Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 94.7 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.24 g, 0.62 mmol) in dry MeOH (10 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.30 mL, 6.20 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. or until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude material was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a brownish solid (0.21 g, 96%). 1H-NMR (CDCl3) δ1.09 (t, 3H, J=6.9 Hz), 1.30-1.66 (m, 3H), 1.48 (s, 9H), 1.80-1.83 (m, 1H), 1.90-1.94 (m, 1H), 1.98-2.04 (m, 1H), 2.11-2.15 (m, 1H), 2.80-2.90 (m, 1H), 3.05-3.22 (m, 2H), 4.12-4.19 (m, 1H), 6.65 (dd, 1H, J=2.1, 8.7 Hz), 6.87 (d, 1H, J=2.1 Hz), 6.96 (s, 1H), 7.15 (d, 1H, J=8.7 Hz), 7.725 (s, 1H); EI-MS (m/z, %) 357 (M+, 100).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19]>CO>[CH3:17][S:18]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 1-chloromethyl-3-nitro-5-trifluoromethyl-benzene (520 mg; 2.170 mmol) and methanesulfinic acid sodium salt (664 mg; 6.511 mmol) in Methanol (10 ml) of was refluxed overnight. The reaction was then cooled to room temperature and the product precipitated was filtered and diluted with dichloromethane. The solid was removed and the organic phase was concentrated in vacuo 520 mg (2 mmol; 85% yield) of 1-methylsulfonylmethyl-3-nitro-5-trifluoromethyl-benzene were obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl>CCO.O.CCO.[Fe]>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[NH2:17])[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN(C)C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
2-(3-(N,N-Dimethylamino)methylphenyl)-4-nitroanisole (200 mg, 0.70 mmol) was dissolved in EtOH/H2O (5 mL:2.5 mL). concentrated HCl (40 uL) was added, followed by iron powder (314 mg). The reaction mixture was refluxed for 1 h, allowed to cool to room temperature, and diluted with EtOH (10 mL). The slurry was filtered and the filtrate evaporated. The resultant oil was taken up in 1 M NaOH (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic phases were dried (Na2SO4) and evaporated to afford 3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline as a brown oil (102 mg, 0.40 mmol, 57%)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:8]>O>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: O=C(O)CCc1ccc(C(=O)CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of sodium azide (2.0g.) in water (20ml.) was added to a stirred suspension of 3-[4-(chloroacetyl)phenyl]-propionic acid (5g.) in water (30ml.). After stirring for 16 hours at room temperature, the residual solid was separated, washed with cold water (2 × 10ml.) and dried in vacuo to give 3-[4-(azidoacetyl)phenyl]propionic acid as a white solid, which possessed a characteristic azide absorption in the infra-red spectrum at 2120 cm-1.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:15][C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4].NC1C=C(C)C=C(C)N=1.C(O)(=O)CC.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:3]([C:5]1[N:15]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]3)=[CH:36][CH:37]=2)[C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4]
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC=CC1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: Cc1cc(C)nc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OC)CC=CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.885 g, 22.1 mmol) in 50 ml of DMF at 0° C. was added a solution of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (3.57 g, 20 mmol, prepared from 2-amino-4,6-dimethylpyridine by nitration, hydrogenolysis to the diamine and condensation with propionic acid and polyphosphoric acid, as described in EP 400974 A2) in 10 ml of DMF dropwise and the reaction mixture was warmed to room temperature. After 20 minutes the reaction was cooled to 0° C. and a solution of the product of Step 4, above, (5 g, 17 mmol) in 10 ml of DMF was added dropwise. The reaction was then allowed to warm to room temperature and stirred overnight then the DMF was removed in vacuo. The residue was taken up in water and extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution, dried with MgSO4, filtered, evaporated and chromatographed on silica gel with a gradient elution from 5:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to yield 5.8 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:6]2([CH2:11][C:12]#[N:13])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].N>>[CH:1]1([C:6]2([CH2:11][C:12](=[N:15][OH:16])[NH2:13])[O:10][CH2:9][CH2:8][O:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NO
Reactant: N#CCC1(C2CCCC2)OCCO1
Agent: Cl
Agent: N
Product: NC(CC1(C2CCCC2)OCCO1)=NO

Procedure:
