Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.C(O[CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])=[O:14])C.Cl.NO>C(#N)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[CH:11]=[N:3][O:26][C:24]=1[CH3:25])=[O:14])([O-:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: CCOC=C(C(C)=O)C(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: NO
Solvent: CC#N
Product: Cc1oncc1C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Triethylamine (1.9 g) was added to a mixture of 2-ethoxymethylene-1-(2-nitrophenyl)-butan-1,3-dione (4.9 g) and hydroxylamine hydrochloride (1.3 g) in acetonitrile (100 ml) with stirring. The mixture was stirred for 2 hours and left to stand overnight. The mixture was evaporated almost to dryness and water (100 ml) was added. The mixture was extracted with ethyl acetate (2×75 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(2-nitrobenzoyl)-5-methylisoxazole (compound 2, 2.4 g) as a brown solid, mp 104.5°-105.5° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:28][CH:27]=1)=[O:25])[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].NN>CO.C1COCC1>[NH2:3][CH2:12][CH:13]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:28][CH:27]=1)=[O:25])[C:14]([CH3:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15]
Reactant: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)NC(CN)C(C)(C)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-{1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-methyl-2-phenylpropyl}-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide (96 mg, 0.20 mmol) in MeOH/THF (20 mL, 3:1) at RT was added hydrazine (45 μL, 1.43 mmol). After stirring for 18 h at RT, the reaction mixture was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:35].[NH4+].[OH-]>C(O)(=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1)(=[O:35])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(NC(=O)c2n[nH]c3ccc(-c4cncc(CN5CCCCC5)c4)cc23)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NC(=O)c2n[nH]c3ccc(-c4cncc(CN5CCCCC5)c4)cc23)cn1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of N-(6-cyanopyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (62) (200 mg, 0.45 mmol) in glacial acetic acid (2 mL) heated at 85° C. was carefully added dropwise sulfuric acid (2 mL). The reaction was heated at 85° C. for another 20 minutes before pouring into ice. The solution was basified with cold 5N NH4OH. The solids formed were filtered, washed with cold washed and dried under vacuum. The dry solid was suspended in DCM and a few drops of MeOH were added. The insoluble solids were filtered and discarded. The filtrate was concentrated and suspended again in DCM, boiled for 15 minutes and filtered. The solid was dried under vacuum to give N-(6-carbamoylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (180) as a white solid (192 mg, 0.42 mmol, 93.7% yield). 1H NMR (DMSO-d6) δ ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.49 (s, 1H), 7.65 (d, J=9 Hz, 1H), 7.80 (d, J=9 Hz, 1H), 7.97 (s, 1H), 8.03 (s, 2H), 8.41 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.54 (dd, J=9 Hz, J=2.5 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.15 (d, J=2 Hz, 1H), 10.83 (brs, 1H); ESIMS found for C25H25N7O2 m/z 456.4 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].[OH-].[Na+]>O.O1CCOCC1>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([O:11][CH2:10][CH2:12][NH2:13])[CH:7]=1
Reactant: NCCO
Reactant: Cc1cc(C)nc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)nc(OCCN)c1

Procedure:
From 2-chloro-4,6-dimethylpyridine by treatment with ethanolamine and sodium hydroxide in a mixture of water and dioxane to afford 2-(4,6-dimethyl-pyridin-2-yloxy)-ethylamine, followed by heating with 1-fluoro-4-nitrobenzene in ethanol to give [2-(4,6-dimethyl-pyridin-2-yloxy)-ethyl]-(4-nitro-phenyl)-amine. The free amine is protected as a trifluoroacetamide by treatment with trifluoroacetic anhydride and sodium hydride in THF then the nitro group is reduced with zinc powder in the presence of ammonium chloride in ethanol. Following coupling with the appropriately-selected acid chloride, a final treatment with lithium hydroxide in methanol removes the trifluoroacetamide to give the final compound described.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH:2]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with di(pyridin-3-yl)methanone (500 mg, 2.72 mmol), MeOH (30 mL), and CH2Cl2 (15 mL) and cooled to 0° C. NaBH4 (51 mg, 1.35 mmol) was added in one portion. The solution was stirred for 1 h at 0° C. and quenched with 1N NaOH and the reaction was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Crude di(pyridin-3-yl)methanol (505 mg, 100%) was used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ 8.32 (s, 2H), 8.24 (d, J=4.8 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.09-7.01 (m, 2H), 5.67 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([NH:18][N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)(=[O:17])=[O:16])=[O:13])[N:4]=1.[K+].[Br-:25]>O1CCCC1>[Br:25][C:20]1[N:19]([NH:18][S:15]([NH:14][C:12]([NH:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[O:13])(=[O:16])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: [Br-]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nn2cccc2)n1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nn2cccc2Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(4,6-dimethoxypyrimidin-2-yl)-N'-{[(1H-pyrrol-1-yl)amino]sulfonyl}urea (I-53; 0.164 g; 0.48 mM) synthesized according to synthesis Example 1 at room temperature was dissolved in 10 ml of tetrahydrofuran. To the solution was added under cooling with ice-water N-bromosuccinimide (0.085 g; 0.48mM). After cooled for a short period of time, the mixture was stirred at room temperature for 3 hours. The solvent in the reaction mixture was then distilled away and the resultant residue was purified with column chromatography on silica gel to obtain the target product. White solid; m.p. 157° C.; Yield 0.095 g (47.5%) IR (KBr cm-1): 3320 3132 1716 1614 1582 1454 1364 1170 NMR(CDCl3, δ): 3.7(6H,s:pyrimidine ring OCH3 ×2) 5.6(1H,s:pyrimidine ring H) 6.0(2H,m:pyrrole ring C3 and C4) 6.7~6.9(1H,m:pyrrole ring C5) 8.5(1H,bs:NH) 12.5(1H,bs:NH)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccccc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (100 mg, 0.586 mmol) and benzohydrazide (80 mg, 0.586 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (90 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.95 (m, 2H), 7.67-7.62 (m, 2H), 7.56 (m, 2H), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.35 (s, 3H). ESI-MS: 289.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1.[Cl:17][C:18]1[C:26]([Cl:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[C:26]([Cl:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[N:8][C:5]=2[CH2:6]1)=[O:21]
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Reactant: CC1Cc2c(nnn2-c2ccccn2)CN1
Product: CC1Cc2c(nnn2-c2ccccn2)CN1C(=O)c1ccc(F)c(Cl)c1Cl

