Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].O1CCCC1.CN(C)C=O.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:23][CH:22]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
To a solution of pyrrolidin-2-one (15 g) in a mixed solvent of tetrahydrofuran/N,N-dimethylformamide (1/1, 100 mL) was added sodium hydride (60% in mineral oil, 8.5 g) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 min. p-Methoxybenzyl chloride (33 g) was added thereto at the same temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28 g).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[NH:4][C:5](=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[Br:19]Br>C(=S)=S>[Br:19][C:11]1[CH:12]=[C:6]([C:5]([NH:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[CH3:1])=[O:13])[C:7]([OH:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)c1ccccc1O
Reactant: BrBr
Solvent: S=C=S
Product: Cc1cc(Cl)ccc1NC(=O)c1cc(Br)ccc1O

Procedure:
135 g. of 2'-methyl-4'-chlorosalicylanilide is dissolved in 2,500 cc. of carbon disulfide with heating. Said solution is then rapidly cooled to form a finely dispersed suspension of 2'-methyl-4'-chlorosalicylanilide. A solution of 80 cc. of bromine in 250 cc. of carbon disulfide is added, drop by drop, at room temperature to said suspension with agitation. Said reaction mixture is allowed to stand over night. Thereby 210 g. of 5-bromo-2'-methyl-4'-chloro salicylanilide are obtained. Resulting compound (compound No. 1) forms colorless prism-shaped crystals having properties shown in Table 1 by recrystallizing from ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=O)=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCOC(=O)c1[nH]c(C=O)c2c1CCCC2
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c2c1CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-formyl-4,5,6, 7-tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.OO.S(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: O=S([O-])O
Reactant: Fc1cccnc1Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: [O-][n+]1cccc(F)c1Cl
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro-3-fluoropyridine (11.8 g, 0.10 mol) and 11.4 ml of 30% hydrogen peroxide in acetic acid, 70 ml, is stirred at 75° C. for 4 hours. Additional 30% hydrogen peroxide, three 5 ml portions, is added over 24 hours followed by 3 ml of a saturated sodium bisulfite solution. The reaction mixture is concentrated to approximately 25 ml under reduced pressure at 55°-60° C., diluted with water, 30 ml, and made basic with potassium carbonate. The crude N-oxide is extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography over silica gel and elution with 2% MeOH- 98% CHCl3 (v/v) mixture gives 2-chloro-3-fluoropyridine N-oxide as a liquid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:33])[CH:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:19][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[C:25]([F:33])[CH:24]=2)[CH3:21])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (2.0 g, 4.19 mmol) in CH3CN (28 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.85 ml, 6.3 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (25 ml) and zinc dust (800 mg) was added portion wise over 3 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4, concentrated under vacuo to afford 0.90 g (44%) of the tile compound as a light brown oil. ES-MS m/e: 387.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH2:24])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1cccc2c1oc1ccccc12
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1cccc2c1oc1ccccc12

Procedure:
2-chloro-3-nitropyridine (4.39 g, 27.7 mmol), dibenzo[b,d]furan-4-amine (5.58 g, 30.5 mmol), triethylamine (4.3 mL, 30.9 mmol), and butanol (90 mL) were mixed in a 250 mL round bottom flask. The reaction mixture was refluxed overnight under nitrogen. The solvent was evaporated, leaving an orange solid which was dried under vacuum. The solid was taken up in ethyl acetate, water was added and the layers were separated. The organic layer with washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified on by column chromatography eluting with 10% ethyl acetate/hexanes followed by ethyl acetate (4.6 g, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CC(N2CCNCC2)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CCC4)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclobutylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.71 (m, 2H) 1.76-1.90 (m, 2H) 1.90-2.07 (m, 2H) 2.37 (br. s., 4H) 2.42 (s, 3H) 2.83 (quin, J=7.71 Hz, 1H) 3.44 (d, J=7.07 Hz, 2H) 3.64 (br. s., 2H) 7.63 (dd, J=7.96, 1.64 Hz, 1H) 7.69 (s, 1H) 7.84 (d, J=8.08 Hz, 1H) 8.03 (dd, J=8.59, 2.27 Hz, 1H) 8.11 (s, 1H) 8.40 (d, J=8.59 Hz, 1H) 8.52 (dd, J=2.27, 0.76 Hz, 1H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([F:12])[S:7]1(=[O:14])=[O:13].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([F:36])([F:12])[S:7]1(=[O:14])=[O:13]
Reactant: COc1ccc(CN2CCCC(F)S2(=O)=O)c(OC)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(F)(F)S2(=O)=O)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6-fluoro-1,2-thiazinane-1,1-dioxide (0.500 g, 1.8 mmol) in anhydrous tetrahydrofuran (30 mL), cooled to −78° C., was slowly added 2.5 N n-butyl lithium in hexanes (1.262 mL, 3.2 mmol). The solution was stirred at −78° C. for 1 hr, a solution of N-fluorobenzene sulfonimide (1.243 g, 3.9 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added over 10 mins, and the mixture stirred at −78° C. for 3 hrs and at room temperature for 3 hrs. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (15-60% ethyl acetate/hexanes) to give a yellow oil (0.09 g). 1H NMR (CDCl3, 300 MHz) δ 7.25-7.21 (d, 1H, J=8.4 Hz), 6.50-6.47 (dd, 1H, J=2.4, 8.4 Hz), 6.45-6.44 (d, 1H, J=2.4 Hz), 4.43 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.38-3.37 (t, 2H, J=5.1 Hz), 2.58-2.45 (m, 2H), 2.00-1.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(F)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-fluorophenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.O[Li].O>C1COCC1.O>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Yield: 94 %

Procedure:
A solution of compound 15d (TFA salt, 500 mg, 1.15 mmol), and LiOH.H2O (132.7 mg, 3.16 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. overnight. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 15e (330 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 306.0.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])[O:3]1.C[O-].[Na+]>CO>[CH3:2][O:3][C:4](=[O:21])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[O:11][CH3:12]
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OC
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A solution of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxy-acetamide (0.64 g, 2.07 mmol) in methanol (50 ml), was treated at 22° C. with 0.025 ml of a 4.6 M solution of sodium methoxide in methanol and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was then quenched by the addition of 1 ml of 1 N hydrochloric acid and the solvent was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent and crystallization of the residue from a mixture of ethyl acetate and hexane gave 0.559 g (95% yield) of the title ester as white prisms; mp 71° C. 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers, major: 3.69 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.80 (2H, s, NCH2), 6.45 (1H, s, CH), 7.03 (2H, m, aromatics), 7.30 (2H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 54.95; H, 4.73; N, 4.67.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30]N>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=358.1 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:8](OC)=[O:9].C(COC1C=CC=CC=1OCC(OC)=O)(OC)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([C:21]([O:23][CH3:24])=[O:22])[C:8]1=[O:9]
Reactant: COC(=O)COc1ccccc1OC(C(=O)OC)c1ccccn1
Agent: COC(=O)COc1ccccc1OCC(=O)OC
Product: COC(=O)C1Oc2ccccc2OC(c2ccccn2)C1=O

