Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44].O.OC1C2N=NNC=2C=CC=1>ClCCl.O>[CH3:39][N:40]([CH2:41][CH2:42][CH2:43][CH3:44])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Reactant: CCCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CCCCN(C)C(=O)CCCCCCCNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Combine 8-(t-butoxycarbonyl)amino-octanoic acid (1.28 g, 5 mmol), N-methylmorpholine (1.2 mL, 10 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride salt (0.95 g, 5.0 mmol), methyl-butyl amine hydrochloride salt (5.0 mmol), and 4-hydroxybenztriazole hydrate (0.05 g) in dichloromethane (20 mL). After 4 hours, add water and extract with ethyl acetate. Dry the organic layer over MgSO4 and evaporate in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].Cl.[OH2:16]>>[OH:16][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: O
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: Cl
Product: COc1cc(C(=O)O)ccc1CO
Temperature: 25 °C
Yield: 35 %

Procedure:
methyl 4-(bromomethyl)-3-(methyloxy)benzoate (300 mg, 1.15 mmol) was suspended in water (3 ml) and concentrated aqueous hydrochloric acid (380 μl) was added. The reaction mixture was refluxed for 16 h, then cooled to room temperature and partitioned with ethyl acetate (10 ml). The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (dichloromethane:methanol 95:5) to provide 4-(hydroxymethyl)-3-(methyloxy)benzoic acid (74 mg, 35% yield). MS (EI) for C9H10O4: 181(M−H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)[CH3:19]
Reactant: CCI
Reactant: c1ccc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCOc2ccccc21
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 ml) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. Iodo-ethane (3.5 ml, 44.4 mmol) was added and heated to 60° C. for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 ml), extracted with ethyl acetate (3×25 ml). The organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:33])=[C:26]([N:28]3[CH:32]=[CH:31][CH:30]=[CH:29]3)[CH:27]=2)OC1>>[F:33][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccc3)c2)OC1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-n1cccc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrrole by the method of Example 65 to furnish 3-[4-fluoro-3-(pyrrol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.37 (1H, d, J 7), 8.33 (1H, s), 7.97 (1H, d, J 8 and 2), 7.75-7.62 (2H, m), 7.52 (1H, d, J 7), 7.30 (2H, q, J 2), 6.32 (2H, t, J 2); m/z (ES+) 347 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:12][CH:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Br:1])[C:3]=1[O:13][CH3:14])[CH3:11])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C(C)O)cc(Cl)c(F)c1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1c(C(C)OS(C)(=O)=O)cc(Cl)c(F)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanol (3.9 g, 14 mmol) in methylene chloride (42 mL), cooled at 0° C. was added DIPEA (4.0 mL, 23 mmol) followed by methanesulfonyl chloride (1.6 mL, 20 mmol). The mixture was stirred for 1 h at 0° C. Water (100 mL) was added while cold. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to give 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl methanesulfonate. The mesylate was dissolved in DMF (41 mL) and sodium azide (1.8 g, 27 mmol) was added. The reaction was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. Purification on silica gel using 0-30% EtOAc in hexane gave the desired compound (3.3 g, 78%). LCMS calculated for C9H8BrClFO (M−N3)+: m/z=264.9, 266.9. found: 265.0, 267.0.
Reaction SMILES: CO[C:3]1[C:18](OC)=[CH:17][C:6]2[CH2:7][C:8](=O)[N:9](CCCI)[CH:10]=[CH:11][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:9]1[C:10]2[CH:11]=[CH:5][CH:4]=[CH:3][C:18]=2[CH:17]=[CH:6][CH:7]=[CH:8]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCI)C=C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C1=CNc2ccccc2C=C1
Temperature: 52.5 °C
Reaction time: 14 h