Procedure:
Example 121 was prepared from 6-methyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine and 2,3-dichloro-4-fluorobenzoic acid using the conditions described in Example 65. MS (ESI) mass calcd. C18H14Cl2FN5O, 405.06. m/z found, 406.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.CCN(C(C)C)C(C)C.[C:45]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:50]=[CH:49][CH:48]=[C:47]([C:51](Cl)=[O:52])[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[CH:46]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:52])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5cccc(-c6ccccc6)c5)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (12 mg, 0.026 mmol) (prepared in Example 101, step A) in 260 μL dichloromethane at 0° C. under nitrogen was added DIEA (14 μL, 0.078 mmol) followed by biphenyl-3-carbonyl chloride (7 mg, 0.031 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was diluted to 10 mL with dichloromethane and stirred rapidly with 10% sodium carbonate solution for 5 minutes. The organics were isolated and dried (MgSO4). The organics were filtered and concentrated to a residue that was loaded onto a Biotage 12S column with dichloromethane and eluted with 4/1 EtOAc/hexanes. The product containing fractions were pooled and concentrated to a yellow oil (10 mg, 59% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH2:31])[NH:27][C:26](=[O:32])[CH2:25]2>>[NH2:31][C:30]1[CH:29]=[C:28]2[C:24]([C:25](=[CH:16][C:13]3[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=3[CH3:15])[C:26](=[O:32])[NH:27]2)=[CH:23][C:22]=1[F:21]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Yield: 61.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one (prepared according to J. Heterocylic Chem., 31, 1513, 1994) as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (42 mg, 61.8%) as a red solid.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)Cc1ccccc1C(=O)O
Product: C=CCN1C(=O)Cc2ccccc2C1=O
Yield: 46 %

Procedure:
A mixture of homophthalic acid (9.0 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) was heated by an oil bath to 185°-190° C. for 40 minutes. The mixture solidified upon cooling, and was recrystallized twice from isopropanol, giving 2-allylisoquinoline-1,3 (2H, 4H)-dione, 4.6 g. (46% yield), m.p. 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[N+:22]([O-])=O.Cl.O>CO.[Fe]>[NH2:22][C:3]1[C:4]([C:20]#[N:21])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: COc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Yield: 49.5 %

Procedure:
4-Amino-6-(4-methoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (65 mg, 0.19 mmol) was suspended in methanol (1.5 ml) and concentrated HCl (0.5 ml) was added dropwise (exotherm). The suspension was stirred while iron powder (37 mg, 0.67 mmol) was added in portions (exotherm), and the mixture was heated to reflux for 1 hour. Mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). Organics were dried and evaporated then flash chromatographed over silica (4 g Combiflash cartridge, 7:3 heptane/ethyl acetate) to afford 29 mg of 3,4-diamino-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile as a light brown solid. 1H NMR (DMSO) δ 8.08-8.01 (m, 2H) 7.05-7.00 (m, 2H), 3.94 (s, 3H). MS m/z 309.7 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH:9]=[O:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC(=O)NC(C=O)CC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
A solution of 3-allyloxycarbonylamino-N-methoxy-N-methyl-succinamic acid tert-butyl ester, 101, (24.3 g, 76.8 mmol) in THF (60 mL) is treated at −78° C. with lithium aluminum hydride (1 M in THF, 39 mL, 39 mmol) dissolved in ether (200 mL) over 5 minutes. After the consumption of starting material, the solution is cautiously quenched with 1.0 N HCl, washed with 1.0 N HCl (2×100 mL) and brine (1×150 mL). The organic layer is concentrated in vacuo to afford 18.2 g (91% yield) of the desired product as a clear oil. 1H-NMR, (300 MHz, CDCl3): δ 1.45 (s, 9H), 2.75–3.01 (m, 2H), 4.37–4.42 (m, 1H), 4.62–4.64 (d, J=5.4, 2H), 5.25–5.38 (m, 2H), 5.89–6.02 (m, 2H), 9.68 (s, 1H); MS (ESI): m/e=258.11 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [O-][n+]1ccccc1SCc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccc(Cl)cc1Cl)c1cccc[n+]1[O-]
Reaction time: 16 h

