Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][CH:22]([O:28]C)[CH2:23][C:24](OC)=O.C(O)(=O)C.P(Cl)(Cl)(Cl)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:24]=[CH:23]/[C:22]([O:21][CH3:20])=[O:28])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(OC)OC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 9 h
Yield: 92.9 %

Procedure:
1.01 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.92 g of methyl 3,3-dimethoxypropionate, 0.72 mL of 90 wt % aqueous acetic acid (containing 4 mmol of water) and 6 mL of glacial acetic acid were mixed, then, 0.33 g of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 9 hours at the same temperature to cause a reaction. After completion of the reaction, 16 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol % aqueous methanol, then, dried to obtain 1.25 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:12].C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32]([NH:12][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:36])[F:37])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloroanthranilic acid (7.89 g, 38.3 mmol) in methylene chloride (130 mL) at 0° C. was added triethylamine (18.6 mL, 134.0 mmol). A solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (13.7 g, 44.0 mmol) in methylene chloride (130 mL) at 0° C. was then added, the reaction allowed to warm to room temperature and then stirred further for 16 h. The reaction was concentrated in vacuo and used directly in the following reaction step.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:18].[Na+].Cl>O>[C:1]1([C:4]2[C:5](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:8]([OH:18])=[O:13])[S:11]1)=[O:3]
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2c(=O)s1

Procedure:
A mixture of 5- (o-carboxybenzylidene) rhodanine (4.68g.) and sodium hydroxide (5.0g.) in water (40ml.) was heated under reflux for 30 minutes, cooled and poured into 5N hydrochloric acid (250ml.). Filtration and recrystallisation from ethanol-water gave the product as a white solid, mp. 260.5° - 261° (lit mp. 261°-3°), (Found: C, 58.10; H, 2.92; S, 15.41. C10H6SO3 requires C, 58.24; H, 2.93; S, 15.55).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:29]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:14][CH2:13][CH2:12][C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:11]=3)[CH2:27][CH2:28]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)cc1
Yield: 57.1 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(diphenylmethyl)piperazine (13 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2.75 hr and followed the same processes as in Example 1 to obtain 12.5 mg (57.1%) of the target compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C)C=O.O>[CH3:19][C:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)([CH3:18])[CH2:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (3.4 g, 0.024 mol), K2CO3 (6.6 g, 48 mmol) and 4-(tert-octyl)phenol (5.0 g, 0.024 mol) in dimethylformamide (50 mL) was heated at reflux for 24 hours. The mixture was allowed to cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (250 mL). The organic phase was washed with water (5×100 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the desired product as a yellow solid (7.8 g, 100%): 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, 9.2 Hz, 2 H), 7.48 (d, 8.8 Hz, 2 H), 7.09-7.05 (m, 4H), 1.72 (s, 2 H), 1.34 (s, 6 H), 0.69 (s, 9 H); MS (FAB) m/z 328 (MH+); Rf =0.92 (15:85 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[N:19]([CH3:28])[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[S:38][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:19]([CH3:28])[S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[N:7][N:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: COCc1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of N-(2-{[2-(methoxyacetyl)hydrazino]carbonyl}-1H-indol-7-yl)-N-methylthiophene-2-sulfonamide (0.29 g), Lawesson's reagent (0.31 g) and tetrahydrofuran (10 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and methanol was added to the residue. The resulting crystals were filtrated, washed with methanol, and dried to give the title compound (0.18 g, yield 62%) as pale-yellow crystals. melting point>238° C. (decomposition).
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([Cl:9])=[CH:7][NH:6][C:5](=[O:10])[N:4]=1.[CH3:11]I.[OH-].[K+]>C(O)C>[CH3:11][N:6]1[CH:7]=[C:8]([Cl:9])[C:3]([CH3:2])=[N:4][C:5]1=[O:10]
Reactant: Cc1nc(=O)[nH]cc1Cl
Reactant: CI
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(=O)n(C)cc1Cl
Yield: 35 %

Procedure:
A solution of the sodium salt of 4-methyl-5-chloropyrimid-2-one (0.005 mol) and methyl iodide (0.0055 mol) in abs. ethanol (70 ml) was heated under reflux until ca. neutral pH. Another 0.005 mol of potassium hydroxide and methyl iodide were added and the heating continued to ca. neutral pH. The reaction mixture was then filtered and the filtrate evaporated to dryness. The residual material was repeatedly extracted with chloroform and the chloroform extracts evaporated and the solid extract recrystallised from isopropanol; yield 35%, m.p. 132°-134° C. (Found: C, 45.51; H, 4.51. Calc. for C6H7ClN2O: C, 45.44; H, 4.43).
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][O:7][C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]2=O>C(O)CO>[CH3:6][O:7][C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: COC12CCC(CC1)CC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COC12CCC(CC1)CC2
Temperature: 195 °C
Yield: 44.9 %

