Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:3]([CH2:4][CH2:5][C:6](=[N:15]O)[C:7]3=[O:14])[C:2]1=[O:17]>ClCCl.CO.[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh]>[NH2:15][C@H:6]1[C@H:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[NH:1][C:2](=[O:17])[N:3]([C:9]=23)[CH2:4][CH2:5]1
Reactant: O=C1C(=NO)CCn2c(=O)[nH]c3cccc1c32
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A catalyst solution was prepared by dissolving (R,R)-(+)-2,2′-bis[(S)—(N,N-dimethylamino)(phenyl)methyl]-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene (52.6 mg; 0.05 mmol; identified above as Ligand Formula (A-1B)) and bis(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (20.4 mg; 0.05 mmol; also known as “Rh(COD)2BF4”) in dichloromethane (1 ml) under argon, and then stirring the resulting mixture at room temperature for 10 min. In parallel, 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime (1.15 g, 5.0 mmol) was charged into a 100 mL autoclave and suspended in 40 mL of methanol. The autoclave was purged 3 times with H2 without stirring at 20 bar, and 3 times with stirring at 20 bar. Afterward, the catalyst solution, diluted with 4 ml of methanol, was charged into the autoclave. Hydrogen pressure (60 bar) was then applied, and the mixture was stirred at that pressure for 22 hr at 40° C. After cooling the mixture to room temperature and releasing the pressure, 2 g of Deloxan® THP II were added, and the resulting suspension was stirred at 55° C. for 10 min and filtered. The solvents were then removed to yield the product.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[N:8]=[CH:7][CH:6]=[CH:5]1.CCC[CH2:13][CH3:14].ICCC.[C:19](=O)(O)[O-:20].[Na+]>C1COCC1.O>[CH2:3]([C:4]1[NH:8][C:7]([CH:19]=[O:20])=[CH:6][CH:5]=1)[CH2:13][CH3:14]
Reactant: CN(C)C=C1C=CC=N1
Reactant: CCCCC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1ccc(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To an anhydrous solution of 6-dimethylamino-1-azafulvene dimer (125; 12.0 g, 49.1 mmol) in THF (500 ml) at -15° C. was added dropwise a solution of 5-butyllithium in pentane (1.7M; 87 ml, 147 mmol) over 5 minutes. The yellow cloudy solution was slowly warmed to 0° C. over 10 minutes and stirred at this temperature for a further 20 minutes. The resulting deep violet colored solution was treated with 1-iodopropane (19.2 ml, 196 mmol) and allowed to warm to room temperature over 2 hours. The mixture was treated with water (20 ml) and saturated aqueous sodium bicarbonate (20 ml) and refluxed for 15 hours. The mixture was extracted into methylene chloride and the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to a dark liquid residue (15.2 g) by rotary evaporation. Flash chromatography (silica gel, 500 g; EtOAc/hexanes, 5/95) gave 7.85 g (60%) of the title compound as a pale brown liquid.
Reaction SMILES: C(N)CCCCCCCCCCC.[CH2:14]([CH2:16][NH2:17])[OH:15].C=O.[CH2:20]([N:32]1[CH2:37]N(CCCCCCCCCCCC)[CH2:35][N:34]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:33]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C.CCOCC>[CH2:50]([N:34]1[CH2:35][N:17]([CH2:16][CH2:14][OH:15])[CH2:37][N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCCCCCCN1CN(CCCCCCCCCCCC)CN(CCCCCCCCCCCC)C1
Reactant: NCCO
Agent: C=O
Agent: CCCCCCCCCCCCN
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCN1CN(CCO)CN(CCCCCCCCCCCC)C1
Reaction time: 24 h

Procedure:
48 g of dodecylamine (259 mmol) and 1.7 ml of ethanolamine (29 mmol) were dissolved in 100 ml of ethanol, after which 8.6 g of paraformaldehyde (287 mmol) were added and the mixture was stirred. The turbidity caused by 1,3,5-tridodecyl-1,3,5-triazacyclohexane was redissolved every now and again by addition of ether. After about 1 day, all the paraformaldehyde had dissolved. The solvent was then removed on a rotary evaporator, the residue was dissolved in a little toluene and the product was then again freed of solvent under reduced pressure. This left 55 g of a viscous colorless product which, according to NMR spectroscopy, consisted of about 75 mol % of 1,3,5-tridodecyl-1,3,5-triazacyclohexane and 25 mol % of 1,3-didodecyl-5-(2-hydroxyethyl)-1,3,5-triazacyclohexane and a little toluene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5]2.[C:16](=[O:19])([O-])[O-].[K+].[K+].CO[CH2:24][CH2:25][O:26][CH3:27]>O.C(OCC)(=O)C.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>[CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:3]3[CH:2]=[C:11]([CH:10]=[CH:24][C:25]=3[O:26][CH3:27])[CH:16]=[O:19])=[C:11]([CH3:12])[CH:10]=2)[CH2:5][CH2:6][CH2:7]1)([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COCCOC
