Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:18](F)(F)F)[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C(C3C=NC=C(C)C=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Agent: Cc1cncc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-methylpyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=447, obsd.=447).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[NH:16][S:24]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: COC(=O)c1cccc(CN2CCCC2)c1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(CN2CCCC2)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of the product of example 316 in 10 mL of dichloromethane was added 10.0 mL of trifluoroacetic acid. The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The resulting residue was diluted with ether washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then triturated with ether to provide 0.93 g (57%) of the product as a pale yellow solid. Electrospray Mass Spec: 405.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccc(OC)cc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-6-methoxy-benzothiazole. MS (ESI) mass calcd. for C23H25N3O4S, 439.54; m/z found, 440.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cccc1CCN
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCc2cccn2C)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-acetamidobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:22])[C@H:13]1[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@H:14]1[OH:15]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][C@H:18]2[O:19][C@H:13]([CH2:12][O:22][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C@@H:14]([OH:15])[C@@H:16]2[OH:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.33 g (27.945 mmol) of p-toluenesulphonyl chloride were added at 0° C. to a solution of 2.16 g (13.15 mmol) of 2,5-anhydro-D-mannitol in 88 ml of pyridine. The mixture was heated to room temperature and stirred for a further 24 hours. The reaction was hydrolysed using ice-water and extracted using CH2Cl2, and the combined organic phases were washed with 3N HCl and NaCl. After drying over MgSO4, the solvent was subsequently removed under reduced pressure. The crude product was purified by means of column chromatography (hexane/ethyl acetate 1:2). Yield: 3.00 g (48% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>O1CCOCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])Cc1cccc(Cl)c1
Reactant: C=CC(=O)OC
Solvent: C1COCCO1
Product: COC(=O)CCC(c1cccc(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of 1 g (5.828 mmol) 1-chloro-3-nitromethyl-benzene (CAS: 38362-91-3) at 0° C. in 2 ml dioxane was added 0.512 g (5.828 mmol) methyl acrylate followed by 3.3 g Amberlyst A-21. The reaction mixture was stirred overnight at room temperature, filtered and the filtrate was dried over sodium sulfate and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 10%) to provide 980 mg (65%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28]([C:30]1([C:33]([O:35]C)=O)[CH2:32][CH2:31]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:38].[Na+]>N.CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28]([C:30]1([C:33]([NH2:38])=[O:35])[CH2:31][CH2:32]1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C(=O)N2CCN(c3ccc(OC)c(OC4CCCC4)c3)C[C@@H]2Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)C3(C(N)=O)CC3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 22 %

Procedure:
A solution of (S)-methyl 1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazine-1-carbonyl)cyclopropanecarboxylate (123 mg, 0.25 mmol) was dissolved in a 7 N ammonia solution in MeOH (10 mL), treated with catalytic amount of sodium cyanide, then heated in a sealed tube at 80° C. for 5 days. The reaction mixture was then evaporated, washed with water and air dried to afford a residue then purified by silica gel flash chromatography with 50% then 100% EtOAc/hexanes as eluant to afford the title compound as colorless foam (26 mg, 22%). LC/MS (Method B) 3.49 min, [M+1]+ 478.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH2:11][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:31])[CH2:11][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CCCCCCCCN(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCN(CC(=O)NO)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-Benzyloxy-2-[octyl-(toluene-4-sulfonyl)amino]-acetamide (1.91 g, 0.0043 mol) was taken up in ethanol (150 ml), and 10% palladium on charcoal (800 mg) was added. Hydrogen gas was bubbled through the mixture for 2 hours at room temperature. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give a crude solid which was purified by recrystallization from ethyl acetate/hexane (940 mg, 61%). m.p. 89° C.; 1H-NMR; δ(CDCl3), 7.69 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 3.76 (2H, s), 3.15 (1H, d, J=7.6 Hz), 3.12 (1H, d, J=7.9 Hz), 2.43 (3H, s), 1.58-1.41 (2H, m), 1.35-1.15 (10H, m) and 0.86 (3H, t, J=6.4 Hz). 13C-NMR; δ(CDCl3), 166.6, 144.2, 134.6, 129.9, 127.4, 50.7, 49.9, 31.6, 29.1, 29.0, 27.9, 26.6, 22.6, 21.5 and 14.0; IR (CDCl3), νmax 3413, 2929, 2858, 1682, 1467, 1401, 1346, 1162 and 1091 cm-1. Found: C, 57.27; H, 7.87; N, 7.95%; C17H28N2O4S requires C, 57.28; H, 7.92; N, 7.86%.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N+:11]2[CH2:14][CH:15]=[CH2:16])=[CH:6][CH:5]=1.[OH-].[K+].[O:19]1CCOCC1>O.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](=[O:19])[N:11]2[CH2:14][CH:15]=[CH2:16])=[CH:6][CH:5]=1
Reactant: C=CC[n+]1cccc2ccc(OC)cc21
Reactant: C1COCCO1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1c(=O)ccc2ccc(OC)cc21
Reaction time: 0.5 h
Yield: 51 %