Procedure:
A well stirred solution of 5.8 gms (0.02 mole) of 2-(2,4-dichlorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform is treated at 0° - 10° with 4 gms (0.02 mole) MCPBA (85%) in 50 ml of chloroform. The mixture is allowed to rise to ambient and held for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate, dried and evaporated to 5.5 gms (89% theory) of product. Melting point 138° - 141° C. Structure confirmed by IR and NMR. (IR N-O 1240 cm-1, SO 1050 cm-1)
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](F)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].C(=O)([O-])[O-:17].[K+:20].[K+]>O>[F:1][C:2]1[C:7]([S:8]([O-:17])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[K+:20]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(F)c1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
25 Grams (93.8 mmols) of pentafluorobenzenesulfonyl fluoride was charged in a flask, and 13.0 g (93.8 mmols) of potassium carbonate and 100 ml of water were added under cooling with ice, followed by stirring at room temperature for 9 hours. Then, 1.3 g (9.4 mmols) of potassium carbonate was further added and the mixture was stirred at 60° C. for 1 hour. A white solid produced was filtered off and purified by recrystallization with water. The resulting white solid was subjected to 19F-NMR measurement and it was confirmed that the resulting white solid was potassium pentafluorobenzenesulfonate (c).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Na].I([O-])(=O)(=O)=[O:32]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([S:22]([CH3:23])=[O:32])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide (prepared as in Example 4, 0.20 g, 0.441 mmol) in tetrahydrofuran (3 mL) was added dropwise to a solution of sodium-meta-periodate (0.189 g, 0.882 mmol) in water (1.5 mL). The resulting reaction mixture was stirred at 25° C. for 72 h. The reaction mixture was then concentrated in vacuo, and the residue was then diluted with chloroform (25 mL). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methane-sulfinyl-pyrazin-2-yl)-propionamide (96 mg, 46%) as a white foam: mp 88–95° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H24ClN3O4S2 (M+H)+ 470.0970 found 470.0976.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10].C(OCC)(=O)C.[ClH:41]>C(O)C>[ClH:41].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][NH:26][CH3:27])=[CH:13]1)(=[O:10])=[O:11]
Reactant: CN(Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
tert-Butyl ({1-[(2,6-difluorophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (430 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 283 mg, 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>>[CH3:1][N:2]([CH3:17])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@H]1CC[C@H](N)CC1
Temperature: 75 °C

Procedure:
To a solution of tert-butyl trans-4-(dimethylamino)cyclohexylcarbamate (805 mg, 3.33 mmol) was added TFA (5 mL) and the reaction mixture was heated at 75° C. for 18 h. The reaction mixture was concentrated and the residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product as the free base (400 mg, 85%) as an orange oil: ESI MS m/z 143 [C8H18N2+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4](O)=[O:5].C[N:16](C=O)C.C(Cl)(=O)C(Cl)=O>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: O=C(O)c1c([N+](=O)[O-])ccc(F)c1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
2-Bromo-3-fluoro-6-nitrobenzoic acid (Example 134f) (24.83 g, 94.0) mmol, (mixture of two regioisomers) was dissolved in anhydrous THF (200 mL) under a nitrogen atmosphere at room temperature. Anhydrous DMF (0.75 mL) was added and the obtained mixture was cooled to 0° C. Oxalyl chloride (12.3 mL, 141 mmol) was slowly added and the reaction mixture was stirred at 0° C. for 10 min, and at room temperature for a further 2 h. The reaction was evaporated to dryness, suspended in anhydrous THF (100 mL) and added slowly to concentrated ammonium hydroxide (350 mL) at 0° C. After stirring for 45 minutes at 0° C. the mixture was extracted with CH2Cl2 (5×100 mL), and the organic extractions were then discarded. At this point the desired regioisomer existed as an insoluble precipitate in the aqueous layer, which was collected by filtration to give 10.3 g (42%) of 2-bromo-3-fluoro-6-nitrobenzamide which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J=8.8, 4.4 Hz, 1H), 8.10 (broad s, 1H), 7.95 (broad s, 1H), 7.66 (dd, J=9.6, 7.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>O1CCCC1>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH3:23])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
0.500 g (S)-5-dibenzylaminopiperidin-2-one are suspended in 15 ml of tetrahydrofuran. While cooling with the ice bath 0.175 g potassium-tert-butoxide are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 0.095 ml methyl iodide are added. The reaction mixture is then stirred for 48 hours at ambient temperature and then combined with a saturated NaCl solution. The product is extracted with ethyl acetate. 0.450 g product are obtained as an oil.