According to the procedure described in Example 133A Step 3, 2-(2-cyclopentyl-1,3-dioxolan-2-yl)acetonitrile (1.5 g, 8.3 mmol) was reacted with hydroxylamine hydrochloride (3.17 g, 45.5 mmol) and liquid ammonia (7.8 mL, 7N in methanol), to afford 2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide, which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.11 (bs, 2H), 4.20-3.95 (m, 4H), 2.38 (s, 2H), 2.33-2.22 (m, 1H), 1.73-1.41 (m, 8H); LC-MS (ESI) m/z 215 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.N(C1C=COC=1C=O)=[N+]=[N-].[C:19]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:20][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>C(O)C.N1CCCCC1>[O:4]1[C:3]2[C:2](=[N:1][C:20]([C:19]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=2)[CH:6]=[CH:5]1
Reactant: Nc1ccoc1C=O
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [N-]=[N+]=Nc1ccoc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2occc2nc1C(=O)OCC
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Amino-2-formylfuran, prepared from 3-azido-2-formylfuran (8.9 g 0.065 mol) is dissolved in ethanol and to this solution diethyl oxalacetate (12.23 g, 0.065 mol) and ten drops of piperidine are added. In addition pulverized 3 A° molecular sieve is added and the reaction stirred at 65°-60° C. for three hours, then additional diethyl oxalacetate (2.2 g) is added. The reaction is essentially complete after 12 hours at 55°-60° C. On cooling the reaction is filtered, and the filtrate concentrated and then dissolved in ethyl acetate, water washed, then brine washed, dried over anhydrous magnesium sulfate and stripped to dryness. The residue is dissolved in 3:1 hexane:ethyl acetate and passed through a flash chromatographic column in two stages. First it is filtered by vacuum through a four to five inch pad of silica from which the last three fractions containing the required product are collected and combined. These combined fractions are then passed through a six inch column eluting under pressure with ethyl acetate:hexane 3:1 and 2.1. Diethyl furo[3,2-b]pyridine-5,6-dicarboxylate 4.15 g (24%) is obtained after crystallization from hexane-ether, of mp 60°-64° C., and with a mass spectrum m/e of 264.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=[O:11].[CH3:13]O>>[NH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: O=C(O)C1CCCN1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7 mL of thionyl chloride was dissolved in 50 mL of methanol in an ice-water bath, followed by addition of pyrrolidine-2-carboxylic acid 10a (5 g, 43.40 mmol). The mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure to obtain methyl pyrrolidine-2-carboxylate 10b (10 g) crude product as a white solid, which was directly used in the next step without purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C1(C)C=CC=CC=1.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 15 g of pyrazole and 200 ml of toluene was added dropwise 23.7 ml of dimethylsulfamoyl chloride at room temperature. Then, 40 ml of triethylamine was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 17.6 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28]([NH:22][CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])[CH2:16][CH2:17]2)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN(CCCCCN1CCC(CN)CC1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(C)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.20-1.88(11 H,m), 2.20(3 H,s), 2.63(2 H,t,J=6.8 Hz), 2.60-2.32(4 H,m), 3.78(2 H,s), 7.25-7.36(5 H,m) (3) A suspension of N-benzyl-N-methyl-5-(4-aminomethylpiperidin-1-yl)-pentylamine (3.52 g), 4-amino-5-chloro-2-methoxybenzoic acid (2.34 g), dicyclohexylcarbodiimide (2.39 g), 1-hydroxybenzotriazole (1.57 g) and triethylamine (2.35 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 12 hr. The solvent was evaporated, and water was added to the residue, which was followed by extraction with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.86 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(N-benzyl-N-methylamino)pentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:22]([O:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25](=[O:41])[CH2:26][CH:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccc(-c2ccccc2)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of (R)-(+)-N-benzyl-α-methylbenzylamine (8.9 mL, 42.6 mmol) in THF (100 mL) was treated with n-butyllithium (26.6 mL of a 1.6 M soln in hexanes; 42.6 mmol). After stirring for 10 min, the purple solution was cooled to -78° C. and treated with a solution of ester 12-2 (5.76 g, 21.3 mmol) in THF (10 mL). After stirring for 20 min, the solution was quenched with satd aq NH4Cl soln (5 mL), and the cold bath removed. The reaction mixture was diluted with Et2O (100 mL), and washed with 10% aq citric acid (50 mL), satd aq NaHCO3 (50 mL), 5% aq acetic acid (30 mL), 10% aq K2CO3 (50 mL), and brine (50 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (90:10 hexanes/EtOAc) to give adduct 12-3.