Procedure:
7-(Methyloxy)-1-(2-propen-1-yl)quinolinium iodide (14.81 g; 45.43 mmol), KOH (11.20 g; 199.89 mmol) and K3-[Fe(CN)6] (32.78 g; 99.95 mmol) were stirred in 1:1 water: 1,4-dioxane (400 ml) at rt under Argon for 1 h. More KOH (1.1 g; 19.9 mmol) and K3-[Fe(CN)6] (3.28 g; 10.0 mmol) were added to the reaction and it was stirred under the same conditions for a further 0.5 h. EtOAc (500 ml) and water (500 ml) was then added. The layers were then separated and the combined organic layers were washed with water and then concentrated. The crude residue was then purified by column chromatography on silica gel using a 0-5% MeOH/DCM gradient to give the desired product (4.90 g; 51%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>O1CCCC1>[N:1]1([CH2:8][CH2:7][CH2:6][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=CC#N
Solvent: C1CCOC1
Product: NCCCn1ccnc1

Procedure:
A mixture of 41 g. of imidazole and 75 ml. of acrylonitrile was heated on a steam bath for 3 hours, then concentrated under reduced pressure to remove excess acrylonitrile. A 300 ml. portion of methanol was added to the residue together with 100 ml. of concentrated ammonium hydroxide and 8 g. of Raney nickel catalyst. This mixture was hydrogenated in a Parr apparatus until hydrogen uptake ceased and then filtered giving a light green liquid. A 300 ml. portion of tetrahydrofuran was added to this liquid and the mixture filtered through diatomaceous earth. The filtrate was concentrated twice from toluene, giving 75.2 g. of the desired intermediate as a clear oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@H](N(C)C)C1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of acryloyl chloride (0.042 mL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of (S)—N1-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-4-[3-(dimethylamino)pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 61, 250 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (194 mg, 70%) as a yellow solid; 1H NMR: 1.69-1.83 (1H, m), 2.05-2.16 (1H, m), 2.19 (6H, s), 2.65-2.78 (1H, m), 3.18-3.29 (3H, m), 3.35-3.46 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.3-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES+ MH+ 533.5.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)C.[C-:15]#[N:16].[K+].CI>CO.O>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:15]#[N:16]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Agent: [K+]
Solvent: CI
Solvent: CO
Solvent: O
Product: N#CCc1c[nH]c2ccc(F)cc12
Temperature: 20 °C

