Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C:32]1([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1)[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (intermediate AM) (215 mg) in toluene:THF (2:1) (3 mL) at −78° C. was added n-BuLi (0.34 mL, 2.5 M in hexane) dropwise. After 45 min, the above mixture was added dropwise into a pre-cooled (−78° C.) solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (453 mg) in toluene (3 mL). After being stirred for 2.5 h at −78° C., the reaction mixture was quenched by saturated NH4Cl and diluted with ethyl acetate. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product which was purified by chromatography to provide intermediate AN (712 mg) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC(C)CC(N)CC(N)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: CC(C)CC(CC(N)=O)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3-amino-5-methylhexanamide hydrochloride (CAN 93169-29-0) as starting materials to yield the racemate mixture. The racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first enantiomer collected and isolated as colorless oil; MS (ESI, m/z): 388.0 (M+H+).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=2[O:2]1.CC(C)=O.[I-:16].[Na+]>CCOCC>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][I:16])=[CH:4][C:3]=2[O:2]1
Reactant: [I-]
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: ICc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
11.65 g 3,4-methylenedioxybenzyl chloride in 128 ml of abs. acetone are treated with 49.7 g of sodium iodide, and this mixture is stirred at RT for 2.5 h under argon and while excluding light. The reaction mixture is diluted with 1.5 l of ether, and this mixture is washed with 10% sodium thiosulfate solution (600 ml) and saline. The title compound is obtained after drying over sodium sulfate and removing the solvent. It is recrystallized from ether/hexane. m.p.: 51° C. TLC Rf (hexane:ethyl acetate, 4:1)=0.43. 1H-NMR (360 MHz, CDCl3): 6.93-6.77(m, 2H), 6.77-6.64(m,1H), 5.95(s, 2H), 4.44 (s,2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:31]([O:38][C:39](=[O:51])[CH2:40][NH:41][CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:51])[CH2:40][N:41]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(CNC1Cc2ccccc2C1)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of N-(tert-butoxycarbony1)-L-valine (4.35 g) and triethylamine (2.13 g) in dry CH2Cl2 (40 ml) was added isobutyl chloroformate (2.87 g) at -20° C. After being stirred at same temperature for 30 minutes, a solution of N-(2-indanyl)glycine benzyl ester (5.37 g) in dry CH2Cl2 (20 ml) was added at -20° C. The reaction mixture was stirred at -10° C. for one hour then at room temperature for 4 hours. After the reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (100 ml×2). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel (50 g) column chromatography (CHCl3:AcOEt=10:1) to give N-(tert-butoxycarbonyl)-L-valyl-N-(2-indanyl)glycine benzyl ester (2.20 g) as an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F

Procedure:
Formula 203 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; Rc is 3-Fluoro-4-methyl-phenyl-; W and Z are —N═; X and Y are —C═: To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) is added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution is stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer is extracted with dichloromethane (5 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (10-20% ethyl acetate/hexanes) to give (±)-N{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=1)[C:14](OC)=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>ClCCl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH2:14][OH:15])[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1CO
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of methyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-methylbenzoate (step 2, 810 mg, 2.89 mmol) in dichloromethane (15 mL) was added a 0.95 M solution of diisobutylaluminum hydride in hexane (6.69 mL, 6.35 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h. The reaction was quenched by addition of water (6.7 mL) at −78° C. The mixture was diluted with dichloromethane (50 mL) and hexane (50 mL), and the mixture was stirred at room temperature for 16 h. The mixture was dried over magnesium sulfate, concentrated to afford 724 mg (99%) of the title compound as a colorless oil:
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=O)=O)=CC=1.[OH-].[Na+]>>[NH:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCNc2ccccc21
Temperature: 100 °C
Yield: 79 %

Procedure:
Polyphosphoric acid (25 g) was heated at 100° C. under nitrogen until it could be stirred. 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.4 (2.6 g, 8.26 mmol) was added portionwise and the reaction mixture was heated at 100° C. for 1.5 h. It was poured into ice and basified with 2M NaOH(aq). The aqueous layer was extracted twice with dichloromethane. The organic extracts were combined, washed with brine, dried and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% hexane) to yield the title compound (1.05 g, 79%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 130 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 1.93 g, 5.69 mmol), (S)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (STEP C, 7.42 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (165 mg, 0.285 mmol), tris(dibenzylideneacetone)dipalladium(0) (130 mg, 0.142 mmol) and N,N-diisopropylethylamine (1.10 g, 8.54 mmol) in 1,4-dioxane (25 mL) was stirred at 130° C. for 18 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (pre-treatment with triethylamine, hexane-ethyl acetate, gradient) to give the title compound (1.83 g, 70%) as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1ccccc1)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
The procedure of the process of P. Quitt et al. (Helv. Chim. Acta, 46, 327 (1963)) was followed. A 16.5 g quantity (0.1 mole) of Phe was dissolved in 50 ml of 2N aqueous NaOH solution, 10.1 ml of benzaldehyde was added to the solution with ice-cooling, and the mixture was stirred for about 10 minutes to obtain a uniform reaction mixture. To the mixture was added 1.14 g of NaBH4 in small portions at a temperature of up to 15° C., and the mixture was stirred for 30 minutes. The above procedure was repeated 3 times with use of benzaldehyde and NaBH4, each in one-half the above amount. The reaction mixture was stirred for 2 hours and then washed with ether. The aqueous layer was neutralized with 1N HCl with ice-cooling, and the resulting precipitate was filtered off and dried. The product was recrystallized from a mixture of 50 ml of dimethylformamide (DMF) and 200 ml of methanol to obtain 20.73 g of Nα -benzyl-phenylalanine (BzPhe), yeild 81.2%. M.p. 250°-253° C.
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[NH:1][C:45](=[O:46])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2noc(=O)[nH]2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To a mixed liquid of 400 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of acetonitrile were added 108 mg of CDI and 0.4 ml of DBU under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction solution, a saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, followed by extraction. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 40 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccc([N+](=O)[O-])cc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2cc(CBr)oc2c1

