Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:37])[C:16]1[CH:36]=[CH:35][C:19]([CH:20]=[N:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1>C(#N)C>[Br-:9].[CH3:37][N:15]([CH3:14])[C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[N:21][N:22]2[CH:26]=[CH:25][N+:24]([CH2:8][C:7]([C:6]3[CH:11]=[CH:12][C:3]([N:2]([CH3:13])[CH3:1])=[CH:4][CH:5]=3)=[O:10])=[C:23]2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:35][CH:36]=1
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc1
Solvent: CC#N
Product: COc1ccc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2CC(=O)c2ccc(N(C)C)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.60 g of p-(dimethylamino)phenacyl bromide is added to a solution of 0.80 g of 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-imidazole in 80 ml of acetonitrile. After stirring at room temperature for 3 days, the product is removed by filtration and washed with ether. There is obtained 3-[[p-(dimethylamino)benzylidene]amino]-1-[p-(dimethylamino)phenacyl]-2-(p-methoxyphenyl)imidazolium bromide of melting point 234°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:33][NH2:34].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([NH:34][CH2:33][C@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:31])=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Reactant: C[C@H](CN)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC[C@@H](C)c4ccccc4)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 85.2 %

Procedure:
The product of Example 430F (62 mg, 0.142 mmol) in dimethyl sulfoxide (2 mL) under a nitrogen atmosphere was reacted with (S)-(−)-β-methylphenethylamine (23 mg, 0. 170 mmol), N,N-diisopropylethylamine (0.123 mL, 0.708 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (55 mg, 0.170 mmol at room temperature for 20 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (50 mL). The organic extract was washed sequentially with water (3×10 mL), saturated aqueous sodium hydrogencarbonate (20 mL), and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride afforded the title compound (67 mg, 0.121 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (d, J=6.99 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 2.91-3.07 (m, 1 H) 3.14-3.29 (m, 1 H) 5.50 (s, 2 H) 6.51 (d, J=8.46 Hz, 2 H) 7.12 (d, J=8.82 Hz, 2 H) 7.16-7.34 (m, 5 H) 7.63 (d, J=8.46 Hz, 1 H) 7.77 (s, 1 H) 8.50 (t, J=5.88 Hz, 1 H) 8.62 (s, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H); MS (ESI+) m/z 555 (M+H)+, 1109 (2M+H)+, MS (ESI−) m/z 553 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C)C=O>[O:28]1[CH2:27][C@H:26]1[CH2:25][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7]
Reactant: O=C1OCCC1=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To α-(2′-hydroxybenzylidene)-γ-butyrolactone (60 g) were added dimethylformamide (600 ml) and potassium carbonate (87 g) and (S)-glycidyl nosylate (82 g) was added. The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate to give the title compound (55 g), melting point 68-70° C.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[K+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: COC(=O)Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 69.5 parts 2-methyl-2-thiopseudourea sulfate and 47 parts of methyl chloroformate in 1,000 parts water at 0°C is added dropwise 56.9 parts of potassium hydroxide in 200 parts of water. The reaction mixture is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated on a rotary evaporator to give 45 parts of methyl N-(1-amino-1-methylthiomethylene)carbamate melting at 72°-77°C.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[CH3:6][C:7]1[CH:8]=[C:9]([NH:14][C@@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH:10]=[CH:11][C:12]=1[CH3:13].[CH3:20]O>>[ClH:3].[CH3:20][O:18][C:17](=[O:19])[C@@H:15]([CH3:16])[NH:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:7]([CH3:6])[CH:8]=1
Reactant: Cc1ccc(N[C@H](C)C(=O)O)cc1C
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)[C@@H](C)Nc1ccc(C)c(C)c1
Reaction time: 0.17 h

Procedure:
Thionyl chloride (5.4 ml) was added dropwise to methanol (60 ml) below 5° C. with ice-salt bath cooling and stirring was continued for 10 minutes at the same temperature. 3,4-Dimethylphenyl-D-alanine hydrochloride (5.0 g) was added to the mixture by small portions over 20 minutes at −15° C. and the whole was stirred at room temperature for 6 hours, and evaporated under reduced pressure. The resulting solid was triturated with isopropyl ether to give colorless crystals of 3,4-dimethylphenyl-D-alanine methyl ester hydrochloride (5.10 g).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:27])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][C@H:12]4[CH3:27])=[N:10][C:6]=3[CH:5]=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=2)=[CH:36][CH:35]=1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(N(C)C)cc3)c2[nH]1

