Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1)#N.O>C1COCC1>[CH3:37][N:29]([CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:15]([C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)=[CH:24][CH:25]=1
Reactant: CN1CCC(N(C)C(=O)c2ccc(C#N)cc2)CC1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of N,N-diethyl-2,3-dimethyl-benzamide (578 mg, 2.82 mmol) in anhydrous THF (3 mL) under N2 at −78° C. was added dropwise n-BuLi (2.5M in n-hexanes, 2.4 mL, 5.92 mmol) to give a deep red solution. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was transferred dropwise, via syringe, to a reaction vessel containing 4-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (725 mg, 2.82 mmol) in anhydrous THF (5 mL) at −78° C. and under N2. The reaction mixture was stirred at −78° C. for 3.5 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL). The combined organic layers concentrated in vacuo and the resultant solid was triturated with 2:1 isohexane/EtOAc, filtered and dried in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 15% MeOH/CH2Cl2 to afford N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (487 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2.[N+:13]([O-])([O-:15])=[O:14].[K+].N.ClCCl.CCCCC>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc2cc(Cl)ccc2cn1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCC
Product: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 6-chloro-3-methylisoquinoline (10.0 g, 57.5 mmol) in concentrated H2SO4 (100 mL) was added dropwise during 10 min. a solution of KNO3 (6.05 g, 60 mmol) in concentrated H2SO4 (50 mL) at 5° C. Care was taken that the temperature of the reaction mixture did not rise above 10° C. The reaction mixture was stirred for 3 h at room temperature, poured onto ice (200 g) and rendered basic (pH=10) with a 33% aqueous ammonia solution. A dark yellow precipitate was formed, which was filtered off, thoroughly rinsed with water and taken up in dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4, filtered and dried in vacuo to afford a pale brown solid. Re-crystallization from dichloromethane/pentane afforded the title compound as pale brown crystals (9.2, 41.4 mmol, 72%). MS (ES+): 223 (M(C10H735ClN2O2)+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:6]=1.O>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:8]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The synthesis method shall be explained concretely following the order below. 50% dimethylamine aqueous solution (2.9 ml) was added to a solution of 4,6-dichloro-2-(4-phenylpiperazin-1-yl)pyrimidine (1.01 g, 3.26 mmol) in tetrahydrofuran (10 ml) solution, and this was agitated overnight at room temperature. Water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer in saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and a 4-chloro-6-dimethylamino-2-(4-phenylpiperazin-1-yl)pyrimidine powder was obtained. This powder was used in the next reaction without separation and refinement. Morpholine (6.0 ml) was added to this powder, and this was agitated at 100 degrees Celsius overnight. After cooling, water was added and extraction was carried out 2 times with dichloromethane. The organic layer was washed with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was washed with ether, and 810 mg (two step yield: 70%) of coarse crystals of 6-dimethylamino-4-morpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 2 are shown below.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Br:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[Br:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(Br)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(Br)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 35 %

Procedure:
3-[(3-Bromo-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 57-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (35% yield); mp 154–157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 7.1 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.54 (1H, m, aromatic). Anal. calcd for C14H14BrFN2O4: C, 45.06; H, 3.78; N, 7.50. Found: C, 44.80; H, 3.81; N, 7.33.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccc(F)cc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as described the preparation of compound 10, except that 2-chloro-4-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.15 (dd, J=8.211, 2.400 Hz, 1H), 6.95-7.06 (m, 2H), 5.40 (s, 1H), 5.09-5.18 (ABq, J=37.7, 15.9 Hz, 2H), 3.33-3.39 (m, 1H), 3.30 (s, 3H), 3.23-3.29 (m, 1H), 2.98 (bd, J=12.9 Hz, 1H), 2.79 (t, J=10.4 Hz, 1H), 2.55-2.66 (t, J=11.2 Hz, 1H), 2.13 (m, 1H), 1.78-1.88 (m, 1H), 1.55-1.65 (m, 2H). MS (ES) [m+H] calc'd for C17H21ClFN4O2, 367.1; found 367.1.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:49]2[CH2:48][CH2:47][N:46]([CH2:45][C:41]3[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=3)[C:38]([NH:37][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:52])[CH2:51][CH2:50]2)=[O:26])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (5.90 g, 9.2 mmol, 5.52 mL) was added dropwise to a solution of 4-ammo-5-chloro-2-ethoxy benzoic acid (1 g, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.40 g, 5.1 mmol) and triethylamine (1.401 g, 13.8 mmol, 1.93 mL) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (2.08 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COCc1c(Br)ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid is added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture is stirred at room temperature for one hour, water (50 ml.) is added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) is added, the solution made basic with ammonium hydroxice, warmed and the insoluble material filtered under suction. The colorless solid is washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding the title product as a colorless solid. Purification is effected by crystallization from methanol/ether to yield the title product.
Reaction SMILES: Cl.CN1C(SC[CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=NN=N1.C(=O)(O)[O-].[Na+].O1CCCC1.Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>O>[Cl:38][C:37]([Cl:40])([Cl:39])[CH2:36][O:35][C:33]([CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=2)[CH2:13][CH2:12][NH:11]1)=[O:34]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)C1NCCc2cc(O)c(O)cc21
Yield: 78.2 %

