Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) according to the general procedure K. Obtained as a light yellow oil (164 mg).
Reaction SMILES: Cl.C(Cl)Cl.C(OC(=O)[NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]3[CH:31]=[C:30]4[C:25]([C:26](=[O:39])[C:27]5[C:37](=[O:38])[NH:36][S:35][C:28]=5[N:29]4[CH:32]4[CH2:34][CH2:33]4)=[CH:24][C:23]=3[F:40])[CH:18]=2)[CH2:13]1)(C)(C)C>C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([C:22]3[CH:31]=[C:30]4[C:25]([C:26](=[O:39])[C:27]5[C:37](=[O:38])[NH:36][S:35][C:28]=5[N:29]4[CH:32]4[CH2:34][CH2:33]4)=[CH:24][C:23]=3[F:40])[CH:16]=[CH:15][C:14]=2[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In air, a solution of hydrogen chloride in acetic acid (1 M, 1.8 mL) is added at room temperature to a solution of methylene chloride (0.6 mL) containing (rac)-tert-Butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (11.4 mg, 0.022 mmol). A yellow precipitate begins to appear within minutes of addition of the solution of hydrogen chloride. After stirring the mixture at room temperature for 18 h, additional methylene chloride is added (2 mL). The precipitate is collected by filtration, washed with methylene chloride (4×5 mL), and dried in vacuo to give pure 31 (97% purity by HPLC analysis) as a yellow powder. mp >257-258° C. dec. 1H NMR (DMSO-d6, 60° C.): δ 1.21 (m, 2H, c-Pr CH2), 1.29 (m, 2H, c-Pr CH2), 1.80 (m, 1H, H-3), 2.12 (m, 1H, H-3), 2.83 (dd, J=17.0 Hz, 10.0 Hz, 1H, H-1), 2.90 (m, 2H, H-4), 3.13 (dd, J=17.0 Hz, 6.0 Hz, 1H, H-1), 3.46 (m, 1H, H-2), 3.57 (m, 1H, c-Pr CH), 7.25 (d, J=8.0 Hz, 1H, H-8), 7.37 (s, 1H, H-5), 7.39 (d, J=8.0 Hz, 1H, H-7), 7.93 (d, JH-F=10.5 Hz, 1H, ITQ H-5), 8.01 (d, JH-F=6.5 Hz, 1H, ITQ H-8). 19F{1H} NMR (DMSO-d6, 60° C.): δ −123.3 (s). NMR spectra collected at room temperature contained broad, unresolved signals. LCMS m/z calcd for C23H20FN3O2S ([M]+) 421. Found 422 ([M+H]+). HRMS m/z calcd for C23H20FN3NaO2S ([M+Na]+) 444.1158. Found 444.1152.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Cc1cc(O)cc2sc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.30 g (1.66 mmol) 6-hydroxy-4-methylbenzo[d]thiazol-2(3H)-one and 0.25 g (1.68 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 0.25 g (1.81 mmol) potassium carbonate were added and the mixture was stirred for 2 h at RT. The reaction mixture was mixed with water and stirred overnight. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:29]([NH2:32])(=[O:31])=[O:30])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: NS(N)(=O)=O
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCCNS(N)(=O)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 76.6 %