Procedure:
To a solution of potassium hydroxide (17 g, 250 mmol) and 85% hydrazine hydrate (11.5 g, 186 mmol) in ethylene glycol (220 mL) was added 1-methoxybicyclo[2.2.2]octan-2-one (11.0 g, 71.4 mmol). The mixture was heated to 195° C. over 1 h and heated for an additional hour. The flask was then fitted for distillation, and approximate 20 mL (two layers) of liquid was collected over a period of 1 h at 195° C. Subsequent dropwise addition of water (215 mL) to the reaction over a period of 3 h afforded a second fraction of distillates (approximately 180 mL). The combined distillates were extracted with ether (3×80 mL), the organic phase was dried over Na2SO4, and the volatiles were removed to produce 1-methoxybicyclo[2.2.2]octane (4.5 g, 45%) which was used in the next step directly without purification. 1H NMR (CDCl3, 400 MHz) δ 3.14 (s, 3H), 1.63-1.59 (m, 6H), 1.58-1.51 (m, 6H), 1.47 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[OH-].[Na+].[I-].[K+].[I:16]([O-])(=O)=O.[K+].S(=O)(=O)(O)O.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[C:6]([I:16])[CH:7]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)cc(I)c1O
Reaction time: 8 h
Yield: 176.4 %

Procedure:
A slurry of 4-fluoro-2-nitrophenol (3.3 g), sodium hydroxide (0.83 g), potassium iodide (2.33 g) and potassium iodate (1.5 g) in water (21 ml) was added to a stirred mixture of ethanol (16 ml), water (3.5 ml) and concentrated sulphuric acid (1.7 ml) at 50°. The mixture was heated under reflux for 2 hours and was then allowed to stand at room temperature overnight. A small quantity of sodium sulphite was added to decolourise the product and the yellow solid was filtered and crystallised from aqueous ethanol to give yellow crystalls of 4-fluoro-2-iodo-6-nitrophenol (3.5 g) m.p. 40°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]1
Reactant: COCc1ccc(C(=O)O)o1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COCC1CCC(C(=O)O)O1
Yield: 102.5 %

Procedure:
A solution of 5-methoxymethylfuran-2-carboxylic acid (3.10 g) in ethyl acetate (40 ml) was hydrogenated over 5% rhodium on carbon (200 mg) until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give the title compound as a colourless oil (3.26 g); νmax (film) 1750 cm-1 ; δH (CDCl3) 1.75-2.1 (2 H,m), 2.1-2.6(2 H,m,), 3.45 (3 H,s), 3.47 (1 H,dd, J 3 and 10 Hz), 3.74 (1 H,dd, J 4 and 10 Hz), 4.15-4.43 (1 H,m) and 4.43-4.63 (1 H,m).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CS(C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH:24]([CH3:26])[CH3:25])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)I
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)On1nnc2ccc(Cn3ccnc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
A mixture of 3.23 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 2.07 parts of potassium carbonate and 20 parts of dimethyl sulfoxide was stirred for 10 minutes at room temperature. Then there were added 2.55 parts of 2-iodopropane and stirring was continued first for 15 minutes at room temperature and then for 1 hour at 50° C. The reaction mixture was evaporated. 50 Parts of water were added. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 14 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 3.3 parts (85.5%) of 6-(1H-imidazol-1-ylmethyl)-1-(1-methylethoxy)-1H-benzotriazole; mp. 114.3° C. (compound 195).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.[C:27]([Cu])#[N:28]>CN1C(=O)CCC1>[NH2:26][C:23]1[O:24][CH2:25][C@@:5]2([N:22]=1)[C:4]1[CH:3]=[C:2]([C:27]#[N:28])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:9][CH:10]=1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CC(C)(C)COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C#N)ccc1O2
Temperature: 200 °C

