Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[CH2:25](OCC)C>CN(C)C=O>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH:13]([O:15][CH3:25])[CH2:14][N:10]1[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1CN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
At 0°-5° C., 1.2 g of a sodium hydride dispersion (80 %) are added in portions to a solution of 8.6 g of 4-hydroxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester in 90 ml of N,N-dimethylformamide. After stiffing for 30 minutes at 0°-5° C., a solution of 2.5 ml of methyl iodide in 10 ml of N,N-dimethylformamide is added dropwise thereto. Stirring is then continued for 3 hours at 0°-5° C. and then 500 ml of diethyl ether are added thereto. The organic phase is washed with water, dried over sodium sulfate and concentrated to yield 8.0 g of the desired product, 4-methoxy-pyrazolidine-N,N'-dicarboxylic acid di-tertbutyl ester, in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>CO>[CH:20]1([NH:23][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[N:10][NH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: NC1CC1
Solvent: CO
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(NC3CC3)n2)cc1
Yield: 26 %

Procedure:
This compound was synthesized by stirring 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 with excess cyclopropylamine in methanol at 50° C. for 12 hours. The product, N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, was obtained as a white solid in 26% yield, mp: 203-204° C.; Anal. Calc'd for C16H14FN5: C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23.58.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCC(C)=O
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 retool) was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 retool) and sodium triacetexyborohydride (13.8 g, 65 retool). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 retool) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) and the layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-aminooctane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][N:15]=1>C(#N)C>[O:2]=[C:1]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:20]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Carbonyldiimidazole (0.70 g, 4.33 mmol) was added to a solution of 2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]pyridine (1.15 g, 3.93 mmol) in acetonitrile (150 mL) at room temperature. After several hours, an additional amount of carbonyldiimidazole was added (0.81 g), and the reaction stirred overnight. The acetonitrile was evaporated in vacuo, the residue partitioned between water and chloroform, and the organic phase washed with saturated brine and dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1.2 to 2.5% methanol in methylene chloride gradient elution), which gave the title compound (1.09 g). 1H NMR (500 MHz, CDCl3) δ 9.39 (br s, 1H), 8.04 (dd, J=1, 5 Hz, 1H), 7.33 (dd, J=1, 8 Hz, 1H), 6.99 (dd, J=5, 8 Hz, 1H), 4.50 (m, 1H), 4.32 (br s, 2H), 2.86 (br s, 2H), 2.20 (m, 2H), 1.86 (d, J=12 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH2:26][CH3:27])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:28][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:28])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: C[Zn]C
Reactant: CCC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CCC(C)n1c(C)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 47 %

Procedure:
To a solution of 5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (20 mg, 0.046 mmol), Pd(dppf)Cl2, (3 mg, 8% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (230 μl, 1.0M in heptane solution). The mixture was heated to about 65° C. until in the sealed tube. MeOH was added dropwise and solvents were removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography to obtain 5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.45 (s, 2H); 4.55 (m, 1H); 3.87 (m, 4H); 3.80 (s, 4H); 2.69 (s, 3H); 2.43 (m, 1H); 2.02 (m, 1H); 1.71 (d, 3H); 0.86 (t, 3H). m/z: 369.22 [MH]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:30]Br)[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:32]#[N:33].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:30][C:32]#[N:33])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A mixture of 13.845 g (27.9 mM) of 2-bromomethyl-3-n-hexadecyloxypropyl benzoate n3 and 1.439 g (27.9 mM) of sodium cyanide (95% purity) in 150 ml of dimethylsulfoxide is heated at 90° C. for 1 hour. Theproduct is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water (four times) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain 12.42 g of the crude product of the titled compound n3'.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:16])[CH:9]=3)=[O:13])[CH2:22][C:21]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1
Yield: 80.3 %

Procedure:
4-Cyclohex-1-en-1-yl-3-methyl-benzoic acid of Step C (0.360 g, 1.66 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.337 g, 1.83 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from 1:1 ethyl acetate/petroleum ether afforded the title compound (0.510 g) as white crystals, m.p. 182–183° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:29]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(Cl)c4)nc3cc21

