Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:23]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Yield: 87.8 %

Procedure:
An ethyl acetate solution of 7.0 g of the so-obtained 2'-hydroxy-3,4',6'-trimethoxy-4-methoxymethoxy3'-(3-methyl-2-butenyl)chalcone was added to an ethyl acetate solution of 1.0 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was strongly stirred and hydrogen was adsorbed. Then, the mixture was stirred overnight, the palladium/carbon was removed by using Celite and the solvent was removed by distillation. The residue was dissolved in diethyl ether and crystallization was effected by addition of hexane to obtain 6.2 g (yield= 92%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][C:6]2=[O:23].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:24](=[C:7]1[C:6](=[O:23])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:8]1)[CH:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH2:30]1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CCN2S(=O)(=O)c1ccc(C)cc1
Product: COc1ccc2c(c1)C(=O)C(=CC1C=CC=CC1)CN2S(=O)(=O)c1ccc(C)cc1
Yield: 62.8 %

Procedure:
By the method of Example 146, 25.0 g (75.5 mmol) of 6-methoxy-1-(p-toluenesulfonyl)-2,3-dihydro-4(1H)quinolinone (J. Am. Chem. Soc., Vol. 71, p. 1901, 1949) and 12.0 g (113 mmol) of benzaldehyde were converted to 20.0 g (63%) of present title product recrystallized from ether-hexane, m.p. 131°-132° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:24][O:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:32]([C@H:29]3[CH2:30][CH2:31][C@@H:26]([O:25][CH3:24])[CH2:27][CH2:28]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(Br)nc32)CC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 mL, 5.94 mmol) in acetonitrile (10 mL) was added (cis)-4-methoxycyclohexanamine hydrochloride (0.413 g, 2.495 mmol). The solution was stirred at 55° C. for 3 h. The resulting precipitate was filtered and washed with acetonitrile and dried under reduced pressure to afford the title compound (0.442 g, 1.29 mmol, 55% yield). MS (ESI) m/z 341.3 [M]+, 343.3 [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].[H][H]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:26]
Reactant: O=C(NCCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NCCCC=Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1

Procedure:
Dissolve 7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pent-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (726 mg) in EtOAc (20 mL). Add 10% Pd/C (Degussa type, 100 mg) and then stir the mixture under 15 psi of hydrogen for 10 min. As reaction is not completed, add extra catalyst (147 mg) and stir under 15 psi of hydrogen for an extra 15 min. Filter the reaction mixture through a short pad of Celite® and concentrate in vacuo to obtain the desired intermediate that was used in the next step without further purification. MS (ES+) m/z=457.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:18]=1)=[N:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[CH:12]=2)([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C>C1(C)C=CC=CC=1.C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:18]=1)=[N:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(NC(C)C)sc2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2ncc(CO)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-(isopropylamino)thiazolo[4,5-b]pyridine-6-carboxylate (0.278 g, 1.05 mmol) in toluene (10 mL) and THF (5 mL) was introduced Dibal-H (5.8 mL, 5.8 mmol) at −78° C. over 10 min. The resulting mixture was allowed to warm to rt and stirred for 4 hr. Additional Dibal-H (1.2 mL, 1.2 mmol) was added at rt, and the mixture was stirred for additional 1.5 hr before it was poured into ice-cold water (100 mL). The mixture was stirred at rt for 30 min, and then filtered through Celite® 545. The organic layer of filtrate was separated. The aqueous layer was basified with saturated NaHCO3 solution and extracted with AcOEt. The combined organic phase was washed with brine and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound as a viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].BrCC1C=CC=C(F)C=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: N#Cc1cccc(CBr)c1
Agent: Fc1cccc(CBr)c1
Product: N#Cc1cccc(COc2cccc(N)c2)c1