Procedure:
A suspension of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in water (300 ml) was dissolved at 61° to 65° C. To the solution was added sodium bicarbonate (13.3 g) over 15 minutes at the same temperature. Tetrahydrofuran (250 ml) was added to the suspension at 50° C. The suspension was cooled and weakly alkalified by adding sodium bicarbonate (30 g) at 0° to 3° C. To the mixture was added 2,2,2-trichloroethyl chloroformate (40.2 g) over 30 minutes below 3° C. Water (300 ml) was added to the reaction mixture and the mixture was twice extracted with ethyl acetate (900 ml and 600 ml). The extract was washed with a sodium chloride aqueous solution (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with ether to give 1-(1-methyl- 1H-tetrazol-5-yl)thiomethyl-2-(2,2,2-trichloroethoxycarbonyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (40.4 g), mp 201° to 207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16](=[O:25])[C:17]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=3[N:19]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[NH3:26]>O>[C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH:19][C:14]([C:4]1[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=[C:2]([Br:1])[CH:3]=1)=[O:15])(=[O:25])[NH2:26]
Reactant: Cc1cccc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: N
Solvent: O
Product: Cc1cccc(C(N)=O)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 72 h

Procedure:
1.00 g 2-[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-8-methyl-benzo[d][1,3]oxazin-4-one was taken up in 10 ml of a 25% ammonia solution in water and stirred for 72 h. The solids were filtered and washed with cold water to yield 0.80 g of the amide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.COCCOC.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:14]1[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: Brc1ccccn1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2cc3ccccc3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A two-necked 250 mL round-bottomed flask fitted with a reflux condenser (with gas inlet) and a rubber septum was flushed with argon before 2-bromopyridine (2.57 mL, 27 mmol) and ethyleneglycol dimethylether (80 mL, dry and degassed) were introduced. Tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) was added and the solution stirred at room temperature for 10 minutes. Benzothiophene-2-boronic acid (5.0 g, 28.1 mmol) was then added, followed by anhydrous sodium bicarbonate (8.4 g. 100 mmol) and water (50 mL, degassed). The septum was replaced with a glass stopper and the reaction mixture was heated at 80° C. for 16 hours, cooled to room temperature and the volatiles removed in vacuo. Organics were extracted with ethyl acetate (3×100 mL), washed with brine and dried over magnesium sulfate. Removal of the organics yielded a pale yellow solid. Recrystallisation from ethanol yielded a colourless solid (3.9 g, 68%, two crops), m.p. 124-6° C.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17].C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 78 %