Procedure:
(S)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (250 mg, 0.599 mmol) and CuCN (268 mg, 3.00 mmol) were brought up in NMP (1997 μL) and heated to 200° C. in the microwave. The reactions were cooled to rt, filtered and purified by reverse-phase preparative HPLC using a Gemini NX c!8 column (150*30 mm, 5 um), 0.1% TFA in CH3CN/H2O, gradient 0% to 70% over 10 min to provide the product. Solvent was removed by evaporation and the product was brought up in sat's aqueous NaHCO3 and DCM and extracted with DCM. The organic washes were combined, dried over Na2SO4, filtered and concentrated to give (R)-2-amino-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthene]-2′-carbonitrile.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: C1CNCCN1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Temperature: 65 °C
Yield: 63.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (1.1 g, 3.1 mmol, from Example 47, Step 2), piperazine (0.40 g, 4.7 mmol) and cesium carbonate (2.8 g, 8.7 mmol) in tetrahydrofuran (20 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with water, and extracted with dichloromethane. The organic phases were combined, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 15% methanol in dichloromethane) to give the desired product (0.57 g, 63%). LCMS calculated for C15H17ClN3O (M+H)+: m/z=290.1; Found: 290.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11]C(C)=O>>[C:1]1([CH2:7][C:8](=[O:10])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)=O
Product: CC(=O)Cc1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid is phenylacetic acid to yield phenylacetone.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[F:17].CCCCCC.CN([CH:27]=[O:28])C>C1COCC1>[F:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:27]=[O:28]
Reactant: Fc1c(Br)ccc2c1ncn2C1CCCCO1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 91.2 %

Procedure:
To a solution of 146 (10 g, 0.034 mol) in dry THF (100 mL) at −78° C. was added dropwise 1.6 M N-butyl lithium solution in hexane (23 mL, 0.0374 mol). After stirring for 45 min at −78° C., a solution of DMF (5 g, 0.068 mol) in THF (20 mL) was added dropwise. After 1 h at −78° C. the reaction mixture was quenched slowly by adding water. The aqueous phase separated was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 15% EtOAc/petroleum ether to afford 7.7 g (93%) of 4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (148) as a yellow solid.
Reaction SMILES: C(Br)C1C=CC=CC=1.I[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: ICCc1ccccc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)nc1C
Yield: 35 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with (2-iodoethyl)benzene to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 35% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 4.25 (q, J=7.2 Hz, 2H), 4.02 (t, J=7.8 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.8 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); MS (ES+) m/z 360.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(OS(=O)(=O)c2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-3-methylphenol (1.0 g, 7.0 mmol) in dry CH2Cl2 (70 mL) at 0° C. was added Et3N (1.45 mL, 10.5 mmol). After stirring at 0° C. for 20 min, benzenesulfonyl chloride (1.34 mL, 10.5 mmol) was added to the reaction mixture. The reaction was slowly warmed to room temperature and stirring was continued for an additional 18 h. Water was added to quench the reaction and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo and resulting crude product was purified by flash column chromatography (silica gel, 10-30% CH2Cl2/hexanes). The desired product was obtained as a white solid (1.9 g, 96%). LC/MS (ES+) m/e 283.0 [M+H]+.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:15])[CH:7]=1.O>O1CCCC1>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Borane-dimethyl sulfide complex (2M in THF; 1150 mL, 2.3 mol) is added over 1.5 hours to a solution of 4-bromo-2-methylbenzoic acid (250 g, 1.16 mol) in anhydrous tetrahydrofuran (1500 mL) at 0° C. The reaction is allowed to warm slowly to ambient temperature and stirred overnight. The solution is cooled to −10° C. and water (500 mL) is added very slowly. Further water (5000 mL) is added and the mixture is extracted with ethyl acetate (2×5000 mL). The combined organic layers are washed with saturated aqueous NaCl solution (5000 mL) and dried over Na2SO4. Filtration and concentration under reduced pressure provides the title compound (226 g, 97% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].Cl.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH2:23][CH2:22][N:24]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4]
Reactant: CCN(CC)CCCl
Reactant: CNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: Cl
Product: CCN(CC)CCn1c(C(=O)NC)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 70 °C

Procedure:
According to the procedure described in Example 1, 28.5 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid methylamide are treated with 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is heated at 70° C. for 5 hours, then cooled and poured into 4 liters of ice-water. After the addition of 200 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is digested with ether, removed by filtration and washed with ether, and there is obtained a first portion of crude 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide having a melting point of 187°-190° C. The ethereal filtrate is extracted with 1-N sulfuric acid and the acidic extract is made alkaline at 0°-5° C. with concentrated ammonia solution. Then, the separated oil is extracted with methylene chloride and the solution dried over sodium sulfate. After evaporation, there is obtained an oil which crystallizes from ether, and is obtained as a second portion of reaction product; melting point 187°-190° C. Both portions of the reaction product are recrystallized together from ethanol, and 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide is obtained in the form of colorless needles having a melting point of 190°-192° C.