Procedure:
3-Chloro-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-chlorobenzoyl chloride (113 μl, 0.89 mmol). The title compound was obtained as light brown powder (105 mg, 29%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH3:9])[C@H:5]([OH:10])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C@@H:5]([OH:10])[C@H:6]([N:8]([CH3:9])[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN1C[C@@H](O)[C@H](NC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 17.0 g. (118 mmoles) of trans-1-ethyl-4-methylamino-3-pyrrolidinol in 180 ml of methylene chloride was mixed with 15 g of powdered anhydrous potassium carbonate and cooled to -5°. The mixture was kept at or below 0° C. while a solution of 22.0 g (118 mmoles) of p-nitrobenzoyl chloride in 100 ml of methylene chloride was added dropwise. After the mixture was stirred at ambient temperature for 18 hr, it was poured into 100 ml of water. The organic layer was separated, dried, and concentrated. The residue was crystallized from benzene to give 30 g (87%) of white crytals; m.p. 104°-108° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:21][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:22][C:23]#[N:24].[K+].BrBr>>[ClH:20].[ClH:1].[NH2:24][C:23]1[S:22][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH2:9][CH2:8][C:7]=3[S:21][C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: Nc1cc2c(s1)CCN(Cc1ccc(Cl)cc1)CC2
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: Nc1nc2sc3c(c2s1)CCN(Cc1ccc(Cl)cc1)CC3

Procedure:
This compound was prepared from 2-amino-6-(4-chlorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:10])/[CH:7]=[CH:8]/[CH3:9]>>[N:1]1([CH:8]([CH3:9])[CH2:7][CH2:6][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C/C=C/C#N
Product: CC(CCN)n1ccnc1

Procedure:
When the above procedure is used to react imidazole with crotononitrile, 3-(1H-imidazol-1-yl)butanamine is obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])(=[O:7])[CH3:6].[Br:23]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:19]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(Br)C(=O)O)cc1OC(C)=O
Temperature: 70 °C
Yield: 91.5 %

