.88 g, 49.4%). 1H NMR (CDCl3, 300 MHz) δ 9.39 (br s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 4.54 (q, J=7.0 Hz, 2H), 4.00 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH:9]=O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH2:9][NH:2][CH3:1]
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
Under N2, a solution of methylamine (2.9 mL, 5.8 mmol, 2.0 M solution in CH3OH) in 20 mL of ethanol was treated with titanium (IV) isopropoxide (1.7 mL, 5.8 mmol) at room temperature. After 5 min., a suspension of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (1.0 g, 2.9 mmol, the title compound of Preparation 1) in 20 mL of ethanol was added and stirred for 16 hr at room temperature. Sodium borohydride (0.165 g, 4.4 mmol) was then added and stirring was continued for an additional 24 hr, at which time the reaction was quenched by the addition of 5 mL of 6 N HCl and 5 mL of water, stirred for 30 min and made basic by the addition of saturated aqueous Na2CO3. The resulting mixture was extracted with EtOAc, and the organic extracts were clarified by filtration throught diatomaceous earth (d.e.), washed with saturated NaCl, dried over Na2CO3and concentrated in vacuo to a clear oil, 0.987 mg.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7].[CH3:23][NH2:24]>>[CH3:23][NH:24][C:3](=[O:2])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1cccc(C)c1
Reactant: CN
Product: CNC(=O)/C(=N\OC)c1ccccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To Product (A') (286 mg), i.e. methyl-(Z)-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, 30% methanolic methylamine (197 mg) was added, followed by stirring at room temperature for 12 hours. Excess amine and methanol were removed from the mixture, which was subjected to silica gel column chromatography with a mixture of hexane and ethyl acetate to give 201 mg of (Z)-N-methyl2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetamide (Compound No. 5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Agent: Cl
Solvent: CC#N
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCNCC3)cc1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)piperazine-1-carboxylate (70 mg, 0.12 mmol) in a solution of HCl(g) in acetonitrile (sat. 10 mL) was stirred for 3 hr at room temperature. Then the mixture was filtered to give the crude product. The crude product was purified by flash chromatography to give the title compound as a hydrochloride salt (35 mg, yield 60%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.63-2.64 (m, 4H), 3.19-3.21 (m, 4H), 3.54 (s, 2H), 4.29-4.31 (d, J=8.0 Hz, 1H), 4.69-4.71 (d, J=8.4 Hz, 1H), 6.89-6.93 (m, 2H), 7.07-7.10 (m, 2H), 7.19-7.26 (m, 5H), 7.54-7.56 (m, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 456 (M+1)+.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[C:12]=3[C:11]=2[N:10]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
In the mixture of toluene (6 mL) and ethanol (2 mL) were dissolved tert-butyl 4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1 (2H)-yl)piperidine-1-carboxylate (0.104 g, 0.241 mmol) and 6-methoxypyridine-3-boronic acid (40.7 mg, 0.266 mmol). To the solution were added tetrakis triphenylphosphine palladium (0) (5 mg) and aqueous sodium carbonate (2 N, 0.36 mL). The mixture was reacted under reflux under the protection of nitrogen for 16 h, then cooled to ambient temperature and filtrated. The organic phase was concentrated under reduced pressure, dissolved in DCM, washed sequentially with water and brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=2/1) to give the product (75 mg, 61.7% yield).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:12]([O:18][C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[C:10]([O:9][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCCCCCOC(=O)C1CCCCC1C(=O)OCCCCCC
Yield: 120.7 %

Procedure:
A mixture of 1,2-cyclohexanedicarboxylic anhydride (60 g), hexanol (85 g), and p-toluenesulfonic acid (100 mg) in toluene (500 mL) was refluxed for 3 days and water removed from the reaction mixture. After reaction was complete, solvent was removed in vacuo to yield a viscous oil. The crude material was redissolved in heptane and passed through a pad of silica gel to obtain cyclohexane-1,2-dicarboxylic acid dihexyl ester (80 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:61]1([CH2:67][CH2:68][C:69](O)=[O:70])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:69](=[O:70])[CH2:68][CH2:67][N:61]6[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)CCN2CCCCC2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 4 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 3-(piperidin-1-yl)propanoic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0009 g (4%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.03 (d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.38 (dd, J=8.54, 2.44 Hz, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, J=8.85, 8.85 Hz, 2H), 6.51 (m, J=9.31, 4.43 Hz, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 2.71 (s, 1H), 2.67 (m, 3H), 2.44 (m, 4H), 1.54 (m, 4H), 1.43 (m, 2H). MS (APCI+) m/z 500.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:26])[CH2:24][CH3:25]>C1COCC1.CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23]1([CH2:24][CH3:25])[CH2:4][O:26]1