Reactant: Cc1cc2c(cc1Br)CCCN2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)N(C(C)C)CCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (0.85 g, 3.16 mmol), 2-methoxy-5-formyl boronic acid (1.13 g, 6.31 mmol) and potassium carbonate (1.70 g, 12.64 mmol) in 1,2-dimethoxyethane (30 mL) and water (1.5 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.63 mmol) was added and the mixture heated at reflux under argon for 35 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.81 g of 3-(1-isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehyde (79%). 1H NMR (500 MHz; CDCl3): δ1.18 (s, 3H); 1.20 (s, 3H); 1.94 (m, 2H); 2.06 (s, 3H); 2.72 (m, 2H); 3.18 (m, 2H); 3.85 (s, 3H); 4.16 (m, 1H); 6.57 (s, 1H); 6.78 (s, 1H); 7.02 (d, 1H); 7.69 (d, 1H); 7.34 (s, 1H); 7.84 (m, 1H); 9.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH:15]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2)c(Cl)c1Cl
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To a stirred suspension of [2,3-dichloro-4-(1-oxo-ethyl)phenoxy]acetic acid (15.78 g 0.06 mole) in 75 ml ethanol was added benzaldehyde (7.95 g, 0.075 mole) with stirring under nitrogen, followed by NaOH (8.0 g, 0.20 mole) in 16 ml of water. An additional 150 ml of ethanol was added and stirring was continued. The reaction mixture was heated at reflux for 11/2 hours, poured into ice water and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate and methylene chloride, washed with dilute hydrochloric acid, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 8.7 g of [2,3-dichloro-4-(1-oxo-3-phenyl-2-propenyl)phenoxy]acetic acid which melted at 190°-191° C. after recrystallization from acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:16]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)=CC(=O)Nc1ccccc1CN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)=CC(=O)Nc1ccccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The product of Example 1 (612 mg, 3.0 mmol) was placed in a 25 mL round bottom flask and dissolved in methanol (6 mL). To this solution was added benzaldehyde (0.32 mL, 3.0 mmol) and the mixture was stirred at room temperature for 1 hr. After this time sodium borohydride (170 mg, 4.5 mmol) was added slowly over 10 minutes, and the mixture was allowed to stir for an additional 20 minutes. 15 mL of 1N NaOH was then added to quench the reaction, and the mixture was transferred to a separatory funnel with ethyl acetate. An additional 25 mL of ethyl acetate was added and the organic layer was washed successively with 1N NaOH (3×15 mL), brine (1×15 mL), and then dried over magnesium sulfate, filtered, and evaporated. The product was purified by flash column chromatography with ethyl acetate-hexane (3:7 then 1:1) to yield 3-methyl-but-2-enoic acid [2-(benzylamino-methyl)-phenyl]-amide (839 mg, 95% yield) of a yellow oil. 1H NMR (250 MHz, CDCl3) 10.44 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.39-6.84 (m, 8H), 5.64-5.56 (m, 1H), 3.78 (s, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.82 (s, 3H). The amine was then converted to the HCl salt with an excess of 1N HCl in ether to be used in further transformations.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=1[NH:36][CH:37]=[C:38]([C:44]([O:46]CC)=O)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCCCCC>[CH3:35][O:34][C:33]1[C:28]([O:27][CH3:26])=[C:29]2[C:30]([C:44](=[O:46])[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][NH:36]2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=CNc1cccc(OC)c1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2c(OC)c(OC)ccc2c1=O
Temperature: 250 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To Dowtherm A (100 mL) heated at 250° C. was added diethyl 2-(((2,3-dimethoxyphenyl)amino)methylene)malonate (48 g, 148 mmol). The mixture was stirred at 250° C. for 1 h. LCMS indicated completion of the reaction. The reaction mixture was allowed to cool a bit and was then added to cold hexane, the precipitates were collected by filtration, washed with hexane and then allowed to dry in the air to afford ethyl 7,8-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (35 g, 126 mmol, 85% yield) as brown solid. LCMS: (M+H)+: 278.2.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: Fc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1F
Yield: 80.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 3,4-difluorobenzaldehyde (0.055 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16j (0.12 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:32](O)([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([O:25][CH:32]([CH3:34])[CH3:33])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:26][CH:27]=1
Reactant: CC(C)O
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(3S)-2-[(4-Chlorobenzylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.08 g) is suspended in isopropyl alcohol (30 ml) and thereto is added dropwise thionyl chloride (0.47 ml) at -20° C. The mixture is stirred at room temperature for 17 hours and then refluxed at 90° C. for 4 hours. After distilling off the solvent, the residue is dissolved in ethyl acetate. The solution is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give the title compound (477 mg), m.p. 178°-180° C. (decomp.).