Procedure:
3-Nitro-phenol was reacted with 3-bromomethyl-benzonitrile according to the procedure from Example 199A substituting 3-bromomethyl-benzonitrile for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][CH:2]=[C:3]([CH3:10])[C:4]=1[CH:19]=[O:20]
Reactant: COc1cc(C)c(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nccc(C)c1C=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 5-bromo-2-methoxy-4-methylpyridine (2.6 g, 13 mmol) in dry THF (40 mL) under argon at −70° C. was added 1.6M n-BuLi in hexanes (8.1 mL, 14 mmol) over ten minutes. The mixture was stirred at −70° C. for 30 minutes and then anhydrous DMF (1.2 mL, 15 mmol) was added portion-wise at a rate that kept the temperature at −70° C. When the addition was complete, the mixture was stirred at −70° C. for 30 minutes and then at RT overnight. The reaction was quenched with 1M hydrochloric acid (40 mL) and then extracted three times with TBME. The combined organic phases were washed with brine, dried, filtered and concentrated. Column chromatography with TBME-light petroleum ether (1:1) as eluent gave 1.8 g (91%) of the title compound as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)CC)C.[K+].[Br-]>CCOCC>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH:16][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: COc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 15.5 g (0.1 mol) portion of o-methylbenzoyl chloride was added dropwise to a stirred solution of 11.9 g (0.1 mol) of m-methoxyaniline and 10.1 g (0.1 mol) of triethylamine in 250 ml of ether and the resulting solution was cooled. After addition of the o-methylbenzoylchloride, the mixture was stirred at room temperature for an additional 5 hours, and the reaction mixture was washed with water to remove triethylamine hydrochloride. The ether layer was dried over anhydrous sodium sulfate and the ether was removed whereby 23.9 g (99%) of fine white prisms having a melting point of 142°-143° C were obtained. IR cm-1 (KBr-tablet), νNH 3250 (S), νCO 1655(S), 1610(S).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Br:9]N1C(=O)C(C)(C)N(Br)C1=O.BrBr>C(Cl)(Cl)(Cl)Cl>[C:1](=[O:8])([O:5][CH:6]([Br:9])[CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(=O)OCC
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)OC(C)Br
Yield: 163.9 %

Procedure:
A mixture of diethyl carbonate (35 g, 0.3 m) in carbon tetrachloride (50 ml) and alpha-azo-isobutyronitrile (AIBN) (0.1 g) was heated to gentle reflux and dibromodimethyl hydantoin (28.6 g, 0.1 m) was added in small aliquots over a period of 8 hours together with further additions of AIBN (8×0.05 g): care being taken to ensure that free bromine did not accumulate in the reaction mixture. At the end of the reaction the mixture was subjected to vacuum fractional distillation to afford pure ethyl alpha-bromoethyl carbonate (32.3 g, 82% yield) identical in all respects with the product of Examples 3 and 4.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:22]C(=O)OCC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH2:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1
Yield: 90.2 %

Procedure:
A suspension of 149E (740 mg, 1.682 mmol) and 5% Pd/C (Degussa type, 300 mg) in a mixed solvent of MeOH-THF (20 mL, 1:1 ratio) was hydrogenated at RT under hydrogen balloon for 1 h. After filtration to remove the catalyst, the filtrate was concentrated and the residue dried in vacuo to afford compound 149F as a clear oil (465 mg, 90%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of compound 12 (0.293 g, 0.79 mmol) and sodium azide (0.154 g, 2.38 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over Na2SO4, and evaporated to give compound 13 as a pale yellow oil (mixture of cis and trans diastereomers, ratio=1:1.1, 0.18 g, 68%). The diastereomers were separated using a preparative chiral HPLC procedure (ChiralPak OD column; hexanes:MeOH=98:2; μ=8 ml/min; and λ=225 nm) to give compounds 13a-13d (retention times: 9.8 min, 12.0 min, 14.5 min and 20.1 min, respectively).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]([O:54][C:55](=[O:59])/[CH:56]=[CH:57]/[CH3:58])[CH3:53]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:52]([O:54][C:55](=[O:59])[CH:56]=[C:57]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:58])[CH3:53]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=C(C)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 20 %

