Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Br[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.[Cl-].[Na+].O.O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=2)[CH2:4][O:3]1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC1(C)OCC(CO)O1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2cccc(C(=O)O)n2)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Solketal 58 (23.5 g, 178 mmol) was added to a suspension of NaH (7.1 g, 178 mmol, 60 wt % dispersion in mineral oil) in THF (400 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 1 h and 6-bromopicolinic acid 57 (12 g, 59.4 mmol) was added. The reaction mixture was heated at reflux for 1.5 h. After cooling to room temperature, H2O (50 mL) was added and the pH was adjusted to 3 by the addition of 3 N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The crude product was recrystallized from pentane/EtOAc to give 59 (10 g, 66% yield). The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h. The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([F:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CC(F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CC(F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. Whites solid. (64%). MS: m/e=608(M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([CH:30]1[CH2:32][NH:31]1)#[N:29]>O1CCCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[CH2:5][CH2:6][C:7]([N:31]1[CH2:32][CH:30]1[C:28]#[N:29])=[O:9])[CH3:12]
Reactant: N#CC1CN1
Reactant: CCN(CC)C(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCC(=O)N1CC1C#N
Reaction time: 2 h

Procedure:
3.46 g. N,N-Diethylsuccinic acid monoamide and 4.3 g. dicyclohexylcarbodiimide are dissolved in 35 ml. tetrahydrofuran and 1.36 g. 2-cyanoaziridine is added to the resultant suspension. After subsequently stirring for 2 hours in an ice bath and leaving to stand overnight at ambient temperature, the dicyclohexylurea is separated off and the filtrate evaporated. There are thus obtained 2.9 g. 1-(N,N-diethylsuccinamoyl)-2-cyanoaziridine in the form of an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:16]2[N:11]3[N:10]=[C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=2)=[CH:22][CH:21]=1)#[N:24]
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(-c4ccc(C#N)cc4)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C#N)cc2)n2nc(C3(C(=O)O)CC3)nc12

