Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:34]([CH3:37])[CH:35]=O)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:34]([CH3:37])[CH2:35][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CN2CCCC2)c1=O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.284 g) was added to N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 328e, 0.3 g), pyrrolidine (0.221 mL) and Hunig's Base (0.467 mL) in DCM (15 mL). The resulting suspension was stirred at 22° C. for 2 h. The reaction mixture was basified with satd sodium bicarbonate solution before extracting with DCM. The combined organic phases were concentrated in vacuo and the residue purified by preparative HPLC (Phenominex column using a 75-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (0.046 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.C([N:23](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:15])[NH:16][NH2:23])=[N:6]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncncc12
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
610 mg (approx. 1.92 mmol, purity 86%) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 10 ml of ethanol and cooled to 0° C. 777 mg (7.68 mmol) of triethylamine and 120 mg (1.920 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 590 mg (purity 89%, 95% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH2:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:23](=[O:25])[CH3:24])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-1H-imidazole-4-methanamine (0.20 g, 0.83 mmol) in THF (30 ml) was added triethylamine (0.079 g, 0.78 mmol) and acetyl chloride (0.082 mg, 1.0 mmol). The reaction mixture was stirred at rt for 12 h. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with H2O. The organic phase was dried (Na2SO4), concentrated and the obtained crude product was chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as an off-white crystalline material (0.17 g, 74%). Mp. 177-180° C. (MeOH/CH2Cl2), MS: m/e=284 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.BrC[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
1-methyl piperazine (805 μl, 7.6 mmol) was added to a solution of 4-(bromomethyl)benzonitrile (1 g, 5.1 mmol) and TEA (1.4 ml, 10.2 mmol) in DCM (15 ml) and the resulting mixture was stirred at room temperature for 24 hours. The solution was then diluted with DCM, washed with a 5% NaHCO3 solution and then with H2O. The organic phase was dried over Na2SO4 and evaporated to dryness to give 0.73 g of 4-(4-methyl-piperazin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: N[C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1Cl)=[O:3].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=[C:15]([C:6]3[CH:5]=[C:4]([CH2:2][OH:3])[CH:9]=[CH:8][CH:7]=3)[C:23]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: NC(=O)c1ccc(B(O)O)cc1Cl
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 48.9 %

Procedure:
A solution of (4-Aminocarbonyl-3-chlorophenyl)boronic acid (16 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA32 (9.7 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 331.1, found 331.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:1][C:2]3[C:3]([CH3:12])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][N:8]=[CH:7][CH:6]=4)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1nc2ccncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
3-Hydroxy-2-methyl-[1,6]naphthyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and 4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (597 mg, yield 56%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].O.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=O)=[CH:21][CH:20]=1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=[N:6][OH:7])=[CH:21][CH:20]=1
Reactant: NO
Reactant: O=CCc1ccc(COc2ccccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=CCc1ccc(COc2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of hydroxylamine sulfate (19.7 g) and water (250 mL) was added 1N aqueous sodium hydroxide (240 mL) at 0° C., which was stirred at the same temperature for 15 minutes. To the reaction mixture was then added dropwise a mixture of 4-(pyridin-2-yloxymethyl)-phenyl-acetaldehyde described in Manufacturing Example 2-3-3 (27.3 g) and methanol (250 mL), which was stirred overnight at room temperature. The precipitated solids were filtered to obtain the title compound (20.3 g) as an E/Z mixture.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.OC1C=CC(CC(=O)C)=CC=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel. After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:14][C:13]1=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:33])=[O:2])[C:13](=[O:32])[CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a stirred solution of (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (310 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (87 mg, 0.004 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (245 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1c2cc(Oc3ccc(Cl)cc3)ccc2CCN1Cc1cccnc1
Yield: 61.6 %