Procedure:
7-Bromo-2-{(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-5-(trifluoromethyl)-1H-benzoimidazole (152 mg, 0.3 mmol, Example 79) and 4-dimethylaminophenylboronic acid (83 mg, 0.5 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 549 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (5, 290.0 g, 698.8 mmol) in anhydrous DMF (700 mL) was treated with sodium azide (NaN3, 90.84 g, 1.4 mol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 6 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (1500 mL) and the resulting mixture was stirred at room temperature for 2 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 248.0 g, 252.97 g theoretical, 98%) as white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1023: 1H NMR (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 3H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H8FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[C:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CCCC(CC)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(CC)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 238A (0.049 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.152 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (m, 6 H) 1.37 (m, 6 H) 3.05 (m, 1 H) 5.68 (m, 1 H) 7.05 (m, 1 H) 7.28 (m, 2 H) 7.52 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.71 (m, 1 H) 8.06 (dd, J=7.72, 1.47 Hz, 1 H) 16.32 (s, 1 H). MS (ESI−) m/z 439 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][O:25][C:26]([CH2:28][C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=O)=[O:27]>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[O:20][CH3:21])[N:1]=[C:29]([CH2:28][C:26]([O:25][CH3:24])=[O:27])[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
Three drops of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (1.55 g), dimethyl acetonedicarboxylate (0.936 g) and acetic acid (30 ml), and the resulting mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crystals were recrystallized from acetone to give methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-methoxycarbonylquinoline-2-acetate (1.41 g, 64%). Colorless prisms. mp. 170°-171° C.
Reaction SMILES: [C:1]1(=[C:11]2C3C(=CC=CC=3)C(=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[CH2:23][C:22]1=[O:32]>CN1C(=O)CCC1.C(O)(=O)C>[O:32]=[C:22]1[C:23](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[C:11]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[C:23]4[C:24](=[O:31])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][C:22]4=[O:32])[NH:12]3)[NH:2]2)[C:24](=[O:31])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:21]1
Reactant: O=C1CC(=O)c2ccccc2N1
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1Nc2ccccc2C(=O)C1=c1[nH]c(=c2[nH]c(=C3C(=O)Nc4ccccc4C3=O)c3ccccc23)c2ccccc12
Temperature: 25 °C

Procedure:
5.0 g of [1,1′]biisoindolylidene-3,3′-diimine and 14.9 g of 1H-quinoline-2,4-dione are stirred in a mixture of 90 ml of NMP and 10 ml of glacial acetic acid at reflux for 6 hours. After cooling to room temperature the suspension is filtered and the filter product is washed with ethanol and then water and dried at 60° C. This gives 6.2 g (59%) of a virtually black powder of a compound of the following formula
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)([CH3:23])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:9][CH:8]=1.[CH:31]([O:33][CH2:34][CH3:35])=[CH2:32].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:3]([O:4][CH:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([O:33][CH2:34][CH3:35])[CH3:32])=[CH:28][CH:29]=2)([CH3:23])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[CH:9][CH:8]=1)[CH3:1])[CH3:2]
Reactant: C=COCC
Reactant: CC(C)(C)OC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(C)Oc1ccc(C(C)(CCC(=O)OC(C)(C)C)c2ccc(OC(C)OCC)cc2)cc1
Yield: 54.9 %

Procedure:
In a solvent mixture of 75 grams of THF and 75 grams of methylene chloride was dissolved 30.9 grams (0.09 mol) of tert-butyl 4,4-bis(4'-hydroxyphenyl)valerate. With stirring, 38.9 grams (0.54 mol) of ethyl vinyl ether was added dropwise while the mixture was cooled with an ice bath so that the temperature would not exceed 10° C. After the reaction mixture was stirred for a further 20 minutes, 2.0 grams (8 mmol) of p-toluenesulfonic acid monohydrate was added and dissolved, with the mixture kept cooled so that the reaction temperature would not exceed 10° C. The ice bath was removed and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction solution was cooled with ice, and 201 grams of a 0.6% sodium hydrogen carbonate aqueous solution was added to neutralize the acid for terminating the reaction. The organic layer was separated and the solvent was distilled off in vacuo, obtaining an oily product. The oily product was purified by silica gel column chromatography (eluting solvent: chloroform), isolating tert-butyl 4,4-bis(4'-(1"-ethoxyethoxy)phenyl)valerate. Amount 24.1 grams, yield 54.9%, purity 95.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClCCl>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:21]3[CH2:20][CH2:19][C:18]([CH2:17][N:15]([CH3:16])[C:8]4[N:7]=[C:6]([NH2:30])[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(Cc4ccc5c(c4)OCCO5)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (250 mg) and 1,4-benzodioxan-6-carboxaldehyde (105 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (140 mg) in one portion. The mixture was stirred at room temperature for two days. Aqueous NaOH (1N, 5 ml) was added and stirring was continued for one hour. The product was isolated by extraction with dichloromethane and purified by flash chromatograpy, to yield N2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 16, MS: 556 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 320 mg of the dihydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].Br[C:34]#[N:35].C(Cl)[Cl:37]>C1COCC1.O>[ClH:37].[ClH:37].[NH2:35][C:34]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]2[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Reactant: ClCCl
Reactant: N#CBr
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(N)nc4c(C)cc(C)nc43)cc2)cc1
Product: Cl
Yield: 71 %