Procedure:
By following substantially the same procedure described in Example 108, Steps B and C, but substituting methyl 2-(2-pyridyl)-2-(2-carbomethoxymethoxyphenoxy)-acetate for the 1,2-bis-(carbomethoxymethoxy)benzene there is obtained sequentially 2-(2-pyridyl)-3-oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin and then 2-(2-pyridyl)-3-oxo-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:4][N:5]([CH3:12])[C:6]=1[CH:7](OC)[O:8]C.Cl.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:4][N:5]([CH3:12])[C:6]=1[CH:7]=[O:8]
Reactant: COC(OC)c1c(Br)c(-c2nccs2)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(-c2nccs2)c(Br)c1C=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
A solution of 2-[4-bromo-5-(dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]-1,3-thiazole (8d) (586 mg, 1.84 mmol) in tetrahydrofuran (15 mL) was treated with 1N hydrochloric acid (2.26 mL) and the mixture was stirred at 50° C. for 5 hours. The reaction was cooled to room temperature and then neutralized with 1N sodium hydroxide (2.26 mL). The resulting mixture was extracted with ethyl acetate (2×15 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo to provide 4-bromo-1-methyl-3-(1,3-thiazol-2-yl)-1H-pyrazole-5-carbaldehyde (8e) (480 mg, 1.76 mmol, 96%) which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:28][CH3:29])=[C:8]([CH:27]=1)[CH2:9][NH:10][C@H:11]1[C@H:15]([C:16]([O:18]C)=[O:17])[C@@H:14]([CH3:20])[NH:13][C@H:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2].[ClH:30]>>[ClH:30].[ClH:30].[C:16]([C@@H:15]1[C@@H:14]([CH3:20])[NH:13][C@@H:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:11]1[NH:10][CH2:9][C:8]1[CH:27]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=[CH:6][C:7]=1[O:28][CH3:29])([OH:18])=[O:17]
Reactant: COC(=O)[C@H]1[C@H](NCc2cc(C(C)C)ccc2OC)[C@H](c2ccccc2)N[C@@H]1C
Agent: Cl
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@H](C(=O)O)[C@@H](C)N[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of (2S*,3S*,4R*,5R*)-3-[N-(5-isopropyl-2-methoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (0.39 g, 0.98 mmol) in 6M HCl aq. solution (6.0 ml) was stirred and heated at a gentle reflux for 30 minutes, wherein precipitation of white solids initiated ca. 10 minutes after refluxing. The reaction mixture was cooled to room temperature, and then EtOH (4.0 ml) was added. After the mixture was ice-cooled for 30 minutes, the white precipitates were filtered off, washed with EtOH (×2), and dried in vacuo at a temperature between 40 and 50 C. for 2 days to afford title compound (0.43 g, 96%) as white needles. ##STR7## mp 159-164 C.: IRmax (nujol): 3400(s), 3200(s), 3130(s), 2370(s), 2300(br., s), 1735(s), 1710(s), 1585(s), 1510(s), 1260(s), 1143(s), 1017(s), 830(s), 770(s), 745(s), 702(s) cm-1 ; 1H-NMR δ (DMSO-d6): 7.907.73(m, 2H), 7.60-7.45(m, 3H), 7.25-7.13(m, 2H), 6.90(d, J=9.2 Hz, 1H), 5.35-5.15(m, 1H), 4.63-4,41(m, 1H), 4.20-4.01(m, 1H), 4.00-3.83(m, 1H), 3.803.15(m, 1H), 3.67(s, 3H), 2.79(sep, J=6.8 Hz, 1H), 2.55-2.42(m, 1H), 1.71(br.d, J=5.9 Hz, 3H), 1.15(d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH2:15]([N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1nc(Cl)nc2c(SC)ncnc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCCCN(CCCC)c1nc(N2CCNCC2)nc2c(SC)ncnc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-di-n-butylamino-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
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].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:32][O:33][C:34](=[O:45])[C@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[NH2:36]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:45])[C@H:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)[NH:36][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]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -70 °C
Reaction time: 16 h

Procedure:
21.7 g of t-butoxycarbonylvaline is dissolved in 200 ml of methylene chloride. 22.2 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 13.1 ml of isobutylchloroformate is then added. The reaction mixture is again cooled to -70° C. 23.2 g of tyrosine methyl ester hydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylvalyltyrosine methyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[N:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33](I)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:14]4[CH:13]=[C:12]5[C:17](=[CH:16][CH:15]=4)[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])=[N:9][N:10]=[CH:11]5)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1
Reactant: C[C@H]1COCCN1c1nncc2cc(B(O)O)ccc12
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NC3CC3)noc2c1-c1ccc2c(N3CCOC[C@@H]3C)nncc2c1
Temperature: 130 °C

Procedure:
A mixture of (S)-1-(3-methylmorpholino)phthalazin-6-ylboronic acid (0.11 g, 0.41 mmol), N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.016 mmol) in 1,4-dioxane (2.0 mL) and 2 N aqueous sodium carbonate (0.2 mL, 0.4 mmol) in a sealed glass tube was heated in a Personal Chemistry microwave at 130° C. for 20 min. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate: chloroform 80:20) afforded the titled compound as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:22][C:23](O)=[O:24])[CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([O:41][NH:42][C:23](=[O:24])[CH2:22][N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)N2CCOCC2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl) amino]acetic acid (0.33 grams, 0.89 mmol) in methylene chloride (10 mL) were added sequentially triethylamine (0.43 mL, 3.1 mmol), O-benzylhydroxylamine hydrochloride (0.15 grams, 0.94 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.43 grams, 0.97 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with 0.5N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using ethyl acetate to afford N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 0.33 grams (78%).