Procedure:
A mixture of 4.97 g of 3,4-dihydro-7-hydroxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, 4.50 g of 4-bromochlorobenzene, 3.88 g of cupric oxide, 5.39 g of potassium carbonate and 30 ml of pyridine was refluxed under heating for 20 hours. After finishing the reaction, the insoluble material was filtered, and the filtrate was concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 4.39 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.O=[C:20]1[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.[C-]#N.[Na+]>O.CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:20]3[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(NC3CCN([C@H](C)CCN)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 4-(4-amino-phenoxy)-benzoic acid methyl ester (see EXAMPLE 96) (300 mg, 1.2 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (225 mg, 1.4 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL). The mixture was stirred at room temperature for 20 minutes to afford 4-{4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-phenoxy}-benzoic acid methyl ester as a white solid (238 mg, 48% over 2 steps) following work-up and purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1I.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(I)cc(OC)c21
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: O
Solvent: Cc1ccccc1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(-c3ccccc3)cc(OC)c21
Temperature: 100 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
A mixture of 150 mg (0.283 mmol) 4-bromo-5-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole (example 30), 38 mg (0.312 mmol) phenylboronic acid, 60 mg (0.567 mmol) sodium carbonate and 16 mg (0.014 mmol) tetrakis(triphenylphosphine)palladium in 6 ml toluene/water (3:1) is stirred at 100° C. for 12 h. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 40 mg of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[S-:18][C:19]#[N:20].[Na+].C(O)C>C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:18][C:19]#[N:20])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (5.7 g) and sodium thiocyanate (5.5 g) were added to ethanol (50 ml), and the mixture was stirred for one hour at 60° C. The reaction mixture was concentrated, and water was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with a solvent mixture of n-hexane:ethyl acetate=10:1 to obtain the desired product (2.2 g, melting point: 129° to 131° C., yield:42%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH2:9][CH2:10][NH2:11])[NH2:7].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>C(N(CC)CC)C>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N+:13]([O-:15])=[O:14])[N:11]2[CH2:10][CH2:9][CH2:8][C:6]2([C:5]([O:4][CH3:3])=[O:12])[NH:7]1)([O-:15])=[O:14]
Reactant: COC(=O)[C@@H](N)CCCN
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C12CCCN1C(c1ccccc1[N+](=O)[O-])C(c1ccccc1[N+](=O)[O-])N2
Temperature: 0 °C

Procedure:
In a 250 ml round-bottomed flask equipped with a magnetic stirrer were taken a mixture of ornithine methyl ester dihydrochloride (5.0 g) and 2-nitrobenzaldehyde (7.5 g) in MDC (70 ml). The suspension was stirred at 0° C. for 15 mts. Triethylamine (4.64 g in 10 ml MDC) was added slowly. The reaction mixture was then allowed to stir at RT overnight. The reaction mixture was diluted with MDC, washed with water twice and dried over sodium sulfate. MDC was evaporated to give the crude product which was crystallized from methanol to give a white crystalline solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1
Product: O=C(c1cnoc1-c1ccccc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(phenyl)isoxazole-4-carboxylic acid (9.5 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (12.9 mg). MS (pos) m/z 243.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([NH:14][S:28]([CH2:27][CH2:26][N:17]2[C:16](=[O:15])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:25])(=[O:29])=[O:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (4-benzyl-piperazin-1-yl)-amide was prepared by an analogous procedure as described for example 1 i) starting from 140 mg (0.73 mmol) 4-benzyl-piperazin-1-ylamine and 200 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as a light yellow foam.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2CCN(C(OC(C)(C)C)=O)CC2)(C)[C:12](=[O:14])[N:13]=1.C12CC(CC1)CC2NC1SCC(=O)N=1.C([N-]C(C)C)(C)C.[Li+].BrCC[O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:16][CH2:17][O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=C1CSC(NC2CC3CCC2C3)=N1
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCCC1SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of tert-butyl 4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carboxylate by using 2-(bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (1.00 g, 4.76 mmol), lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 8.5 mL, 19.0 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (Aldrich, 6.83 g, 28.5 mmol). The title compound was obtained as an off-white solid (950 mg). MS (ESI, pos. ion) m/z: 369 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C-:27]#[N:28].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: [C-]#N
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(S(=O)(=O)c2ccc(CCc3ccc(F)cc3F)cc2)cc1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
2,4-Difluoro-1-(2-{4-[(4-fluorophenyl)sulfonyl]phenyl }ethyl)benzene (Example 122, 20 mg, 0.053 mmol) was dissolved in dimethylsulfoxide (0.1 mL) and sodium cyanide (5.2 mg, 0.106 mmol) was added. The reaction was heated to 100° C. overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield the title compound as a white solid (7 mg, 36%). δH (400 MHz, d6 DMSO): 8.10–8.07 (4H, m), 7.89 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz), 7.29 (1H, q, J=7.6 Hz), 7.14–7.10 (1H, m), 6.98–6.94 (1H, m), 2.94–2.86 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:15])([F:16])[F:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[N:10]([CH3:21])[N:9]=2)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(C(F)(F)F)c1C(F)(F)F
Product: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C

Procedure:
9 g (27 mmol) of 3-(4-chlorophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole were added at (-40)° C. to 100 ml of concentrated nitric acid, whereupon the mixture was stirred for 2 hours at this temperature. The solution, which was subsequently warmed to 0° C., was treated with ice-water. The product was subsequently extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated.