Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[Cl:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: Nc1ccc(O)c(Cl)c1Cl
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-amino-2,3-dichlorophenol (1.00 g, 5.62 mmol) in dry DMF (20 mL) under N2 was added K2CO3 (854 mg, 6.18 mmol) and the mixture kept at RT for 10 min and then treated with a solution of 4-chloro-3-nitropyridin-2-amine (1.024 g, 5.90 mmol) in dry DMF (5.0 mL) in a single portion. The reaction mixture was maintained at RT for 19 hr and was then partitioned between EtOAc (100 mL) and water (100 mL). The aq layer was separated and was extracted with EtOAc (4×70 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-70%, gradient elution) to afford 4-(4-amino-2,3-dichlorophenoxy)-3-nitropyridin-2-amine as a dark solid (1.28 g, 70%); Rt 1.85 min (Method 2); m/z 315 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li][CH2:12]CCC>C1COCC1>[CH3:12][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [Li]CCCC
Reactant: Brc1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 19-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. Mel (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0-15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 20-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 20-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 20-2 in 96% yield: MS-ES m/z 258.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[C:8]([C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:21]=[CH:20]4)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=[O:36]>O.O1CCOCC1.C([O-])(O)=O.[Na+]>[F:13][C:12]([F:15])([F:14])[C:11]([C:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:36])[C:3]=2[NH:10][CH:9]=1)([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[OH:16]
Reactant: O=C(O)C(F)(F)F
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)ncnc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]cnc2c(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c[nH]c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A mixture of 1-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (43 mg, 0.09 mmol) and 1 mL of trifluoroacetic acid in 1 mL of water and 2 mL of dioxane was warmed at 70° C. After 18 hours, the reaction was diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of DMF and purified by reverse phase HPLC (5-95% CH3CN/water+0.1% TFA). The desired fractions were combined and the CH3CN was removed in vacuo. The aqueous layer was made basic with saturated sodium bicarbonate and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo to provide 18 mg (44%) of the title compound as a white solid. MS m/z 444.27 (MH+).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1>C(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCO
Product: O=C([O-])/C=C/c1ccc(O)cc1

Procedure:
Sitagliptin free base (0.25 gms) and coumaric acid (0.10 gms) were dissolved in ethanol (2 ml) at 60° C. to 65° C. and the resultant solution left for slow solvent evaporation at room temperature for 48 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 4 hours to obtain the title compound. Yield: 0.12 gms.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5](=[O:16])[CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>O>[C:8]([NH:7][CH2:6][CH:5]([OH:16])[C:4]([F:18])([F:17])[F:3])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(NCC(O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of g (0.263 mol) of NaBH4 in 100 ml of H2O was added to 14.8 g (59.4 mmol) of N-(3,3,3-trifluoro-2-oxo-propyl)benzamide in 1000 ml of H2O. After stirring for 2 hours at 25° C., the solution was acidified with concentrated HCl (pH 1), basified by adding NaOH pellets (pH 10) and extracted with AcOEt (3×500 ml). After drying (MgSO4), the organic layer was flash evaporated to give 11 g of a white solid, which was recrystallized from CHCl3 to yield 10.0 g (72%) of pure trifluoromethylalcohol; m.p. 156° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH2:25]([NH2:28])[CH:26]=[CH2:27].O>CN1CCN(C)C1=O.C(Cl)(Cl)Cl>[CH2:25]([NH:28][C:7]1[N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][C:2]=1[NH2:1])[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN1CCN(C)C1=O
Product: C=CCNc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and allylamine (0.0881 ml) in 1,3-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give syrup. The syrup was crystallized from a mixture of acetone and hexane to give 6-[6-(allylamino)-5-amino-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (71 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([OH:27])=[O:26])[C@@H:15]([CH3:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:35]1(O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[NH:13]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C@H:14]([C:25]([O:27][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:26])[C@@H:15]([CH3:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
EDC.HCl (7.5 g, 40 mmol) was added to a stirring solution of Boc-Thr(Bzl)-OH (10 g, 32 mmol), cyclohexanol (5.0 mL, 48 mmol), and OMAP (0.66 g, 5.3 mmol) in OCM (75 mL) at 0° C. The mixture was warmed to room temperature (rt) over 30 min and stirred additionally overnight. After removal of the solvent in vacuo, the residue was dissolved in AcOEt, washed successively with 5% citric acid (3×), 5% NaHCO3 (3×) and saturated NaCl (3×), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (AcOE:hexane 1:8) to yield oily Boc-Thr(Bzl)-OcHex (12 g, 30 mmol, 95%). 1H NMR (CDCl3 400 MHz) 67.34-7.25 (m, 5H), 5.28 (d, J=9.6 Hz, 1H), 4.83-4.77 (m, 1H), 4.54 (d, J=11.6 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 4.26 (dd, J=2.2, 9.6 Hz, 1H), 4.15 (dq, J=2.2, 6.4 Hz, 1H), 1.84-1.81 (m, 1H), 1.78-1.62 (m, 4H), 1.56-1.46 (m, 1H), 1.45 (s, 9H), 1.44-1.28 (m, 4H), 1.26 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](O)=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:27]=C=NC2CCCCC2)CCCCC1.N.C(O)(=O)C>C(Cl)Cl.C(Cl)(Cl)Cl>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([NH2:27])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1S2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C(N)=O)c1ccc2c(c1)CCc1cccnc1S2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
An amount of 50 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionic acid was dissolved in the mixed solvents of 20 ml of methylene chloride and 20 drops of chloroform by heating, and to this were added 50 mg of dicyclohexylcarbodiimide with ice-cooling, then dropwise 3 ml of methylene chloride saturated with liquid ammonia. The resulting mixture was stirred for 1.5 hours under a stream of nitrogen. After the completion of the reaction, to the mixture were added pieces of ice and acetic acid and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was chromatographed over silica gel, eluted with n-hexane/acetone (4/1-1/1), and there was obtained colorless solid. This was recrystallized from ethyl acetate to give 38 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionamide as colorless crystals having a melting point of 173.5°-175° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[NH:49]([C:61](OC(C)(C)C)=[O:62])[C@H](C(O)=O)CC1C=CC=CC=1.N1CCOCC1>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:20]1([C:61]([NH2:49])=[O:62])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml flask was charged with Boc-Phe-OH (10 g, 38 mmol), morpholine (3.3 g, 38 mmol) and 1-hydroxybenztriazole (5.1 g, 38 mmol) in 100 ml dry dimethylformamide (DMF). To this solution was added diisopropylethylamine (DIEA) at zero degrees C. until the pH value reached 8, followed by addition of EDC (8.8 g, 46 mmol). The solution was slowly warmed to room temperature. The mixture was stirred for eight hours at room temperature (about 22° C.). The DMF was removed by vacuum evaporator, ethyl acetate and water were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 ml×2), combined extracts were washed with 1N HCl, saturated NaHCO3, water and brine, dried with MgSO4, filtered and concentrated to give a colorless liquid (12.8 g, 37.7 mmol; 99 percent yield) that was characterized by 1HNMR as Boc-Phe-morpholine.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:34][CH:35]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, light yellow solid (81 mg, 63%), MS (ISP) m/z=517.3 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH2:3][C:4]#[N:5].[NH2:16][NH2:17]>CCO>[CH3:15][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[C:7]=1[CH2:6][C:2]1[CH:3]=[C:4]([NH2:5])[NH:16][N:17]=1
Reactant: NN
Reactant: Cc1cc(C)c(CC(=O)CC#N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(Cc2cc(N)[nH]n2)c(C)c1
Temperature: 25 °C

Procedure:
3-Oxo-4-(2,4,6-trimethyl-phenyl)-butyronitrile (1.37 gms.) is then suspended in 20 mL of anhydrous EtOH. This suspension is treated with 0.428 mL of anhydrous hydrazine, and subsequently is heated to refluxing temperature overnight. The reaction mixture is cooled to room temperature and evaporated to dryness in vacuo to yield 1.73 gms. of a yellow oil. This oil is then triturated with warm ethyl acetate for 45 min. to provide a yellow-white precipitate. Collection of this precipitate by filtration provides the desired 5-(2,4,6-trimethyl-benzyl)-2H-pyrazol-3-ylamine in the amount of 0.498 gms.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].N12CCCN=C1CCCCC2>>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: Cc1ccc(C(=O)O)nc1Cl
Reactant: OCC(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(=O)O)nc1OCC(F)(F)F
Temperature: 150 °C
Reaction time: 120 h
Yield: 72 %

Procedure:
A mixture of 6-chloro-5-methyl-pyridine-2-carboxylic acid (CAN 1166828-13-2, 200 mg, 1.17 mmol), 2,2,2-trifluoroethanol (466 mg, 336 μl, 4.66 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (CAN 83329-50-4, 887 mg, 870 μl, 5.83 mmol) was shaken in a sealed tube for 2 days at 140° C. and subsequently for additional 5 days at 150° C. The brown solution was poured into 25 mL ice/0.1 N HCl and extracted with i-PrOAc (2×25 mL). The organic layers were washed with ice/brine (2×25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (198 mg, 58%) as off-white solid containing traces of starting material, MS (EI): m/e=233.9 [M−H]−.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:5][C:6]2[CH2:1][CH2:4][CH2:8][C:7]=2[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: N#CCC(=O)c1cccs1
Reactant: CC(=O)c1cccs1
Agent: [S]
Solvent: O=C1CCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Yield: 67 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 67%; IR (KBr) cm−1: 3344, 3242, 3130, 1566, 1435, 1264, 1031, 771, 747; 1H NMR (CDCl3):δ2.27 (m, 2H), 2.47 (t, 2H, J=7.4 Hz), 2.70 (t, 2H, J=7 Hz), 6.65 (bs, 2H), 7.06 (dd, 1H, J=3.8 and 4.8 Hz), 7.37 (dd,1H, J=1.0 and 4.6 Hz), 7.53 (dd, 1H, J=5.0 and 1.2 Hz); yellow solid, mp: 133-134° C. (petroleum ether).
Reaction SMILES: [N:1]([C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:5][OH:6])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: [N-]=[N+]=N[C@H](CO)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Reaction time: 1 h