Procedure:
Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(4-Hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) was obtained as a yellow crystalline solid; mp 207.5-208.5° C., lit. [25] 230-233° C.; δH (500 MHz, DMSO-d6) 3.83 (s, 3H, OCH3), 6.71 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.13 (dd, J5′,6′=8.5, J2′,6′=1.5 Hz, 1H, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.34 (d, J2′,6′=1.5 Hz, 1H, H2′), 7.52 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=2.0 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=2.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[OH-].[K+]>CO.O>[O:4]=[C:5]1[CH2:3][CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of diazomethane (Diazald, 2.70 g) in MeOH (15 mL) was added dropwise to a mixture of ketone 1A (997 mg) and KOH (3.81 g) in MeOH (10 mL) and water (1.8 mL) at 0° C. over a period of 1.5 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The resulting suspension was concentrated and was diluted with water (50 mL). The resulting aqueous suspension was extracted with ether (1×), then with DCM (2×), and the combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0/100 to 10/90 MeOH/EtOAc) to provide 964 mg of ketone 8A as a white solid. Data: LC/MS (ESR) m/z 222 [M+1]+, 244 [M+Na]+.
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][C:9]#[CH:10])[CH:3]([OH:6])[C:4]#[CH:5].[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15](Cl)=[O:16])([CH3:13])[CH3:12].N1C=CC=CC=1>>[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15]([O:6][CH:3]([C:2]([CH3:1])=[CH:7][CH2:8][C:9]#[CH:10])[C:4]#[CH:5])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reactant: C#CCC=C(C)C(O)C#C
Solvent: c1ccncc1
Product: C#CCC=C(C)C(C#C)OC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)C
Yield: 87.5 %

Procedure:
By the same procedure as in Example 1, 1.22 g (10.0 millimoles) of 4-methylocta-4-ene-1,7-diyne-3-ol, 2.66 g (10.0 millimoles) of α-isopropyl-3,4-dichlorophenylacetyl chloride and 1.58 g (20.0 millimoles) of pyridine are reacted, followed by purification on silica gel column. Thus, 3.18 g of the objective ester is obtained as a pale yellow oily substance (87.5% of theoretical yield). nD24.0 1.5314.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.[CH3:22][O:23]C1C=CC(OC)=CC=1C1C(C(OC)=O)=CC([N+]([O-])=O)=CC=1>>[CH3:21][O:20][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[C:12]([O:23][CH3:22])[CH:13]=1
Reactant: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Product: COc1ccccc1-c1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate (2.07 g) to afford 1.93 g (99%) of 2',5-dimethoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.64 (d, J=2.5, 1H), 8.43 (dd, J=8.4, 2.6, 1H), 7.67 (d, J=8.5, 1H), 6.94 (m, 2H), 3.80 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC(Cl)=CC=1>O>[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Product: CON=C(C1=NCCO1)c1ccccc1O
Yield: 56 %

Procedure:
Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1.5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10](Cl)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)NC(C)(C)C1=O

Procedure:
640.6 g (5 mols) of 5,5-dimethylhydantoin, 420.9 g (5 mols+10% excess) of allyl chloride, 380.1 g (2.5 mols+10% excess) of potassium carbonate and 1,000 ml of dimethylformamide are reacted, and worked up, analogously to Example 1. 820 g (97.5% of theory) of a brownish waxy crude product are obtained and are purified by distillation. 713.7 g (84.9% of theory) of a distillate are obtained; this boils at 114° C./13.3 Pas and melts at 66.2°-68.7° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][O:16][C:17]=3[CH:18]3[CH2:20][CH2:19]3)=[N:11][N:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>>[CH:18]1([C:17]2[O:16][N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][C:4]=3[O:27][CH3:28])=[N:12][N:11]=2)[CH2:20][CH2:19]1
Reactant: NC1CCOCC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Yield: 34.6 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.53 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 4-aminotetrahydropyran (161 mg, 1.59 mmol) and N,N-diisopropylethylamine (137 mg, 1.06 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 84 mg, 35%) which was obtained as a white solid. MS: m/e=459.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[S:12]1CC(O)S[CH2:14][CH:13]1O.C(NCC)C>C(O)C>[NH2:5][C:4]1[S:12][CH:13]=[CH:14][C:3]=1[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccccc1
Solvent: CCNCC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 1.45 g (10 mmol) 3-oxo-3-phenyl-propionitrile, 0.76 g (5.0 mmol) [1,4]dithiane-2,5-diol, 0.40 ml (10 mmol) diethylamine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.42 g (23%) (2-amino-thiophen-3-yl)-phenyl-methanone as a light brown crystals. ES-MS m/e (%): 204 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].N1C=CC=CC=1>C(O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][N:20]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)[CH3:1]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: NOCc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(C)=NOCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.063 g, 0.377 mmol), O-(3-fluorobenzyl)hydroxylamine hydrochloride (0.100 g, 0.569 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with water. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 95:5 petrol/ethyl acetate, to give 3′-fluoro-4′-methoxyacetophenone-O-3-fluorobenzyloxime (CP9-126) as a white solid (0.099 g, 90%), m.p. 67°.