Procedure:
To a stirred solution of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol) in THF (6 ml) was added a solution of BrCN (175 mg, 1.65 mmol) in water (2 ml). The resultant mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and washed with brine. The organic layer was dried over MgSO4 and filtered. After concentration in vacuo, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 224 mg (71%) of the title compound.
Reaction SMILES: [OH-].[K+].[I-].[K+].[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19].[CH3:20]Cl>C(O)(C)(C)C>[CH3:5][C:6]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]1=[O:19]
Reactant: CC1CCCC(=Cc2ccccc2)C1=O
Reactant: CCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC1(C)CCCC(=Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
66 g of 85% strength potassium hydroxide solution and 750 ml of tert-butanol were placed in a 1 l 4-necked flask, and the mixture was heated briefly at reflux with stirring. Then 8.3 g of potassium iodide were added, the mixture was cooled to room temperature and 200 g of 2-methyl-6-benzylidene-cyclohexanone were added. 101 g of methyl chloride were passed in at room temperature over 8 hours. The mixture was subsequently stirred at room temperature for 8 hours, and then 450 ml of tert-butanol were distilled off. 500 ml of water were added to the residue, the mixture was stirred thoroughly, and the product which separates out was filtered off with suction. Recrystallization from methanol gave 161 g (75% of theory) of pure product with a melting point of 79°-81° C.,
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnn1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1cccnn1

Procedure:
Reacting 3-chloropyridazine with 1,3-diaminopropane in ethanol containing sodium ethoxide according to the procedure of Example 89 gives 3-(3-aminopropylamino)-pyridazine. Using this intermediate as the starting material in the procedure of Example 18 gives N-cyano-N'-[3-(3-pyridazinylamino)propyl]guanidine.
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.C[S+](C)C.[OH-].[Na+].C[C:14]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:15]([C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=O)[C:16]1C=CC=CC=1Cl.O.C(Cl)[Cl:40]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2([C:15]([CH3:16])=[CH:14][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:40])[CH2:1][O:2]2)=[CH:26][CH:27]=1
Reactant: CC(=C(C(=O)c1ccc(Cl)cc1)c1ccccc1Cl)c1ccccc1
Reactant: ClCCl
Reactant: COS(=O)(=O)[O-]
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=Cc1ccccc1Cl)C1(c2ccc(Cl)cc2)CO1
Temperature: 20 °C
Reaction time: 13.5 h
Yield: 83 %

Procedure:
54 g of trimethylsulfonium methylsulfate and 120 ml of sodium hydroxide solution (50% strength by weight) are added to a solution of 84 g of 4-chlorophenyl β-methyl-2-chlorophenylstyryl ketone in 300 ml of methylene chloride. The reaction mixture is stirred for 12-15 hours at room temperature (20° C.), after which 300 ml of water are added to the solution and the organic phase is separated off. The organic phase isolated is washed twice with water, dried over sodium sulfate and evaporated down, 73 g (83%) of 2-(4-chlorophenyl)-2-(1-methyl-2-[2-chlorophenyl]-ethenyl)-oxirane being obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)O1.C(N(CC)CC)C.[C:28]1(=[O:33])[CH2:32][CH2:31][CH:30]=[CH:29]1>O1CCOCC1.O.[Cl-].[Na+].O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:30]2[CH2:31][CH2:32][C:28](=[O:33])[CH2:29]2)=[CH:10][C:11]=1[C:16]([F:17])([F:18])[F:19]
Reactant: O=C1C=CCC1
Reactant: CC1(C)OB(c2ccc(O)c(C(F)(F)F)c2)OC1(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CC[C@H](c2ccc(O)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[Rh(S-BINAP)(nbd)]BF4 (0.03 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenol (preparation 9) (1.5 mmol) were added to a 25 mL-flask containing a magnetic stir bar and a septum inlet. The flask was flushed with argon. Triethylamine (1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) dissolved in 1,4-dioxane —H2O (6:1, 3 mL) were then added. The mixture was stirred for 6 h at 25° C. Brine was added, the mixture was extracted with ethyl acetate, and the solvents were removed in vacuo to afford the title compound. 1H NMR (300 MHz, DMSO) δ 10.37 (bs, 1H), 7.45-7.36 (m, 2H), 6.97 (d, 1H), 3.43-3.23 (m, 1H), 2.57-2.44 (m, 1H), 2.37-2.17 (m, 4H), 1.96-1.77 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](NC(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CC(C)(C)O
Product: COC(=O)CCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2.85 g of (S)-4-carboxymethyl)alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 12 mL of t-butyl alcohol was treated with 2.06 g of dicyclohexylcarbodiimide followed by 0.013 g of 4-pyrrolidinopyridine. A white precipitate formed after a few minutes and the reaction mixture was allowed to stir for 18 hours. The mixture was filtered, and the solid washed with ether. The other extracts and the filtrate were combined and washed with 1N hydrochloric acid, water, and saturated sodium bicarbonate solution and were dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to afford 1.613 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-]2-(1,1-dimethylethoxy) -2oxoethyl]benzenepropanoic acid methyl ester as a colorless oil, [α]D +6.07 (ethanol).