Reactant: C[S+](C)C
Reactant: CCC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
To a solution of sodium hydride (35.72 g, 1.49 mol) in THF (1 L) and dry DMSO (2 L) was added under argon drop wise at 5° C. a solution of trimethylsulfonium iodide (290.5 g, 1.42 mol) in dry DMSO (2 L). The mixture was stirred 1 hour at 5° C. followed by a dropwise addition of 1-[2-chloro-4-(4-chlorophenoxy)phenyl]propan-1-one (199.0 g, 0.65 mol) in DMSO (500 mL). The resulting mixture was then warmed to room temperature overnight and quenched with an aqueous solution of ammonium chloride and iced water, and then extracted with MTBE. The organic solvents were washed with water, dried and evaporated to give 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-ethyl-oxirane as a yellowish solid (216.0 g, 97%). 1H-NMR (CDCl3; 400 MHz) • • (ppm)=0.9 (t, 3H); 1.75 (m, 1H); 2.10 (m, 1H); 2.80 (d, 1H); 3.05 (d, 1H); 6.85 (d, 1H); 6.95 (m, 3H); 7.30 (d, 2H); 7.40 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([N+:25]([O-])=O)[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]>C(O)(=O)C.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([NH2:25])[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2CCN(C(=O)Cn3ncc4cc([N+](=O)[O-])cnc43)CC2)ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cc(N)cnc43)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-pyrazolo[3,4-b]pyridine-1-yl]-ethanone (15 Mg) is combined with 200 Mg of iron powder in 2 mL of acetic acid at 100° C. for 30 min. After cooling to rt, the reaction solution was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo and purified by HPLC to provide 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-amino-pyrazolo[3,4-b]pyridine-1-yl]-ethanone: HPLC retention time=1.46 minutes (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=414.2, found=415.1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>CCOCC>[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: COC=C1CCC(c2cccc(F)c2F)CC1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
First, 27.4 g of (methoxymethyl)triphenylphosphonium chloride, 9 g of potassium t-butoxide, and 225 ml of dry ether were placed in a 500 ml flask whose content was replaced with argon. The mixture was stirred for 30 minutes under ice water cooling. Then, 50 ml of an ether solution containing 16.8 g of 4-(2,3-difluorophenyl)cyclohexanone was added dropwise to the reaction mixture. The reaction mixture was stirred under ice water cooling for 30 minutes and at room temperature for 8 hours. Thereafter, a precipitate was filtered out. The filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/4) to obtain 17.1 g of 1-(2,3-difluorophenyl)-4-methoxymethylene cyclohexane (Y: 89.7%). The compound thus obtained had a purity of 99.2% by GC.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Br:13][C:14](=[CH2:28])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[Br:13][C:14](=[CH2:28])[CH2:15][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])[C:41]([C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:44][CH:45]=[CH2:46])=[O:42]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(Br)CNCc1ccc(OC)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Yield: 58.1 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg, 0.285 mmol) was added to a solution of 2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol) in dichloromethane (5 mL). After 18 h the mixture was concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (77 mg). MS 517 (M+1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[CH:5]=[CH2:6]>O1CCCC1>[CH2:1]([NH:3][CH2:6][CH2:5][C:4]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCN
Reactant: C=CC(=O)OCC
Solvent: C1CCOC1
Product: CCNCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 110 ml of a 2M solution of ethyl amine in tetrahydrofuran (THF) at 0° C. was added dropwise ethyl acrylate (8.0 ml, 73.92 mmol) in 40 ml of tetrahydrofuran (THF). The reaction mixture was stirred overnight at room temperature. The reaction solution was filtered through a cotton wool plug and concentrated under reduced pressure to yield the title compound 10 (9.01 g, 84%) as a clear liquid. υmax/cm−1 3319.68, 2969.10, 1732.07, 1191.87 (FT-IR: FIG. 8)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1.C(Cl)(=O)C(Cl)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2,3-dimethylbenzoic acid (2.0 kg, 13.2 mol) in toluene (20 L) was added N,N-dimethylformamide (20 ml), followed by oxalyl chloride (2.0 kg, 15.6 mol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by thin layer chromatography. If necessary, excess oxalyl chloride (25 g) was added until no starting material was observed. Excess toluene and oxalyl chloride were removed by distillation under vacuum at temperatures below 70° C. To the residue was added toluene (150 ml) and the mixture was again concentrated in vacuo to give 2,3-dimethylbenzoyl chloride (2.0 kg).