Procedure:
A solution of 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.82 g) and sulphamide (0.96 g) in dioxane (30 ml) was heated under reflux for 70 minutes and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.75 g), m.p. 150°-152° C. Found: C, 49.33; H, 5.35; N, 8.93. C20H26ClN3O7S requires C, 49.23; H, 5.37; N, 8.61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([NH2:30])=[NH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccccc1NC(=N)N
Product: COc1ccccc1Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(2-methoxyphenyl)guanidine were converted to I-16 (39%): HRMS Calcd. for C11H11ClN4O2: 367.0961, Found 367.0947.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][OH:36])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][O:36][CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:4][CH:3]=1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Reactant: CCC(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(OCCc1c2c3c(c(OCc4ccc(-c5ccccc5)cn4)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of product from Step 6 (130 mg, 0.23 mmol) in THF (2 mL) there was added 97% NaH (23 mg, 1 mmol) and the mixture was stirred at r.t. for 15 min. There was added a solution of 2-bromobutyric acid (84 mg, 0.5 mmol) in THF (1.5 mL) and the mixture was refluxed for 20 hours. After cooling, there was added more NaH (46 mg) and 2-bromobutyric acid (170 mg) and the mixture was refluxed for a further 24 hours. The cooled mixture was diluted with H2O, made strongly basic with 1N aq NaOH, and extracted twice with Et2O. The aqueous fraction was then acidified with 1N HCl and extracted 3× with EtOAc. The crude product thus obtained was purified by esterification with ethereal diazomethane and the resulting ester chromatographed on preparative TLC silica gel plates, eluting with a 1:4 mixture of EtOAc and toluene. After extraction of the silica with EtOAc, the purified ester (54 mg) was hydrolyzed. It was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and there was added 1M aq LiOH (0.8 mL). The mixture was heated to 50° C. for 30 min., then the organic solvents were evaporated. The residue was diluted with H2O (4 mL) and centrifuged. The supernatant was decanted and the insoluble lithium salt was suspended in H2O (4 mL). The mixture was acidified with 1N aq HCl, stirred vigorously and filtered to afford the title compound as a light yellow solid; m.p. 159°-162° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>O1CCCC1.CN(C)C=O>[CH3:28][CH:21]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:20][CH2:19][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=CCCC(C)CCBr
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CCn1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
In a flask equipped with a stirrer, condenser and nitrogen inlet tube, there is added 90 ml. of anhydrous tetrahydrofuran, 30 ml. of anhydrous dimethylformamide and 9.7 g. (0.05 mole) of 2-phenylbenzimidazole. The resulting system is then blanketed with nitrogen, stirring is initiated and 2.2 g. (0.053 mole) of 57% sodium hydride mineral oil dispersion is added in one portion. The mixture is then heated to 50° for about 2 hours. After cooling to room temperature, a solution of 12.0 g. (0.053 mole) of (±) 1-bromo-3,7-dimethyl-6-octene in 50 ml. of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred overnight at room temperature and the resultant salts are removed by filtration. The filtrate is concentrated in vacuo. The resultant oil is dissolved in chloroform and chromatographed on silica gel using methylenechloride as the eluant to give (±)1-(3,7-dimethyl-6-octen-1-yl)-2-phenylbenzimidazole, NMR (CDCl3) δ0.72-2.18 (16H, complex multiplet, ##EQU1## 4.23 (2H, triplet, J=7cps, CH2N), 5.00 (1H, triplet, J=7cps, HC=C), 7.13-7.95 (9H, multiplet, C6H5 and C6H4). Anal. Calcd. for C23H28N2 :C, 83.1; H, 8.5; N, 8.4. Found:C, 83.3; H, 8.8; N, 8.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH3:14])[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])(=O)C.[Na+].CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[CH2:12]([C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[N:3]=1)[CH2:13][CH3:14]
Reactant: CCCc1nc(N)c(C(=O)OCC)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-amino-2-propylimidazole-5-carboxylate from above (9.34 g, 47 mmol) and sodium acetate (23.2 g) in acetic acid (100 mL) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (6.75 mL, 52 mmol). The reaction was held at reflux for 30 minutes, then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated under reduced pressure, then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2 -ethyl acetate (80:20). Evaporation of solvents gave a solid which was recrystallized from hexane/EtOAc (1:1) to give 7.4 g of the title compound, mp 134°-135° C.; MS (CI), 248 (m +1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][S:18]([C:15]2[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: COc1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from 5-bromo-2-(methyloxy)aniline and 4-iodobenzenesulfonyl chloride using a similar method to that described for Examples 82-100 (E82-E100). MS (ES−) 466/468 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(OCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 82.5 °C
Yield: 32.6 %

Procedure:
To a solution of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 17, Step A; 50 mg, 0.121 mmol) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (71 mg, 0.297 mmol) in N,N-dimethylacetamide (2 mL) was added cesium carbonate (79.0 mg, 0.242 mmol). The mixture was heated to 80-85° C. for 90 minutes. After allowing to cool the mixture was diluted with ethyl acetate and methanol, filtered and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol and 1% triethylamine in ethyl acetate to give the product 21.9 mg (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:16]=2[CH3:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1cc(S(C)(=O)=O)ccc1C(=O)O
Product: Cc1cc(S(C)(=O)=O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of 2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give 2-methyl-4-(methylthio)benzoic acid. 430 mg of 2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide. MS (Q1) 401.0 (M)+.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[N:16][CH:17]=1.[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH2:28][CH:29]=[N:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH2:28][C@H:29]([NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[C:12]1[CH:17]=[N:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Reactant: CCCOc1ccc(Br)cn1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCOc1ccc([C@H](CO[Si](C)(C)C(C)(C)C)N[S@](=O)C(C)(C)C)cn1
Reaction time: 0.5 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (15.2 mL, 25.8 mmol) was added drop wise to a stirring solution of 5-bromo-2-propoxypyridine IM3 (2.54 g, 11.8 mmol) dissolved in dry THF (29.4 mL) at −78° C. under Ar. The solution was subsequently stirred at this temperature for 30 min. A solution of (R)-2-methyl-propane-2-sulfinic acid [2-(tert-butyl-dimethyl-silanyloxy)ethylidene]-amide IM49 (3.26 g, 11.8 mmol) in dry THF (15 mL) was then added drop wise at −78° C. and the solution was stirred at this temperature for 30 min. The cooling bath was removed and the mixture was allowed to reach room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl solution (75 mL) and EtOAc (150 mL). The phases were separated and the organic layer was washed with brine and then dried over MgSO4. Flash chromatography (silica, 10-100% EtOAc in heptanes) gave (R)-2-Methyl-propane-2-sulfinic acid [(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]amide, the fastest eluding isomer, as a clear oil (2.33 g, 48%) sufficiently pure for the next step. Diastereomeric excess >95% based on 1H NMR.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:15][C:16](=[O:21])C(Cl)(Cl)Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26](CC2C=CC=CC=2)[CH2:25][CH2:24]1>>[NH:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[NH:15][C:16]2=[O:21])[CH2:24][CH2:25]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(c1ccccc1)c1cccnc1NC(=O)C(Cl)(Cl)Cl
Product: O=C1Nc2ncccc2C(c2ccccc2)N1C1CCNCC1