Procedure:
7,8-Dimethoxy-3-[3-iodopropyl]-1,3-dihydro-2H-3-benzazepin-2-one (38 g) and potassium carbonate (60 g) were added to a mixture of (S)—N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine (20 g) and demineralized water (100 ml) at room temperature. The reaction mixture was heated and stirred at 50-55° C. for 12-16 hours. After completion of reaction, reaction mass was cooled to 25-30° C. and the product is extracted in ethyl acetate (100 ml). The aqueous layer was further extracted with ethyl acetate (60 ml). Combined ethyl acetate layers was acidified with aqueous hydrochloric acid and stirred. The layers were separated and pH of the aqueous layer was adjusted to 10.5-12.5 with aqueous sodium hydroxide solution. The aqueous layer is extracted with ethyl acetate (140 ml+60 ml). Ethyl acetate was distilled out completely under vacuum to get the title compound.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[N+:16]([O-:18])=[O:17].[OH-].[Na+].O.Cl>CO>[N+:16]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])([O-:18])=[O:17]
Reactant: COC(=O)/C=C/c1ccc2ccccc2c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1ccc2ccccc2c1[N+](=O)[O-]

Procedure:
(E)-3-(Nitronaphthalen-2-yl)-acrylic acid methyl ester (1.3 g, 5.05 mmol) was dissolved in MeOH (50 ml) and treated with 2N NaOH (3.8 ml; 7.6 mmol) and water (25 ml) for 1 hour at 50° C. The mixture was acidified with 2N HCl (4.2 ml; 8.33 mmol), water (100 ml) added and filtered to render the desired acid as yellow crystals (1.05 g; 80%).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([OH:32])=O)[C:23]=3[CH:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[C:23]=3[CH:22]=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1COCCN1
Reactant: O=C(O)C=C1CCCc2c1cnn2-c1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=C1CCCc2c1cnn2-c1ccccc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 30.8 %

Procedure:
Triethylamine (0.054 mL, 0.39 mmol) and ethyl chloroformate (0.037 mL, 0.30 mmol) are added to a solution of a mixture of E/Z of 2-(1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene)acetic acid (100 mg, 0.39 mmol) in CH2Cl2 (5 mL) cooled to 0° C. and is stirred for 45 minutes at 0° C. Then morpholine (0.034 mL, 0.39 mmol) is added following the reaction by means of TLC. The solution is washed with diluted NaOH, the organic phase is separated, dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography giving an E/Z mixture (80/20) of 4-(2-(1-phenyl-6,7-dihydro-1H-indazol-4(5H)-ylidene)acetyl)morpholine (40 mg, 0.12 mmol, 32%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[C:1]1(/[CH:7]=[C:8]2/[CH:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1=Cc1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCC/C1=C\c1ccccc1
Temperature: 10 °C
Reaction time: 19 h

Procedure:
Molecular sieve (size 3A, 2 g) was added to a solution of 2-(phenylmethylene)cyclohexanone (1.86 g, 0.01 mole) in 20 ml of methanol, followed by a solution of ammonium acetate (7.7 g, 0.1 mole) in 20 ml of methanol. The mixture was cooled to about 10° C., and a solution of sodium cyanoborohydride in 20 ml of methanol was added during five minutes. The mixture was stirred at ambient temperature for 19 hours. The mixture was filtered, and the filtrate was cooled and brought to pH 11 by the addition of 20% aqueous sodium hydroxide. The methanol was evaporated and the mixture was extracted with ether. The extract was washed with water (water layer discarded) and then with three 10 ml portions of 10% aqueous hydrochloric acid. Water was added to dissolve the resulting solid. The aqueous acidic layer was cooled, basified with sodium hydroxide and extracted with chloroform. The chloroform extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 1.2 g of (±)-(E)-2-(phenylmethylene)cyclohexylamine which was identical (by tlc, UV, and nmr comparison) to the amine prepared in Part D of Example 1 above.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([F:6])([CH3:5])[CH3:4].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][Br:14])[C:3]([F:6])([CH3:5])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(F)C(C)(C)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(F)C(F)c1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of 1-(1,2-difluoro-2-methylpropyl)-3-methylbenzene (2.747 g, 14.91 mmol), N-bromosuccinimide (2.65 g, 14.9 mmol) and 2,2′-azobis(isobutyronitrile) (0.1 g) in carbon tetrachloride (30 ml) was heated under reflux for 1.5 hrs. After cooling the reaction solution to room temperature, white precipitate was collected by filtration and washed with hexane. The solvent of the recovered filtrate was evaporated under reduced pressure to give a crude product of 3-(1,2-difluoro-2-methylpropyl)benzyl bromide as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:21])[C:11]([CH3:20])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([OH:30])(=[O:29])[C:23]([CH2:25][C:26](O)=[O:27])=[CH2:24]>C(OCC)(=O)C>[CH2:1]([NH:9][C:10](=[O:21])[C:11]([CH3:20])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH:23]([C:22]([OH:30])=[O:29])[CH2:25][C:26]2=[O:27])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCNC(=O)C(C)=Cc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)C(C)=Cc1cccc(N2CC(C(=O)O)CC2=O)c1

