Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[CH:38][O:37][N:36]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[O:37]1[CH:38]=[N:39][C:35]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][N:11]([C@@H:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:19][OH:20])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:30][CH:31]=2)=[N:36]1
Reactant: BrCc1ccc(-c2ncon2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@@H]1CO)c1ccc(Cl)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCCC[C@@H]1CO
Yield: 6.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (119 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (99 mg, 0.41 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 40) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (12 mg, 7%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.05 (2H, d, J=8.56 Hz), 7.68-7.70 (1H, m), 7.66-7.68 (1H, m), 7.47 (2H, d, J=8.56 Hz), 7.43-7.45 (1H, m), 7.41-7.43 (1H, m), 4.67 (1H, d, J=16.62 Hz), 4.44 (1H, d, J=16.62 Hz), 4.23-4.35 (1H, m), 3.60 (1H, dd, J=11.33, 8.56 Hz), 3.35 (1H, dd, J=11.46, 5.41 Hz), 1.99 (1H, br. s.), 1.38-1.81 (6H, m), 1.09-1.32 (5H, LC/MS R.T.=3.09 min; [M+H]+=476.23.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]([CH3:38])[CH3:37])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: CC(C)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(C)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 11 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(isopropylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 9, preparation of starting materials) to give the title compound in 11% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 3.81 (t, 2H), 3.93-4.01 (m, 1H), 4.14-4.18 (m, 2H), 4.35-4.47 (m, 3H), 5.31 (s, 2H), 7.21-7.29 (m, 2H), 7.32-7.40 (m, 2H), 7.56-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 8.04 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 10.02 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[C:14][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[CH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C#C[Si](C)(C)C)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CC(C)(C)COCc1ccccc1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5° C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20° C. exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25° C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25° C. is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. 1H NMR (400 MHz, C6D6) δ 7.28 (d, 2H, J=7.4 Hz), 7.18 (t, 2H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.35 (s, 2H), 3.24 (s, 2H), 1.91 (s, 1H), 1.25 (s, 6H).
Reaction SMILES: [C:1]([CH2:3][S:4]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[NH:15][C:16](=O)[CH3:17])(=[O:6])=[O:5])#[N:2].[OH-].[Na+]>>[CH3:17][C:16]1[NH:15][C:8]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=2[S:4](=[O:6])(=[O:5])[C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(NC(C)=O)c(S(=O)(=O)CC#N)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)S(=O)(=O)C(C#N)=C(C)N2

Procedure:
Treatment of N-(2-cyanomethylsulfonyl-4-methoxyphenyl)acetamide with aqueous sodium hydroxide by a procedure similar to the procedure described in EXAMPLE 1 c) gave the title compound; mp 307-308° C. (from methanol), 1H-NMR (DMSO-d6), δ (ppm): 11.89 (br s, 1H, NH), 7.51-7.27 (m, 3H, Ar—H), 3.86 (s, 3H, CH3O), 2.44 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[CH:20][CH:19]=1)=[O:34])[CH3:9]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: O=C(O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
{3-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.100 g, 0.21 mmol), 4-bromobenzoic acid (0.042 g, 0.21 mmol), and potassium carbonate (0.073 g, 0.53 mmol) were combined in DME (10 mL) and water (5 mL). The solution was purged with N2 for 10 minutes, and then (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.014 g, 0.02 mmol) was added. The reaction was stirred at 70° C. overnight, until no starting material was seen by analytical LCMS. The mixture was cooled to room temperature and quenched with water. The mixture was extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH:24]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:51]=[CH:50][CH:49]=[CH:48][C:29]=1[CH2:30][NH:31][CH2:32][C:33](=[O:47])[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Na].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][N:31]([CH2:30][C:29]1[CH:48]=[CH:49][CH:50]=[CH:51][C:28]=1[O:27][CH3:26])[CH2:32][C:33](=[O:47])[CH:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CNCC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Under nitrogen atmosphere, to a solution of (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (2.64 g) and 3-(2-methoxybenzylamino)-1,1-diphenylpropan-2-one (3.66 g) in dichloromethane (30 ml) was added acetic acid (0.607 ml) and sodium tritacetoxyborohydride (4.82 g) under ice-cooling, and then it was stirred at room temperature for 3 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate (100 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (82 g) using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.24 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][N:12]1[CH:16]=[C:15](I)[CH:14]=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][N:12]1[CH:16]=[C:15]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)[CH:14]=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(COCc1ccccc1)Cn1cc(I)cn1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CC(F)(F)COCc3ccccc3)c2)OC1(C)C
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 736.5 %