Procedure:
Thionyl chloride (60 ml) was added to a suspension of 3,4-diacetoxyphenylacetic acid (51.1 g) in carbon tetrachloride (105 ml) and the mixture was heated at 70° C. for one hour. After cooling to room temperature, N-bromosuccinimide (42.3 g), carbon tetrachloride (105 ml) and a little amount of hydrobromic acid were added, and the mixture was heated for an additional one hour. The resulting mixture was concentrated under reduced pressure, and the residue was redissolved in carbon tetrachloride. After filtering off the insoluble matters, the filtrate was dissolved in acetone (400 ml) and the pH of the solution was adjusted to 4.0 with saturated sodium bicarbonate aqueous solution under ice cooling. The resulting mixture was extracted with chloroform. The chloroform layer was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 61.4 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH:3]=1.[Li]CCCC.[CH3:19][Si:20]([CH3:23])(Cl)[Cl:21]>CCOCC.CCCCCC>[Cl:21][Si:20]([CH3:23])([CH3:19])[CH:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: Cc1cc2c(s1)Cc1ccccc1-2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc2c(s1)C([Si](C)(C)Cl)c1ccccc1-2
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Suspension of 1.86 g (0.01 mol) 2-methyl-8H-indeno[2,1-b]thiophene in 25 mL ether was treated dropwise with 6.25 mL (0.01 mol) of 1.6M BuLi in hexane at −40° C. under stirring. Then the mixture was stirred in additional 3 h. The resulting mixture was treated with 1.20 mL (0.01 mol) of dimethyldichlorosilane in 5 mL of ether at −70° C.; then it was allowed to warm to r.t. and stirred overnight. The solution was isolated and evaporated to give 2.47 g (89%) of the crude product that was used without further purification.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C1CCCC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of cyclopentanone (25.0 mL, 0.28 mol, 1.0 eq.) in toluene (100 mL), was added pyrrolidine (27.5 mL, 1.2 eq.). The reaction was equipped with a Dean-Stark and heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated to give the crude 1-cyclopent-1-enyl-pyrrolidine (45.8 g, >100%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:29])/[CH:16]=[CH:17]/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[N:22][CH:23]=2)[CH2:5][CH2:4]1.C1C=CC2[N:38]([OH:39])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:39][NH:38][C:26](=[O:28])/[CH:25]=[CH:24]/[C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[O:29])=[CH:23][N:22]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)nc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
(E)-3-(5-{(E)-3-[2-(4-Methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid hydrochloride (crude mixture from Step A, 400 mg) was suspended in DMF (10 ml). HOBT (240 mg, 1.78 mmol), EDC (340 mg, 1.78 mmol), TEA (0.371 ml, 2.67 mmol) and NH2OTHP (125 mg, 1.06 mmol) were added to the resulting slurry. The mixture was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (DCM/MeOH/NH4OH 95:5:0.2). The collected fractions were evaporated and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off and purified by preparative LC-MS to give 23.7 mg of (E)-N-hydroxy-3-(5-{(E)-3-[2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylamide as its trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[C:11](=[CH:15]N(C)C)[C:10](=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH2:23][C:22]1[N:24]=[CH:15][C:11]2[C:10](=[O:19])[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[N:21]=1
Reactant: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (0.8 g, 2.89 mmol) from stage 1, guanidine hydrochloride (551 mg, 5.77 mmol) and sodium carbonate (919 mg, 8.67 mmol) were stirred in ethanol (10 ml) at reflux for 4 h. The reaction mixture was cooled to ambient temperature and water (10 ml) was added to the flask. The resulting precipitate was recovered by filtration, washed with water (15 ml), heptane (15 ml) and air dried.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:16]=1)(=[O:14])[CH3:13]>ClCCl>[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[O:9])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Solvent: ClCCl
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(S(=O)c2ccc(F)cc2F)c1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of m-chloroperbenzoic acid (80%; 0.76 g) in dichloromethane (12 ml) was added dropwise to a stirred solution of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.2 g) in dichloromethane (12 ml) at 5° to 10° C. The solution was stirred for 1 hour at the same temperature, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. The oily residue (0.9 g) was crystallized from ethanol to give crystals of 4'-acetyl-2'-(2,4-difluorophenylsulfinyl)methanesulfonanilide (0.73 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:35][C:23]([F:22])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane (50 mL) solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.90 g, 19.4 mmol), 4-(dimethylamino)pyridine (0.23 g, 1.9 mmol), and triethylamine (8.0 mL, 57 mmol) was added 4-(trifluoromethyl)benzenesulfonyl chloride (4.75 g, 19.4 mmol). The reaction mixture was stirred for two hours at room temperature. The reaction was quenched with 1.0 M hydrochloric acid (100 mL) and extracted with diethyl ether (2×250 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. It was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=8.2 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 4.79 (tt, J=7.6, 3.6 Hz, 1H), 3.62 (ddd, J=13.6, 7.4, 4.0 Hz, 2H), 3.27 (ddd, J=13.8, 7.8, 3.9 Hz, 2H), 1.86-1.79 (m, 2H), 1.75-1.68 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:27])([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:21]#[N:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:27])[CH2:23][CH:24]1[CH2:26][CH2:25]1)#[N:22]
Reactant: CC(N)(C#N)CC1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C#N)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3-cyclopropyl-2-methyl-propionitrile (example 66a) as starting materials and isolated (376 mg, 67%); MS (ESI, m/z): 368.6 (M+H+).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.[CH3:24][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([OH:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)([CH3:27])[CH3:26]>O>[CH3:27][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([O:40][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:23])([F:22])[F:12])[CH:15]=2)=[O:39])=[C:32]([C:34]([F:35])([F:37])[F:36])[N:33]=1)([CH3:24])[CH3:26]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Yield: 161.3 %

Procedure:
A reaction vessel was charged with 50 ml of dimethylformamide, 2.6 g (18.8 mmol) of potassium carbonate, and 5.36 g (28 mmol) of m-trifluoromethyl benzyl chloride. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 4.03 g (17 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 36 hours. Then, the mixture was added to water and extracted four times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 11.25 g of a yellow oily solid material. This solid material was dissolved in ethyl ether, washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 10.8 g of a gold viscous oil. Then, 5.0 g of this oil was subjected to Kugelrohr distillation (83°-85° C. @ 0.5 mm Hg) to yield 1.38 g of a gold viscous oil which upon standing overnight formed an oily solid product identified in Table I.