Procedure:
A mixture of 4.3 g. of N-octyl-2-methyl-3-(3-aminophenyl)propenamide and 2.0 g. of itaconic acid was heated at ca. 140° C. for 1.25 hours. The reaction mixture was allowed to cool somewhat and then a small volume of ethyl acetate was added. This gave a clear solution. The solution was diluted to ca. 75 ml. with further ethyl acetate, and then it was extracted with 1 N potassium hydroxide. The potassium hydroxide solution was washed with ethyl acetate and then it was acidified using concentrated hydrochloric acid. This caused a gum to precipitate. The gum was extracted into ethyl acetate, and the ethyl acetate solution was dried using sodium sulfate. The dried solution was evaporated in vacuo to give 4.5 g. of an oil. The oil was triturated under ether causing formation of a solid. The solid was collected by filtration to give 2.5 g. of a solid, which was recrystallized from ethyl acetate-cyclohexane and then from acetonitrile. This afforded 1.3 g. of the title compound, m.p. 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([NH:14][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCN
Reactant: Brc1cccnc1
Product: CCCCCCNc1cccnc1
Yield: 81.9 %

Procedure:
Using the general procedure, 3-bromopyridine (96 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 90° C. for 18 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (1:1) as eluent afforded the desired product as a colorless oil (146 mg, 82% yield). Rf=0.2 (hexane/ethyl acetate=2:1).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=1.C([Mg]Cl)(C)C>C1COCC1>[O:18]=[CH:4][C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][C:25]1[CH:26]=[CH:21][CH:22]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C[C@H](Cc1cccc(OC(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
To a solution of the commercially available benzyl {(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (5.52 g, 20.75 mmol) and 1-bromo-3-(trifluoromethoxy)benzene (5 g, 20.75 mmol) in THF (100 ml) cooled in an ice/methanol/dry ice cooling bath was added isopropylmagnesium chloride (20.75 ml, 41.5 mmol) dropwise under nitrogen while internal temperature was maintained between −35 and −15° C. (monitored w/ an immersed temperature probe). After addition, the reaction was stirred cold and allowed to warm to ambient overnight. The reaction crude was then cooled to −20° C. and slowly quenched into a stirred mixture of crushed ice and HCl (1N, ice bath cool). The resulting mixture was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure. The pot residue was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and concentrated in vacuo to afford a colorless oil of 3.9824 g as the titled compound. LCMS calc.=367.1. found=390.00 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
4-(4-Aminobenzyl)phenyl-carbamic acid benzyl ester (0.997, 3 mmol) was added to a solution of phenylisocyanate (0.393 g, 3.3 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 1 hour at room temperature under nitrogen. The reaction mixture was quenched with water and concentrated in vacuo. The residue was suspended in water, filtered, washed with water, and dried to give {4-[4-(3-phenylureido)benzyl]phenyl}-carbamic acid benzyl ester (1.38 g) as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][C:5]1=[O:11])[C:2]#[CH:3].[CH3:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[N+:25]([C:18]1[CH:17]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=1[C:20]([CH:6]1[C:5](=[O:11])[CH:4]([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:21])([O-:27])=[O:26]
Reactant: C#CCC1CCC(=O)CC1=O
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCC1CCC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C1=O
Reaction time: 3 h
Yield: 44.9 %