Procedure:
A mixture of (S)-2-azido-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (604 mg, 2.60 mmol) in ethyl acetate (28 mL) and 10% Pd—C (70 mg) was stirred under H2 (1 atm) for 1 hr. The catalyst was filtered off and the filtrate was concentrated to afford the title compound. 1H-NMR (300 MHz, CDCl3): 8.64 (s, 1H), 7.86 (d, 1H, J=8.1 Hz), 7.60 (d, 1H, J=8.1 Hz), 4.16 (m, 1H), 3.73 (dd, 1H, J=10.5, 4.2 Hz), 3.56 (dd, 1H, J=10.4, 7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:46])[CH:5]=[C:6]([Cl:45])[C:7]=1[CH2:8][C@@H:9]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)[CH:31]=1)[O:10][C:11](=[O:29])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20](S(C)(=O)=O)[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:46])[CH:5]=[C:6]([Cl:45])[C:7]=1[CH2:8][C@@H:9]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:38])[F:39])=[C:32]([O:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)[CH:31]=1)[O:10][C:11](=[O:29])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)N(c1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(4-(N-(methylsulfonyl)methylsulfonamido)benzylcarbamoyloxy)ethyl)pyridine 1-oxide (218 mg, 0.301 mmol) was dissolved in MeOH (10 ml), and potassium carbonate (125 mg, 0.903 mmol) was added. The mixture was stirred at 60° C. for 1 hour. The solvent was removed under vacuum, and the crude material was portioned between water and EtOAc. The organic layer was dried over Na2SO4, and the solvent was evaporated affording a crude material that was purified by flash chromatography on silica gel (DCM:MeOH 100:0.2) affording the desired product (90 mg, 0.139 mmol, 46.3% yield, MS/ESI+ 645.85 [MH]+ [αD]=−32.16, c 0.523, DCM).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:28][C:29]([OH:31])=O)[C:22]=3[CH:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:13]1([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:28][C:29]([N:32]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:31])[C:22]=3[CH:21]=[N:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CC1CCCc2c1cnn2-c1ccccc1
Reactant: C1CCCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CC1CCCc2c1cnn2-c1ccccc1)N1CCCCCC1
Temperature: 45 °C
Yield: 33.3 %

Procedure:
CDI (63.2 mg, 0.39 mmol) is added to a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetic acid (100 mg, 0.39 mmol) in CH2Cl2 (20 mL) cooled in an ice bath, and is heated to 45° C. for 2.5 hours. Then it is cooled to 0° C. and azacycloheptane (38.7 mg, 0.39 mmol) is added and is heated at 45° C. for 1 hour. The solvent is evaporated under reduced pressure, diluted in AcOEt and washed with diluted HCl. The organic phase is dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography, giving 1-(2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetyl)azepane (45 mg, 0.13 mmol, 33%, oil).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: CN1CCC(Nc2cccc3nc(NC(=O)c4ccccc4)nn23)CC1

Procedure:
The title compound was prepared following procedure and work up described for example 71 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (ABCR, 0.50 mL) as a white powder (59 mg, 46%). 1H NMR (DMSO-d6) δ 10.91 (brs, 1H), 8.00 (d, J=7.2 Hz, 2H), 7.57 (m, 4H), 6.87 (d, J=8.3 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 3.84 (m, 1H), 2.74 (m, 2H), 2.16 (s, 3H), 2.03 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H). HPLC, Rt: 1.70 min. (purity 99.4%). LC/MS, M+(ESI): 351.4, M−(ESI). 349.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[C@@H:3]2[CH2:17][CH2:18][CH2:19][C@@H:2]12.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:17][CH2:18][CH2:19][C@@H:2]12
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCO[C@@H]2CCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C1C[C@H]2NCCO[C@@H]2C1

Procedure:
To (4aR,7aR)-benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (199.5 mg, 0.76 mmol) dissolved in ethyl acetate (5 mL) was added palladium (10 weight % on carbon, 81 mg, 0.076 mmol). Added hydrogen gas via balloon, and the reaction was stirred under a hydrogen atmosphere for two hours at room temperature. The mixture was filtered over celite and concentrated under reduced pressure to afford (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine. 1H NMR (500 MHz, CDCl3) δ 3.90 (d, J=11.5, 1H), 3.64 (t, J=11.6, 1H), 3.17 (dd, J=9.2, 18.3, 1H), 2.96 (t, J=11.9, 1H), 2.88 (d, J=12.2, 1H), 2.59-2.47 (m, 1H), 1.89 (dd, J=9.1, 18.4, 1H), 1.84-1.61 (m, 4H), 1.57-1.44 (m, 1H), 1.38-1.26 (m, 1H).