Procedure:
1-[5-(4-Cyano-phenyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-cyclopropanecarboxylic acid ethyl ester (0.39 g, 1.08 mmol) was suspended in 1,4-dioxan (10 mL) and aq. LiOH (68 mg, 1.6 mmol in 1.6 mL H2O) and stirred at it for 17 h. The mixture was concentrated in vacuo. The crude was suspended in H2O (3 mL) and 4N HCl (0.6 mL) was added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. This afforded the title compound as a slightly coloured solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)=[O:30]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:33][CH:34]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C1CCCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C1CCCN(C(=O)c2ccc(NC(=O)Cc3ccccc3Cl)cc2)c2ccccc21
Yield: 99.6 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the mixture was added 66.5 g of 4-[2-(2-chloro-phenyl)acetylamino]benzoyl chloride with ice-cooling and stirring. The mixture was stirred overnight at room temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography and then recrystallized from methanol to obtain 99.3 g of 5-dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.FC1C=CC(OC2C=CC(C(=O)C)=CC=2)=CC=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: CC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
1H NMR (DMSO-d6): δ 15.0 (bs, 2H), 9.25 (s, 1H), 8.18 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H); mp 230-232° C. The intermediate 1-[4-(4-trifluoromethylphenoxy)phenyl]ethanone was prepared from 4-hydroxyacetophenone and 4-fluorobenzotrifluoride using the method described for the synthesis of 1-[4-(4-fluorophenoxy)phenyl]ethanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](OC)=[O:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc(S(=O)(=O)C2CCN(CCc3ccc(F)cc3F)CC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(CO)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
1-(2-(2,4-Difluorophenyl)ethyl]-4-(4-methoxycarbonylphenylsulphonyl)piperidine (0.6 g, 1.42 mmol) was dissolved in anhydrous CH2Cl2 (15 ml) and stirred under nitrogen at −78° C. DIBAL-H (1M in THF, 4.25 ml, 4.25 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min, allowed to warm up to room temperature and stirred for 1 h. Crushed Na2SO4.10H2O (5 eq.) was added and the mixture left at room temperature overnight. Inorganic solid was filtered off and washed with CH2Cl2 and EtOAc. The organic filtrate was concentrated to give a beige solid. δH (360 MHz, CDCl3) 1.64-1.77 (2H, m), 1.94-2.06 (4H, m), 2.47-2.55 (2H, m), 2.70-2.76 (2H, m), 2.83-2.94 (2H, m), 3.02-3.08 (2H, m), 4.82 (2H, s), 6.71-6.82 (2H, m), 7.06-7.14 (1H, m), 7.55 (2H, d, 8 Hz), 7.85 (2H, d, 8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[S:22]1(=[O:30])[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH:28]=O>>[O:21]=[S:22]1(=[O:30])[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=CCN1CCCS1(=O)=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCS1(=O)=O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and (1,1-dioxido-2-isothiazolidinyl)acetaldehyde employing methods similar to those described in Example 265 and was obtained as a brownish oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1 H), 7.89 (br, 1 H), 7.14 (dd, J=8.4, 5.4 Hz, 2 H), 6.98 (t, J=8.6 Hz, 2 H), 6.92 (s, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 3.91 (s, 2 H), 3.41 (m, 2 H), 3.29-3.24 (m, 4 H), 3.13 (t, J=7.7 Hz, 2 H), 2.31 (m, 2 H), 1.41 (t, J=7.0 Hz, 3 H); MS m/z 422 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[C:13]([CH:19]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].[Cl-].[NH4+]>ClCCl.O1CCCC1>[Cl:11][C:12]1[C:13]([CH:19]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=2)(=[O:29])=[O:30])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:14][C:15]([NH:18][S:39]([CH3:38])(=[O:41])=[O:40])=[N:16][CH:17]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cn2)c(Cl)cn1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cn2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1M, 0.705 ml, 0.71 mmol) of sodium bis(trimethylsilyl)amide was added to a tetrahydrofuran (4 ml) solution of [5-chloro-4-[(5-chloropyridin-2-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (92 mg, 0.21 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. To the reaction mixture was added methanesulfonyl chloride (0.055 ml, 0.71 mmol). At the same temperature, the resulting mixture was stirred for 2 hours. The temperature of the reaction mixture was then raised to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride. The product thus obtained was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:ethyl acetate=19:1 eluate was concentrated under reduced pressure. The residue thus obtained was washed with an ethanol/hexane mixed solvent and then, collected by filtration to give the title compound (27 mg, 0.053 mmol, 25%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]OS(CC1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[I:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: Cc1ccc(CS(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(C#N)ccc1I
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2.0 g (8.16 mmol) of 3-hydroxy-4-iodobenzonitrile was dissolved in 20 ml of DMF. 5.8 g (16.3 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine and 3.37 g (24.4 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 50° C. for 16 hours. 1.5 g (4.2 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine was added to the obtained mixture, and they were stirred at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>O1CCOCC1.CCOCC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:20][CH2:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCNc1ccc(C#N)cn1
Reaction time: 48 h

Procedure:
A solution of 6-chloronicotinonitrile (1.0 g, 7.2 mmol), 4-aminobutyric acid tert-butyl ester hydrochloride (2.12 g, 10.8 mmol, Sennchem 09600) and DIEA (4.9 mL, 28.9 mmol) in anhydrous dioxane (20 mL) was heated at 80° C. After 48 hours, an additional amount of 4-aminobutyric acid tert-butyl ester hydrochloride (0.55 g, 2.80 mmol) was added. After 24 additional hours at 80° C., the reaction mixture was diluted with Et2O (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. After purification by flash chromatography (silica, EtOAc/cHex), the title compound was obtained as a beige powder. HPLC (Method A), Rt: 3.3 min (purity: 91%). UPLC/MS, M+(ESI): 262.1, M−(ESI): 260.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (d, J=2.2 Hz, 1H), 7.63 (m, 2H), 6.52 (d, J=8.9 Hz, 1H), 3.29 (m, 2H), 2.26 (t, J=7.4 Hz, 2H), 1.73 (tt, J=7.4, 7.0 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:23])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC(C)CCO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH:2]([NH:31][CH3:26])[CH3:23])[S:6]1(=[O:21])=[O:22]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: CC(Br)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: CC(Br)CCO
Product: CNC(C)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-(3-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromobutan-1-ol giving 0.27 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]([OH:23])[C@@H:4]([C:20]([OH:22])=[O:21])[N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].F[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]>CN(C)C=O>[CH2:6]([N:5]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:4]([CH:3]([O:23][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37])[C:2]([F:24])([F:25])[F:1])[C:20]([OH:22])=[O:21])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)[C@H]([C@H](O)C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
To 15.4 g (43.6 mmol) DL-4,4,4-trifluoro-N,N-bis(phenylmethyl)-threonine in 60 ml dimethylformamide were added in portions 4.03 g (92.4 mmol) sodium hydride (55%) at 0° C. The suspension was stirred for 2 hours and then 10.5 ml (95.9 mmol) 2,5-difluoro-nitrobenzene were added. After stirring overnight at 0° C. the mixture was poured on ice/water. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:1 (and adding 30% methanol after the first five 250 ml fractions) yielded 11.7 g (55%) racemic (2S,3S and 2R,3R)-2-dibenzylamino-4,4,4-trifluoro-3-(4-fluoro-2-nitro-phenoxy)-butyric acid acid as yellow oil, MS m/e (%): 491.1 (M−H+, 100).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1)=[CH:3][C:4]#[N:5].C(N)(=[S:17])C.Cl>O1CCOCC1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1)=[CH:3][C:4]([NH2:5])=[S:17]
Reactant: CC(N)=S
Reactant: COc1ccc(C(N)=CC#N)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(N)=CC(N)=S)cc1F
Reaction time: 6 h
Yield: 98.5 %