Reaction SMILES: NC(N)=O.[I:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>N1C=CC=CC=1>[CH2:13]([NH:15][C:16]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([I:5])=[CH:11][N:10]=1)=[O:17])[CH3:14]
Reactant: Nc1ccc(I)cn1
Reactant: CCN=C=O
Agent: NC(N)=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
Step-1. 5-tributylstannanyl-pyridin-2-yl)-urea. (85) To 5-iodo-pyridin-2-ylamine (0.5 g, 2.27 mmol) in pyridine (2.5 mL) was added ethylisocyanate (0.24 g, 3.4 mmol)). The reaction mixture was stirred at room temperature for 72 h, concentrated. Water (40 mL) was added, stirred for 0.5 h, filtered, washed with water, dried to afford 0.61 g (92%) of 1-ethyl-3-(5-iodo-pyridin-2-yl)-urea, MR-66, as white solid. To MR-66 (0.5 g, 1.72 mmol) and bis-tributyltin (5.6 g, 9.64 mmol) in dioxane (25 mL) was added bis-triphenylphosphine palladium dichloride (0.28 g, 0.4 nmol). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 90° C. under Ar for 20 h. The reaction was cooled to room temperature, concentrated. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexanes to afford 0.41 g (53%) of (85) as viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:24][O:23]1)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)([OH:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CCCCC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.3 g, 5 mmol) was dissolved in DMF (10 mL) and stirred for 5 min. Sodium hydride (709 mg, 17.7 mmol) was then added portionwise under nitrogen. This was followed by addition of 2-butyl-2-(4-fluorophenyl)oxirane (3.4 g, 17.7 mmol) at RT and the reaction mixture was stirred for 18 h. After completion of reaction, the reaction mixture was poured into ice water and the product extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by silica gel (#100-200 mesh) column chromatography using 1% MeOH in DCM as eluent. The pure compound was converted into the oxalate salt. 1H NMR (CDCl3, oxalate salt) δ (ppm): 7.30 (m, 3H), 7.10 (d, 1H), 6.95 (m, 3H), 4.20 (m, 1H), 4.0 (m, 1H), 3.62 (m, 2H), 2.70 (m, 3H), 2.50 (s, 3H), 2.20 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H), 1.22 (m, 3H), 1.0 (m, 1H), 0.80 (t, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22](O)=O)[N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]([F:13])([F:12])[F:14])=[CH:8][CH:9]=3)[N:15]=2)[N:18]=1
Reactant: Cc1nc(C(=O)O)n[nH]1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of N′-hydroxy-4-(trifluoromethoxy)benzimidamide (1.3 g, 5.1 mmol) and 5-methyl-1H-1,2,4-triazole-3-carboxylic acid (650 mg, 5.1 mmol) in DMF (15 mL), EDC.HCl (980 mg, 5.1 mmol) and HOBT (690 mg, 5.1 mmol) were added at RT. The mixture was stirred at RT for 1 h, and then heated to 140° C. for 3 h. The resulting mixture was cooled, diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% trifluoroacetic acid) to give 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (590 mg, 37%). MS (ES+) C12H8F3N5O2 requires: 311. found: 312[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:29]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:29])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (147 mg, 0.44 mmol) in toluene (5 mL) with N,N-dimethylformamide (2 drops) at 25° C. was treated with oxalyl chloride (0.05 mL, 0.53 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated with ammonium hydroxide (0.50 mL, 3.8 mmol). The resulting suspension was allowed to warm to 25° C. and stirred at 25° C. for 1 h. At this time, the reaction was quenched by the addition of a 2N aqueous hydrochloric acid solution (1 mL) and then extracted with diethyl ether (3×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 65/35 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (130 mg, 89%) as a white foam: EI-HRMS m/e calcd for C5H20ClNO3S (M+) 329.0852, found 329.0852.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22])=[CH2:18].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]1([CH2:1][N:8]2[CH2:12][CH2:18][CH:17]([C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccccc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccccc1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (16.62 g,70.0 mmol) in dichloromethane (15 mL) are added dropwise, over a 45-minute period, to a solution of 2-ethenylbenzonitrile (6.00 g, 46.0 retool) and trifluoroacetic acid (0.57 g, 5.0 retool) in dichloromethane (55 mL). The resulting solution was stirred at room temperature for an additional 10 to15 minutes, and then heated with saturated aqueous sodium bicarbonate solution (ca 10-15 mL). The organic layer was decanted, washed with water,and dried over anhydrous magnesium sulfate. Filtration and concentration ofthe solution provided an orange oil which was chromatographed (silica-gel, hexanes-ethyl acetate 5:1) to afford the title compound (6.95 g, 58%) as apale yellow oil. 1H-NMR (300 MHz, CDCl3): δ=1.80-1.92 (1H,m), 2.43-2.55 (1H, m), 2.63-2.75 (2H, m), 2.88-2.96 (2H, m), 3.71 (2H, AB quartet, JAB =13.0 Hz), 3.78-3.86 (1H, m), 7.25-7.41 (6H, m), 7.53-7.66 (3H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1.Br[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][N:19]([C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)[CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1
Reactant: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCNCC2
Reactant: Brc1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCN(c1nc3ccccc3s1)CC2
Temperature: 160 °C
Yield: 59.2 %

Procedure:
To the solution of 2-((1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (60 mg, 0.20 mmol) and 2-bromobenzo[d]thiazole [2516-40-7] (56 mg, 0.26 mmol) in ethanol (0.7 ml) was added DIPEA (176 μl, 1.0 mmol) and DMAP (1.2 mg, 0.01 mmol). The mixture was heated at 160° C. for 1.25 h under microwave conditions. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane 2:3) to yield 51 mg (56%) of the title compound as a pale yellow solid. [1H NMR (600 MHz, DMSO-d6) ♀ ppm 10.96 (br. s., 1H), 7.76 (d, J=7.9 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22-7.32 (m, 2H), 7.01-7.11 (m, 2H), 6.96 (t, J=7.3 Hz, 1H), 4.63 (s, 2H), 3.82-3.96 (m, 2H), 3.38-3.49 (m, 2H), 3.17 (t, J=5.9 Hz, 2H), 2.06-2.18 (m, 2H), 1.74-1.84 (m, 2H), 1.61-1.74 (m, 2H), 1.53 (d, J=13.7 Hz, 2H); LCMS RtC=2.37 min, [M+H]+=431.2].