Procedure:
A solution of 1-(3-benzyloxy-2,2-difluoropropyl)-4-iodo-1H-pyrazole (Compound 59F, 1.8 g, 4.7 mmol) in THF (40 mL) was cooled to −78° C., treated with iPrMgCl (4.75 mL, 9.5 mmol, 2M) and the temperature was raised to −40° C. After 20 min stirring at −40° C., reaction mixture was cooled to −78° C. and treated with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.091 mL, 0.56 mmol). The reaction mixture was allowed to warm to RT, treated with sat. aq. ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 1.56 g (89%) of desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 5H), 4.64-4.59 (m, 4H), 3.56 (t, J=12 Hz, 2H), 1.26 (s, 12H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:18])=[C:11]2[C:16]=1C(O)[CH2:14][CH2:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:18][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:2](=[O:3])[O:4][CH:5]3[CH2:14][CH2:13][CH2:12][C:11]=1[C:16]=23
Reactant: Nc1ccc(Br)c2c1C(O)CCC2
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Br)c3c2C(CCC3)O1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To prepare this compound, DMAP (6 mg, 0.043 mmol) and methyl chloroformate (27 mg, 0.29 mmol) were added to a solution of 8-amino-5-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (70 mg, 0.29 mol) in 1.5 mL pyridine at −10° C. The reaction was stirred for 0.5 hour, then extracted with ethyl acetate and water. The organic layer was washed sequentially with 2% aqueous HCl solution, water, and brine an then was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1.5 ml dry DMF and then potassium carbonate (80 mg, 0.58 mmol) was added. That suspension was heated at 100° C. for 2 hours, and was extracted with EtOAc and water. The organic layer from that extraction was washed sequentially with 2% aqueous HCl, water, and brine and was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 6-bromo-7,8,9,9a-tetrahydro-3H-naptho[1,8-de][1,3]oxazine-2-one. 1H NMR (500 MHz, CDCl3) δ 8.55 (broad s, 1H), 7.41 (d, J=8.2, 1H), 6.60 (d, J=8.4, 1H), 5.3-5.4 (m, 1H), 2.90 (dd, J=17.8, 5.0, 1H), 2.55-2.65 (m, 1H), 2.40-2.50 (m, 1H), 2.15-2.25 (m, 1H), 1.70-1.90 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:3]1[C:4]([Br:10])=[C:5]([Br:9])[C:6]([C:7]#[N:8])=[C:2]1[Br:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(Cc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a stirred mixture of 1.00 g (3.04 mmol) of 2,4,5-tribromopyrrole-3-carbonitrile and 0.68 g (6.1 mmol) of potassium t-butoxide in 30 mL of dry THF under a nitrogen atmosphere is added 1.10 mL of benzyl bromide. The mixture is heated to reflux and stirred overnight. After dilution with 100 mL of water and 150 mL of ethyl acetate, the organic mixture is separated and washed with salt solution, dried over magnesium sulfate, and concentrated in vacuo to leave 2.34 g of orange oil. The oil is triturated under a mixture of 5:1 hexane/ether to give a white solid collected by filtration; 0.81 g, mp 100°-103° C. The filtrate yields a second crop; 0.11 g, mp 100°-103° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1.[OH-].[K+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OC1CCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (CAN 29241-62-1; 3 g, 12.7 mmol) was dissolved in DMSO (30 mL); cyclobutanol (1.19 g, 1.29 ml, 16.5 mmol) and potassium hydroxide (powder) (2.14 g, 38.1 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. More cyclobutanol (0.5 mL) and KOH (1 g) was added and the reaction mixture was stirred at room temperature for another 2 days. Water (30 mL) was added and the mixture was acidified (cooling) with 5 mL 37% HCl in water (pH=2). The suspension was filtered and washed with water. The cake was dried in vacuo to obtain the title compound (3.1 g, 88.7%) as white solid; MS (ESI) 270.2 (M−H)−.
Reaction SMILES: CO[C:3]1[C:4](=O)[C:5](=[O:9])[C:6]=1[O:7]C.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:3]2[C:6](=[O:7])[C:5](=[O:9])[C:4]=2[N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCN1CCNCC1
Solvent: CCO
Product: CCN1CCN(c2c(N3CCN(CC)CC3)c(=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, refluxing solution of 0.6 gram of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 20 ml. of absolute ethanol is added dropwise a solution of 1.8 grams of 1-ethylpiperazine and 20 ml. of absolute ethanol. The resulting solution is stirred overnight under a nitrogen atmosphere at room temperature. The reaction mixture is then concentrated under reduced pressure, cooled, and the resultant crystals filtered and dried to afford, as a white solid, 3,4-bis(4-ethyl-1-piperazinyl)-3-cyclobutene-1,2-dione. This compound melts at about 164°-166° C., and is represented by the following structural formula. ##STR6##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1ccnc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
3-(2-Bromo-pyridin-4-yl)-acrylic acid (5.0 g, 21.9 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (2.4 g, 24.1 mmol), HOBT (5.9 g, 43.9 mmol), EDAC (8.4 g, 43.9 mmol) and triethylamine (9.1 mL, 65.8 mmol) were added to N,N-dimethylformamide (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.6 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[N:5]([CH2:6][C:7](OCC)=[O:8])[N:4]([CH:12]2[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)[C:3]1=[O:22].[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1CO.O>[CH3:1][C:2]1([CH3:23])[N:5]([CH2:6][CH2:7][OH:8])[N:4]([CH:12]2[CH:13]3[CH2:14][CH:15]4[CH2:16][CH:17]([CH2:18][CH:19]2[CH2:20]4)[CH2:21]3)[C:3]1=[O:22]
Reactant: CCOC(=O)CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: OCC1CCCO1
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCO
Reaction time: 1 h
Yield: 124.6 %