Procedure:
N-Boc-2-bromobenzylamine (7.15 g, 25 mmol) was dissolved into tributylamine (12 mL) and degassed under vacuum. Palladium acetate (224 mg, 1 mmol) and tri-o-tolylphosphine (608 mg, 2 mmol) was then added and the mixture degassed under vacuum. Trans-ethylcrotonate (6.25 mL, 50 mmol) was then added and the mixture was degassed with nitrogen. The tube was sealed and the mixture was heated to 110° C. for 48 h. The solution was cooled to room temperature, diluted with diethyl ether (200 mL) and filtered through celite. The solution was washed with 1N HCl (2×50 mL) and brine (50 mL) dried over magnesium sulfate and concentrated to dryness. Flash chromatography (9:1 hexanes/ethyl acetate) gave the title compound as a yellow oil (1.6 g, 20%). 1H NMR 7.22–7.37 (m, 3H), 7.08 (dd, J=7.4, 1.6 Hz, 1H), 5.75 (d, J=1.3 Hz, 1H), 4.29–4.31 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.45 (d, J=1.3 Hz, 3H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([Cl:20])[C:12]=1[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1[F:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:11]2[N:16]3[CH:17]=[CH:18][N:19]=[C:15]3[N:14]=[C:13]([Cl:20])[C:12]=2[C:21]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[F:29])[N:5]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: Cc1cc(C)[nH]n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2c(-c3c(F)cc(F)cc3F)c(Cl)nc3nccn23)n1
Yield: 47.7 %

Procedure:
Into a mixture of 0.040 g of sodium hydride (60% in oil) and 2 ml of tetrahydrofuran, a solution of 0.096 g of 3,5-dimethylpyrazole in 3 ml of tetrahydrofuran was added dropwise. The mixture was added to a solution of 0.32 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine in 5 ml of tetrahydrofuran under ice-cooling. To the reaction mixture, chloroform and aqueous citric acid solution were added. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of 5-(3,5-dimethylpyrazol-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CCN(C(C)C)C(C)C.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5])(=[O:26])=[O:25]
Reactant: CC(C)(N)CCO
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12.5 h

Procedure:
To a 20 mL vial were added a stirbar, 3-amino-3-methylbutan-1-ol (428 mg, 4.15 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (994 mg, 3.89 mmol) and stirred for 12.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (676 mg, 54%). MS (ESI): mass calcd. for C11H16BrNO3S 321.00, m/z found 344.0 [M+Na]+; 1H NMR (600 MHz, CDCl3) δ 8.15 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 1H), 6.15 (s, 1H), 3.93-3.81 (m, 2H), 1.76 (t, J=6.0, 2H), 1.20 (s, 6H).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20][C:21]2[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH:18]=O)=[CH:13][CH:12]=1>Cl.CO>[C:7]([NH:6][N:5]=[CH:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[CH:20][C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)(=[NH:9])[NH2:8]
Reactant: N=C(N)NN
Reactant: O=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)O
Solvent: CO
Product: N=C(N)NN=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1