Procedure:
In similar way as in Preparation Example 89, the title compound was synthesized from 3-benzoyl-2-trichloroacetylaminopyridine and 4-amino-1-benzylpiperidine.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:52])[C:4]([NH:7][CH2:8][CH2:9][CH:10]([CH2:42][CH2:43][NH:44][C:45]([CH3:51])([CH3:50])[C:46](=[N:48][OH:49])[CH3:47])[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:18][CH:17]=1)=[O:15])([CH3:6])[CH3:5].CN1CCOCC1.C1CN([P+]([O:76][N:77]2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Si](ON)(C(C)(C)C)(C)C>CN(C)C=O>[OH:76][NH:77][C:23]([CH:22]([N:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:12][CH2:11][CH:10]([CH2:42][CH2:43][NH:44][C:45]([CH3:50])([CH3:51])[C:46](=[N:48][OH:49])[CH3:47])[CH2:9][CH2:8][NH:7][C:4]([CH3:5])([CH3:6])[C:3](=[N:2][OH:1])[CH3:52])=[O:15])=[CH:41][CH:40]=1)[S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)O)C(C)C)cc1
Reactant: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)NO)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The hydroxamic acid was attached via tert-butyldimethylsilyl protected intermediate (Compound 11*). Thus, a mixture of the acid (Compound 10*) (57 mg, 0.76 mmol), 4-methylmorpholine (34 μl, 0.30 mmol), [7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate] PyAOP, 40 mg, 0.076 mmol) and O-(tert-butyldimethylsilyl)hydroxylamine (12 mg, 0.08 mmol) in dimethylformamide (4 ml) was stirred at ambient temperature and the reaction monitored by HPLC. The reaction was stopped after 3 hours and solvents were evaporated. The residue was re-dissolved in dichloromethane and at ambient temperature, hydrochloric acid gas was bubbled through the mixture for 10 minutes. The mixture was evaporated to dryness and the residue co-evaporated with dichloromethane (5×5 ml). The product was obtained as a white powder after HPLC, M+H, 762. Yield 15 mg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:28][C:29]([NH2:31])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[NH2:31][C:29](=[O:30])[CH2:28][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:23][S:24](=[O:26])(=[O:27])[CH2:25]1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC3CC3)c(N3CC(F)(F)C3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (example 53e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (35 mg, 42%); MS (ESI, m/z): 445.3 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH2:9][CH2:8]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH2:9][CH2:8]1
Reactant: c1cn[nH]c1
Reactant: BrCCCCN1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccn3)CC2)nc1

Procedure:
A mixture of 4 g (13.3 mmol) of 1-(2-pyrimidinyl)-4-(4-bromobutyl)piperazine, 1.02 g (15 mmol) of pyrazole and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide is heated to reflux for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the organic phase is washed with water, dried over sodium sulphate and evaporated under vacuum, and 3.5 g of an oil which is 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-piperazinone (1.802 g, 18 mmol, CAS [5625-67-2], commercially available e.g. from Sigma-Aldrich) and triethylamine (3.01 mL, 21.60 mmol) were dissolved in Dichloromethane (DCM) (100 ml) at 0° C. 2-Chloro-3-(trifluoromethyl)benzoyl chloride (4.81 g, 19.80 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added portionwise and the solution was stirred at room temperature for 48 hr. The solution was diluted with Dichloromethane (400 ml), was washed with 1N HCl (100 ml), water (100 ml), saturated sodium bicarbonate solution (100 ml), water (3×100 ml), and brine (100 ml), was dried over anhydrous magnesium sulfate, and was concentrated to a crude solid (5.92 g). The crude product was purified by flash chromatography (Biotage SP4, 40+M, 0% to 25% methanol/Dichloromethane as eluent) to afford crude product (5.01 g), that was recrystallised from toluene to afford pure 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (4.54 g, 14.80 mmol). LC/MS [M+H]+=307, 309, retention time=1.74 minutes (5 minute method).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=1
Reactant: CSc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CSc1cccc(C2=CCNCC2)c1F

Procedure:
Preparation according to preparation 2: Tert-butyl 4-[2-fluoro-3-(methylthio)-phenyl]-4-hydroxy-piperidine-1-carboxylate (2.0 g, 5.86 mmol), trifluoroacetic acid (20 ml). Yield: 1.42 g. MS m/z (rel. intensity, 70 eV) 223 (M+, bp), 222 (32), 147 (61), 146 (47), 133 (27).