Procedure:
4Propargyl-1,3-cyclohexanedione (3.75 g, 25 mmol) and 4-methanesulfonyl-2-nitrobenzoyl chloride (6.06 g, 23 mmol) were dissolved in acetonitrile (100 mL) at 0° C. Triethylamine (9.6 mL, 69 mmol) was added. The mixture was then stirred for 3 hours. To the mixture was then added potassium cyanide (5.0 g) and 18-crown-6 ether (0.5 g) in one portion. The mixture was stirred for 3 days. After dilution with ether, the solution was washed with 1N HC1 and extracted with 5% K2CO3. The basic extract was acidified with concentrated HC1 and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSO4, and concentrated under vacuum, yielding 3.9 g of the desired product, an orange solid, m.p. 65-70° C. The structure was confirmed by nuclear magnetic spectroscopy, infrared spectroscopy, and mass spectroscopy.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]=2)(=[O:3])[CH3:2].[N:20]1([CH2:26][CH2:27][N:28]([CH2:37][CH3:38])[C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1.C1(C)C=CC=CC=1>O>[CH2:15]([N:14]([CH2:17][CH3:18])[C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([C:1](=[O:3])[CH:2]=[CH:33][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:37][CH3:38])[CH2:27][CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:36][CH:35]=3)[C:5](=[O:19])[O:6]2)=[CH:11][CH:10]=1)[CH3:16]
Reactant: CCN(CCN1CCCCC1)c1ccc(C=O)cc1
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc2cc(C(=O)C=Cc3ccc(N(CC)CCN4CCCCC4)cc3)c(=O)oc2c1

Procedure:
3-acetyl-7-diethylaminocoumarin (1.04 g, prepared according to the procedure described in U.S. Pat. No. 4,147,552), 1.20 g N-(2-piperidinoethyl)-N-ethyl-4-aminobenzaldehyde, 0.10 g piperidinium acetate, and 40 ml toluene were placed in a 100 ml round-bottomed flask fitted with a Dean-Stark trap and condenser. The solution was refluxed for 16 hr with removal of collected water. The toluene was evaporated under reduced pressure and a mixture of 20 ml water and 5 ml ethanol was added to the resultant viscous material. Upon stirring a solid precipitated which was isolated by filtration and drying to give 1.5 g of 7-diethylamino-3-(3-(N-ethyl-N-(2-piperidinoethyl)-4-aminophenyl)propenoyl)coumarin (4) as a red solid; λmax (ethanol)=475 nm. ##STR10##
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[N:8]1.[BH4-].[Na+].C(OCC)(=O)C>CO>[CH3:15][Si:2]([CH3:1])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[CH:9]=[N:8]1
Reactant: CC(=O)c1cnn(COCC[Si](C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanone (39.7 mg, 0.17 mmol) in methanol (2 mL) was mixed with sodium borohydride (12.5 mg, 0.34 mmol) and stirred at room temperature for 90 minutes. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (43.7 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A mixture of Intermediate 81d (319 mg, 0.85 mmol), Intermediate 29c (335 mg, 0.85 mmol) and DIPEA (294 μL, 1.69 mmol) in dioxane (10 mL) was stirred at 80° C. for 18 hours. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (362 mg, 66%). LCMS (Method 4): Rt 3.29 min, m/z 649 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1)=[N:7][N:6]=[CH:5]2
Reactant: CN1CCNCC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.12 g, 0.5 mmol), 1-methylpiperazine (0.11 mL, 1.0 mmol) and potassium carbonate (0.07 g, 0.5 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for about 20 min. After about 20 min. all starting material was converted to product (M+1=307, 309). The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give (0.14 g) 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine as a yellow solid. Found MS (ES+): 307, 309(M+H)+.