Procedure:
A solution of 0.46 g of aminoguanidine hydrogen carbonate in 5 cc of 10% hydrochloric acid is added to 1.0 g of 2-(4-chlorophenyl)-3-(5-nitro-2-thienyl)acrolein in 20 cc of methanol, and the mixture is heated to 50° for one hour. Upon cooling, the hydrochloride of the title compound is obtained as yellow crystals having a M.P. of 225°-227°.
Reaction SMILES: Cl.[CH2:2]=[C:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.O.C([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([N:4]([CH2:2][CH:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2)[CH2:5][C:6]1[CH:17]=[CH:16][N:15]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: C=C1C(=O)C2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CCN(Cc1ccncc1)CC1C(=O)C2CCN1CC2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone hydrochloride (0.5 g, 0.0036 mol) in water (3 ml) N-(4-pyridylmethyl)ethylamine (0.49 g, 0.0036 mol), triethylamine (1.09 g, 0.0108 mol) and tetra-n-butyl ammonium bromide (116 mg, 0.00036 mol) were added and the reaction mixture were allowed to stir at 80° C. for 18 h. The completion of reaction was monitored by tlc. The reaction mixture was quenched with ice-cold water (10 ml), extracted with dichloromethane (2×50 ml), organic layers were washed with 10% NaHCO3 solution, brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified as yellow solids (200 mg, 22%) by flash column chromatography on neutral silica gel using chloroform as eluent.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=O)[S:24][CH:25]=1>[OH-].[K+].CCO>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])[S:24][CH:25]=1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1cc(Br)cs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cc(Br)cs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 43 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.252 g, 0.98 mmol) was reacted with 4-bromothiophene-2-carboxaldehyde (0.282 g, 1.5 mmol) in 5 mL of 4% KOH in EtOH to afford 0.181 g (43%) of the title compound as a light tan powder, mp 164-166° C.: CI-MS m/e 428, 430 (M+); 429, 431 (M+ +1); 1H-NMR (CDCl3): δ 8.03 (1H, d, J=8.8 Hz), 7.82 (1H, s), 7.58 (1H, s), 7.33 (1H, s), 7.20 (1H, s), 7.05 (1H, s), 7.01 (1H, s), 6.80 (1H, dd, J=8.8 Hz, J=2.4 Hz), 6.66 (1H, d, J=2.2 Hz), 4.34 (2H, m), 4.25 (2H, m), 3.10 (2H, m), 2.93 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.CC(C)=O.C(=O)=O.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1
Reactant: COc1ccc(C)c(-n2cccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(O)cc1-n1cccc1

Procedure:
A solution of 86.6 g (0.46 mole) of 4-methyl-3-(pyrrol-1-yl)-anisole in 1.5 liters of absolute methylene chloride is cooled to -78° with acetone/dry ice. At this temperature, 231.7 g (0.92 mole) of boron tribromide are added dropwise. Subsequently, the cooling bath is removed and the reaction mixture is heated to from 0° to 5°, then poured into 2 liters of ice/water, and the methylene chloride phase is removed and washed with saturated sodium chloride solution. The aqueous phases are then extracted a further twice with methylene chloride. The organic phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-phenol, b.p. 105°-107°/0.03 torr, Rf (toluene/ethyl acetate=10:1):0.38.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][NH2:17]>CCO>[CH3:16][NH:17][C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1cccnc1
Yield: 76.8 %

Procedure:
In 50 ml of EtOH was dissolved 2.3 g (0.01 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene with heating and, then, a solution of 1.2 g (0.015 mole) of 40% aqueous methylamine in 10 ml of EtOH was added dropwise over a period of 30 minutes while refluxing. The mixture was further refluxed for 2 hours, after which it was concentrated. The crystals were collected by filtration and recrystallized from acetonitrile to give 1.6 g of the title compound as white prisms.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([S:34]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 342.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride (Aldrich) (0.063 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0714 g, 34%) as a yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1>>[Br:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:17][C:5](=[O:7])[CH3:6])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(N)c1ccc(Br)nc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(C)c1ccc(Br)nc1

Procedure:
Reagents: acetic anhydride and 1-(6-bromo-pyridin-3-yl)-ethylamine
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]2=[CH:5][N:4]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[NH2:26][CH:23]1[CH2:22][CH2:21][CH:20]([CH2:19][N:9]2[C:7]3=[N:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]3[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:10]2)[CH2:25][CH2:24]1.[C:36]([OH:38])([C:35]([F:40])([F:39])[F:34])=[O:37]
Reactant: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(N)CC3)c2n1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.064 g, 0.14 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.6 mL) at ambient temperature. After stirring for 2 h, the solvent was evaporated. The residue was purified by preparative HPLC to provide 1-((4-aminocyclohexyl)methyl)-N-methyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (UNC00000478A) as a yellow solid (TFA salt) (0.063 g, 95%). MS m/z 351.3 [M+H]+.