Reaction SMILES: [Li][CH3:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:21]4[CH:28]=[CH:27][C:24]([CH:25]([OH:26])[CH3:2])=[CH:23][CH:22]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [Li]C
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
MeLi (0.00258 mol) was added dropwise at −70° C. to a solution of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzaldehyde (described in Example B6) (0.001 mol) in THF (5 ml) under N2 flow. The mixture was stirred at −70° C. for 2 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (58%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1-hydroxyethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 181° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CC(C)=O.O>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 4-hydroxybenzotrifluoride (8.55 g, 52.78 mmol) in acetone (200 ml) was treated with benzyl bromide (9.87 g, 6.86 ml, 58.05 mmol) and potassium carbonate (10.94 g, 79.16 mmol). The mixture was stirred and heated to reflux under nitrogen for 3 h. After cooling, diethyl ether (400 ml) and water (400 ml) were added and the aqueous phase re-extracted with diethyl ether (100 ml). The combined organic layers were washed with water, dried (MgSO4) and the solvent removed in vacuo to leave the title compound as a white solid. (12.71 g, 95%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
To 7.88 g of 6-chloronicotinic acid were added 7.3 ml of thionyl chloride and a few drops of DMF. The mixture was heated under reflux for 2 hours, and then the excess of thionyl chloride was distilled off to give crystals of 6-chloronicotinoyl chloride. A solution of the crystals in 60 ml of tetrahydrofuran was added dropwise to a solution of 15.47 g of 5-aminopentanol in 200 ml of tetrahydrofuran at a temperature below 0° C. The mixture was stirred overnight while gradually raising the temperature to room temperature. The solvent was distilled off and to the residue was added water followed by extraction with ethyl acetate. Then, the extract was washed successively with water and a saturated brine solution, dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethyl acetate to give 11.24 g of N-(5-hydroxypentyl)-6-chloronicotinamide (yield 93%).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1.[Cl-].ClC=[N+](C)C.ClC1C(C(OCC)=O)=CN=C(C2C=CC=C([N+]([O-])=O)C=2)N=1.[NH2:49][NH2:50]>CCOCC.CCCCCC>[NH:49]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1)[NH2:50]
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1O
Agent: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1NN
Yield: 33 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.9 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 33% of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.8 g, 6 mmol) with citraconic anhydride in analogy to Example 21, to afford 80% (0.5 g) of the title compound; m.p. 118-120° C.
Reaction SMILES: C([C:3]([CH2:8][OH:9])(CO)CC)O.CCC(C)([NH2:14])O.CN(CCO)CCO.C1C=C[C:27]([CH:30](N=C=O)[N:31]=[C:32]=[O:33])=[CH:26]C=1>C(OCCO)C.C(OC(=O)C)C>[NH2:14][CH2:26][CH2:27][CH2:30][NH:31][C:32]([O:9][CH2:8][CH3:3])=[O:33]
Reactant: CCC(CO)(CO)CO
Reactant: O=C=NC(N=C=O)c1ccccc1
Reactant: CCC(C)(N)O
Agent: CN(CCO)CCO
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: CCOC(=O)NCCCN
Temperature: 60 °C
Reaction time: 3 h

Procedure:
603 g of anhydrous ethylacetate, 603 g of trimethylol propane, 133.5 g of dimethyl amino ethanol and 178.5 g of methyl diethanol amine are dissolved. Into this solution in a double wall flask there is added drop by drop a solution of 522 g of anhydrous ethylacetate and 1044 g of toluylene diisocyanate at 40° C., under thorough agitation and simultaneous cooling, over a period of 3 hours, wherein the temperature does not exceed 50° C. To complete the reaction, the mixture is then heated to 60° C. and after attaining a NCO proportion of 0% it is diluted with 490 g of ethylene glycol monoethyl ether. The ethylacetate is distilled off as completely as possible in vacuo at 60° C. and the product diluted with further 500 g of ethylene glycol monoethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[OH:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1C1CCNCC1
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccccc2O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 147 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.368 g) was coupled to 4-(2-methoxyphenyl)piperidine (0.177 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.424 g); mp 150°-160° C.; MS: m/z=508(M+1); NMR(CD3SOCD3): 1.93-2.08 (m,4), 2.75 (m,1), 3.07 (s,3), 3.39 (m,5), 3.67-3.71 (m,32), 4.87 (d,1, J=3.7), 6.77-6.80 (m,3), 6.97-7.07 (m,3), 7.31 (m,1), 7.50 (m,2), 7.67 (m,1), 7.94 (d,1, J=7.7). Analysis for C29H29Cl2N2O2.1.5 HCl.0.5 H2O: Calculated: C, 60.88; H, 5.55, N, 4.90; Found: C, 61.09; H, 5.64; N, 4.73.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][CH:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][CH:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](OCC(O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)[Si](OCC1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Slowly add trichloromethyl chloroformate (8.74 mL; 2.0 equiv; 72.84 mmoles) over 10 minutes to a 0° C. solution of 1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (13.86 g; 1.0 equiv; 36.42 mmoles) and pyridine (23.56 mL; 8 equiv; 291.36 mmoles) in acetonitrile (500 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (50 mL) and concentrate the reaction mixture to 75 mL volume. Add dichloromethane (100 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired 6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (9.48 g; 64%) as a light pink gum: MS (m/z): 407(M+1).