Procedure:
Add dioxane (65 mL) to 3-amino-3-(3-fluoro-4-methoxyphenyl)acrylonitrile (25.0 g, 130 mmol) and thioacetamide (19.5 g, 260 mmol); then add 4 N HCl in dioxane (650 mL, 2,600 mmol) and allow the reaction to stir 4-8 h until complete by TLC. Evaporate the reaction mixture to dryness; then add dioxane (200 mL); add slowly TEA (dried with K2CO3, 1000 mL); and then add satd K2CO3 (1000 mL) and extract with EtOAc (2000 mL). Dry the organic phase (K2CO3) and evaporate to afford 3-amino-3-(3-fluoro-4-methoxyphenyl)thioacrylamide. Yield: 98.5%. ES-MS: m/e 227.0 (m+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[N:11]1([C:14]([C:16]2[CH:17]=[C:18]([F:24])[C:19]([F:23])=[C:20]([F:22])[CH:21]=2)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(c1cc(F)c(F)c(F)c1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cc(F)c(F)c(F)c1)N1CCNCC1
Reaction time: 6 h
Yield: 102.4 %

Procedure:
10% Pd/C (80 mg) was added to a stirred solution of (4-benzyl-piperazin-1-yl)-(3,4,5-trifluoro-phenyl)-methanone (800 mg, 2.4 mmol) in methanol (20 mL) and the mixture was stirred under an atmosphere of hydrogen for 6 hours. The mixture was then filtered over celite and the filtrate concentrated to afford 600 mg (95%) of piperazin-1-yl-(3,4,5-trifluoro-phenyl)-methanone. LCMS: 245.09 (M+1)+, 92.4%
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:21][CH2:22][O-:23].[Na+]>C(O)C>[CH2:22]([O:23][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1)[CH3:21]
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1c(C)nn(C)c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn2c1c(OCC)nc1c(C)nn(C)c12

Procedure:
5.86 gms. of 5-chloro-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, in ethanol is refluxed with 20 mM of sodium ethylate for 30 minutes. Upon cooling, the product, 5-ethoxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, crystallizes in the form of white needles. The product is recrystallized from n-propanol, yield 4.2 gms, m.p. 116°-118°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: COc1c(Br)cc(C(=O)O)c(O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OC)c(Cl)c1O
Temperature: 13 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoic acid (10.4 g) in dichloromethane (150 mL) were added a solution of oxalyl chloride (7.05 g) in dichloromethane (10 mL) and DMF (3 drops) under ice-cooling, and the mixture was stirred at 13° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (50 mL). This solution was added dropwise to a solution of triethylamine (1.20 g) in methanol (150 mL) under ice-cooling, and the mixture was stirred at 13° C. for 16 hr. The solvent was evaporated under reduced pressure from the reaction mixture, and the residue was diluted with ethyl acetate and water. 1N Hydrochloric acid was added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.9 g).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([N:8]=[C:9]=[O:10])[CH2:4][CH2:3]1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[NH2:36][C:22]1[N:23]=[C:24]([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:9]([NH:8][CH:5]4[CH2:4][CH2:3][C:2]([F:11])([F:1])[CH2:7][CH2:6]4)=[O:10])[CH2:33]3)=[CH:28][CH:27]=2)[CH:25]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)[N:21]=1
Reactant: O=C=NC1CCC(F)(F)CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCC(F)(F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1,1-difluoro-4-isocyanatocyclohexane and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=486.2.