Procedure:
N-Bromosuccinimide ("NBS") (1.11 g, 6.2 mmole) was added to a solution of 2-methyl-6-nitrobenzofuran (1.00 g, 5.65 mmole) and azobisisobutyronitrile (20 mg) in carbon tetrachloride and the mixture was heated at reflux temperature for 11/2hours in the presence of a bright light. The solvent was then evaporated and the residue dissolved in methylene chloride, washed with water, dried (MgSO4), evaporated to dryness and purified by column chromatography on silica eluting with methylene chloride/hexane (7:3). The product-containing fractions were combined and evaporated to give the title compound, yield 1.43 g. 'H-N.m.r. clearly showed that the product contained 20% of 2-dibromomethyl-6-nitrobenzofuran, however, it was not considered necessary to remove this and the product was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
5.75 g (17.2 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-chlorophenyl) acetamide, 9.00 g (51.6 mmol) of t-butoxybis(dimethylamino)methane and 90 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 6.68 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH2:24][C:25]([O:27]C)=[O:26])#[N:22]>>[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:31][CH:30]=1)[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 34.7 %

Procedure:
Compound 16 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl) methanol (0.264 g, 0.98 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.2 g, 0.98 mmol) by following the procedure described in Scheme 5 (0.15 g, yield: 34.7%); Purity: 98.2%:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.C([N-]C(C)C)(C)C.[Li+].[I:40]I.C(O)(=O)C>O1CCCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([I:40])[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: -70 °C
Yield: 63.2 %

Procedure:
In 18 mL of tetrahydrofuran, 300 mg (0.67 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was suspended, and the suspension was cooled to −70° C. To the suspension, 3 mL of a tetrahydrofuran solution of lithium diisopropylamide (1.8 M) was added dropwise, and with stirring the temperature of the suspension was raised to 0° C. over two hours. Again, the suspension was cooled to −70° C., and 350 mg (1.38 mmol) of iodine was added thereto, and the suspension was stirred one hour. To the reaction solution, 100 μL of acetic acid was added, and the reaction solution was concentrated, and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 243 mg (63%) of a target product as a yellow solid.
Reaction SMILES: [C:1]([N:5]([C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30]C(=O)C)=[C:24]([O:34][CH3:35])[CH:23]=1)=[O:21])[NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH3:19])=[O:8])([CH3:4])([CH3:3])[CH3:2].N>CO>[C:1]([N:5]([C:20](=[O:21])[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([OH:30])=[C:24]([O:34][CH3:35])[CH:23]=1)[NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH3:19])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N(NC(=O)c2ccc3c(c2C)OCCO3)C(C)(C)C)cc(OC)c1OC(C)=O
Agent: N
Solvent: CO
Product: COc1cc(C(=O)N(NC(=O)c2ccc3c(c2C)OCCO3)C(C)(C)C)cc(OC)c1O
Temperature: 25 °C
Yield: 40.1 %

Procedure:
Acetic acid 4-[N-tert-butyl-N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazinocarbonyl]-2,6-dimethoxy-phenyl ester (300 mg) was dissolved in methanol with 28% aqueous ammonia (750 mg). The mixture was stirred at ambient temperature over the weekend. The precipitate was filtered to provide 110 mg of white solid 4-hydroxy-3,5-dimethoxy-benzoic acid N-tert-butyl-N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 1.59 (s, 15H), 2.02 (s, 3H), 3.85 (s, 6H), 4.21 (m, 4H), 5.6-5.7 (broad s, 1H), 6.22 (d, 1H), 6.58 (d, 1H), 6.81 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19]>>[OH:12][C:11]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([CH:7]=[C:23]2[N:17]([CH3:16])[C:18](=[O:19])[NH:20][C:21]2=[O:22])=[CH:9][C:10]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CN1CC(=O)NC1=O
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Product: CC(C)c1cc(C=C2C(=O)NC(=O)N2C)cc(C(C)C)c1O
Yield: 11 %

Procedure:
Prepared according to the procedure described in Example 92 using 3,5-diisopropyl-4-hydroxybenzaldehyde (2.7 g, 13 mmoles) and 1-methyl hydantoin (1.4 g, 12 mmoles). Recrystallization from acetonitrile gave the pure product (0.4 g), mp 197°-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]3)=[O:20])=[CH:17][CH:16]=1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cccc3c2CCN(C)C3)cc1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 4-methoxybenzoyl chloride according to the procedure of Example 19 to yield 5-(4-methoxybenzamido)2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 169.5°-171.5° C. after purification from ethanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11]CC)=[O:10])[CH:4]=[N:3]1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(/C=C/C(=O)O)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a mixture of ethyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (2.5 g), methanol (20 ml) and tetrahydrofuran (20 ml) was added a 2N aqueous sodium hydroxide solution (13.9 ml) and the mixture was stirred at 60° C. for 3 hrs. 1N Hydrochloric acid was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give (2E)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid (1.75 g, 83%) as an amorphous form.