Procedure:
Under an argon atmosphere, a mixed solution of ethyl [4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]acetate (150 mg, 0.470 mmol) in tetrahydrofuran-methanol-water (10:1:1, 4 mL) was added with lithium borohydride (80.8 mg, 3.76 mmol) at room temperature, and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with a saturated aqueous solution of ammonium chloride, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=2:1), and 4,4-dimethyl-1-(2-hydroxyethyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (163 mg, 78.7%) was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](=[S:8])[NH2:7])[N:3]=[CH:2]1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[NH:1]1[CH:5]=[C:4]([C:6]2[S:8][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=2)[N:3]=[CH:2]1
Reactant: NC(=S)c1c[nH]cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2c[nH]cn2)n1

Procedure:
1H-Imidazole-4-carbothioamide (1 g, 7.86 mmol) and ethyl bromopyruvate (0.987 ml, 7.86 mmol) were dissolved in ethanol (20 ml). The resulting mixture was refluxed for 1.5 hours. The mixture was kept at 0° C. for an hour and filtered. Both the filtered precipitate and filtrate contained the product and both were evaporated. The filtrate was triturated twice from ethanol. In the end all precipitates were combined. LC-MS: [M+1]=224.25.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:16][CH:15]=1)(=[O:27])=[O:26]
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 4-(pyridine-3-carbonyl)-benzyl alcohol (85 mg, 0.399 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.056 mL, 0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (115 mg, 100%). GC-MS m/z: 291 (M4).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[I-].[K+]>CN(C)C=O.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:2]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1
Reactant: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nn2c(-c3ncc[nH]3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Yield: 33.4 %

Procedure:
Three 5 mL microwave vials were charged 7-chloro-2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl) pyrazolo[1,5-a]pyrimidine (50 mg, 0.127 mmol), imidazole (130 mg, 1.909 mmol), potassium iodide (42.3 mg, 0.255 mmol), copper(I) iodide (48.5 mg, 0.255 mmol) and palladium(II) acetate (8.57 mg, 0.038 mmol) in N,N-Dimethylformamide (DMF) (0.75 mL). The reaction was purged with nitrogen, sonicated for 3 min and subjected to microwave irradiation at 185° C. for 10 min. The reactions were combined and filtered through a pad of celite. The filter pad was washed with DCM (10 mL×4), and the filtrate was concentrated. Two products with same molecular weight were detected. The residue was purified by reversed phase HPLC (10˜90% CH3CN (0.1% TFA)/Water (0.1% TFA)) to give the product (18 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 3.68 (m, 4H) 3.70-3.76 (m, 4H) 4.39 (s, 2H) 7.17-7.55 (m, 7H) 7.77 (d, J=8.08 Hz, 1H) 7.86-7.94 (m, 1H) 8.45-8.53 (m, 1H) 12.95 (s, 1H); LC/MS: MS (ES+) m/e 425.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[NH:21]([C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1)[NH2:22]
Reactant: COc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nc(NN)nc(-c3ccccc3)c2c1

Procedure:
To a solution of 9.7 g of 2-chloro-4-phenyl-6-methoxyquinazoline in 300 ml of ethanol were added 15 ml of hydrazine hydrate and 8 ml of glacial acetic acid and the mixture was refluxed for 5 hours. After the precipitate was filtered off, the filtrate was concentrated in vacuo to give crystals. The crystals were collected by filtration, washed with ethanol, and dried to give 7.8 g of 2-hydrazino-4-phenyl-6-methoxyquinazoline, a part of which was recrystallized from ethanol to give yellow scales, m.p. 151° - 152° C.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[C:16]1([CH3:24])[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:22]([C:17]1[C:16]([CH3:24])=[CH:21][CH:20]=[CH:19][CH:18]=1)=[NH:23])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1C#N
Reactant: CC(C)NC(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1C(=N)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of MeMgBr in ether (12.9 mL, 3.0 M, 38.7 mmol) was added to a solution of diisopropylamine (3.91 g, 38.7 mmol) in toluene (60 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and tolunitrile (4.53 g, 38.7 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h subsequently. The mixture was quenched with water (100 mL). The organic phase was separated from the aqueous phase and the latter was extracted with diethylether (150 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure giving a sticky residue. This residue was triturated with ligroin giving 4.40 g (52%) pure product.