Procedure:
A mixture of 38 g of 3-dimethylaminomethyl-5-fluoroindole (0.198 mole; cf. Hoffman et al. J. Heterocyclic Chem. 2, 298 (1965); of the 5-fluorogramine therein) in 500 ml of methanol was prepared. Then a solution of 25.7 g of KCN (0.396 mole) in 50 ml of water was added, with stirring. The stirred mixture was cooled to 20° C. and 34.6 ml of methyl iodide (0.556 mole) was added over a 20 minute period. The mixture was then stirred at about 20° C. for 16 hours. The solvent was removed by evaporation and the residue was partitioned between ether and water. The ether portion was washed with water, 5% HCl, saturated NaHCO3 solution, water, and brine, dried over MgSO4 and evaporated to leave a liquid residue. This residue was distilled at reduced pressure in a Kugelrohr apparatus. The fraction distilling at 134°-140° C. and 0.3 to 0.1 Torr was collected and crystallized from ethyl acetate-petroleum ether, mp 58°-59°, yield 5.3 g (44%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.CCCCC.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(C)C)cc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mg dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([F:18])[C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[OH-].[Na+].Cl.[CH3:24][C:25]([CH3:27])=[O:26]>O.C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([F:18])[C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH:24][C:25](=[O:26])[CH3:27])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: O=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a slurry of 28.5 g (0.10 mol) of 4-(5-(trifluoromethyl)-3-fluoro-2-pyridyloxy)benzaldehyde in 250 mL of acetone and 250 mL of water was added 7.5 mL of 1N sodium hydroxide. The slurry was stirred at ambient temperature for 19 hours and then diluted with 300 mL of methylene chloride and 200 mL of water and made acidic to a pH of 2 with concentrated HCl. The organic layer was separated in a separatory funnel and washed with 500 mL of water and dried over sodium sulfate. The solvent was removed in vacuo leaving 32.5 g (100 percent of theoretical) of the above named compound, as the crude product. The above named product (melting at 71°-72.5° C.) was recovered in a yield of 27.9 g (85.8 percent of theoretical) after recrystallization of the crude product from hexane; Rf -0.19 (silica gel, 15:85 EtOAc:hexane), 1H NMR (CDCl3): δ 2.35 (s, 3H, --CH3), 6.65 (d, 1H, J=15 Hz, vinyl), 7.15-8.3 (m, 6H, ArH and vinyl).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C([O:55][C:56](=O)[CH:57]([CH:68]1[CH2:72][CH2:71][CH2:70][CH2:69]1)[CH2:58][NH:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:68]1([CH:57]2[CH2:58][N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[C:19](=[O:21])[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)=[C:56]2[OH:55])[CH2:72][CH2:71][CH2:70][CH2:69]1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(CNCc1ccc(F)cc1)C1CCCC1
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)C(C3CCCC3)CN(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 19 h
Yield: 18.2 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.120 g, 0.340 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.142 g, 0.373 mmol) and 4-methylmorpholine (0.075 mL, 0.682 mmol) were added sequentially to a solution of rac-2-cyclopentyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.100 g, 0.341 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 19 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (12 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.663 mL, 2.04 mmol) was added and the reaction mixture was heated to 70° C. for 66 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether)N-{3-[5-cyclopentyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.036 g, 0.062 mmol, 18%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.07-1.12 (1H, m), 1.16-1.62 (7H, m), 1.76-1.86 (1H, m), 2.28-2.35 (1H, m), 2.95 (3H, s), 3.21 (1H, d, J=14.9 Hz), 3.63 (1H, dd, J1=4.0 Hz, J2=14.0 Hz), 4.24 (2H, d, J=6.3 Hz), 4.34 (1H, d, J=14.6 Hz), 4.85 (1H, d, J=14.2 Hz), 7.15-7.19 (2H, m), 7.25 (1H, s), 7.37-7.40 (2H, m), 7.64 (1H, t, J=6.4 Hz). LC-MS (ESI) calculated for C24H27FN4O6S3 582.11. found 583.1 [M+H+].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[N+:17]([C:20]1[C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[C:24]([Cl:37])[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.Cl>[N+:17]([C:20]1[C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH:2][C@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=4)[C:4]3=[O:16])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[C:24]([Cl:37])[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(CN2CCC(N)C2=O)cs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc(Oc4c(Cl)cccc4[N+](=O)[O-])cc3)C2=O)cs1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
4-{3-(S)-[(4-(6-Nitro-2-chlorophenoxy)benzenesulfonyl)amino]-2-oxopyrrolidin-1-ylmethyl}thiophene-2-carbononitrile is prepared as described in EXAMPLE 125, Part C from of 4-(3-Amino-2-oxopyrrolidine-1-ylmethyl)thiophene-2-carbonitrile hydrochloride (0.36 g, 1.4 mmol), and 4-(6-Nitro-2-chlorophenoxy)-benzenesulfonyl chloride (0.63 g, 1.8 mmol) and triethyl amine (0.57 g, 5.7 mmol). After 18 hours, the solution is diluted with CH2Cl2 and 0.5 N HCl. The layers are separated; the organic layer is dried over NA2SO4, filtered and concentrated. The crude product is triturated with ether to afford the title compound (0.72 g, 1.35 mmol) as a white foam.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:8]([C:6]2[CH:5]=[CH:4][N:3]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccn([C@H](C)c3ccccc3)c(=O)c2)c(O)n1
Temperature: 0 °C
Reaction time: 13 h
Yield: 68.1 %

Procedure:
To a solution of (R)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (336 mg, 1.4 mmol), 1-hydroxybenzotriozole (373 mg, 2.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (531 mg, 2.8 mmol), triethylamine (1.0 mL) in dichloromethane (30 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (210 mg, 1.4 mmol). The reaction mixture was stirred at 0° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as a white solid (360 mg, 68%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.53 (t, J=4.8 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.38-7.26 (m, 5H), 6.78 (s, 1H), 6.51 (dd, J=1.8 Hz, J2=6.9 Hz, 1H), 6.13 (q, J=7.2 Hz, 1H), 5.84 (s, 1H), 4.22 (d, J=4.8 Hz, 2H), 2.13 (s, 3H), 2.10 (s, 3H), 1.68 (d, J=7.2 Hz, 3H).