Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].OS(O)(=O)=O.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
5 g of (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 50 ml methanol and the solution was cooled till −15° C. 15 mL (0.28 mol) of conc. H2SO4 (98%) was added dropwise in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was gradually increased, and stirred at 31° C. for 30 min, and then refluxed at 70° C. for 21 hrs. The solvent was distilled off under reduced pressure and to the residue 50 mL of water was added and stirred for 30 min followed by cooling to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The yield was 3.8 g of crude product purified by column, using hexane:ethyl acetate (9:1) as eluent.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH2:3][OH:4].[CH2:16](O)[CH3:17]>[Pd]>[CH3:16][C:17]1[N:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=1
Reactant: CCO
Reactant: CC(C)(CO)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1nc2ccccc2n1C(C)(C)CO
Yield: 98 %

Procedure:
2-(1,1-dimethyl-2-hydroxyethyl)aminonitrobenzene (10 g) in ethanol (200 ml) was hydrogenated at 50 p.s.i. (345 kPa) over 5% Pd/C (0.5 g) for 2 hours. The catalyst was filtered off and the solvent removed under reduced pressure yielding the title compound as a yellow foam 8.4 g (98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=1)[NH:25][CH2:24][CH2:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=1)[N:25]([S:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:11])(=[O:9])=[O:8])[CH2:24][CH2:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 104 %

Procedure:
3,5-Dimethylisoxazole-4-sulfonyl chloride (0.034 g, 0.18 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.075 g, 0.18 mmol) and Et3N (0.037 ml, 0.26 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 21 hr, then evaporated in vacuo to a residue that was suspended in a mixture of saturated NaHCO3 solution (4 ml) and H2O (4 ml). This was extracted with CHCl3 (4×5 ml) and the combined extracts were dried over MgSO4, then concentrated in vacuo to give 0.110 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (1:1) gave 0.078 g (76% yield) of white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27].Cl>O.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH:29][C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:28])=[O:27]
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1Cl
Yield: 101 %

Procedure:
In the presence of potassium carbonate (625 mg), 2,3-dichloroquinoxaline (275 mg) and 2-chlorobenzenesulfonamide (264 mg) were allowed to react in the solution of dimethylformamide (4 mL) for 3 hours at 90° C. To the reaction mixture, water and hydrochloric acid were added and extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated to obtain the title compound (493 mg) having the following physical data.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH:34]=1>>[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][N:3]([C:4]([CH:6]2[CH2:7][CH2:8]2)=[O:5])[CH2:1][CH3:2])[CH:36]=[C:37]([C:39]([F:41])([F:40])[F:42])[CH:38]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1.CCN(CC)CC.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>C(Cl)Cl>[CH:40]([NH:37][C:38]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1)=[O:39])([CH3:42])[CH3:41]
Reactant: O=C(Nc1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12)c1ccccc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of N-[4-(piperidin-4-yl sulfamoyl)-naphthalen-1-yl]-benzamide (C-1) in CH2Cl2 was added Et3N followed by 2-isocyanato-propane. The reaction mixture was stirred at 25° C. overnight. Aqueous work-up followed by purification using reverse phase HPLC provided the title compound. 1H NMR (300 MHz, MeOD) δ 8.74 (d, 1H), 8.29 (d, 1H), 8.17 (d, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.81 (d, 1H), 7.63 (m, 5H), 3.75 (m, 3H), 3.21 (m, 1H), 2.68 (t, 2H), 1.51 (m, 2H), 1.26 (m, 2H), 1.05 (d, 6H); LC/MS (M+H)+ m/z 495.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30](=[CH2:32])[CH3:31].OS(O)(=O)=O>ClCCl>[C:30]([O:27][C:26](=[O:28])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])([CH3:32])([CH3:31])[CH3:29]
Reactant: C=C(C)C
Reactant: O=C(O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 84.4 %

Procedure:
A solution of 150 mg (0.389 mmol) of 8-(9-Fluorenylmethoxycarbonylamino)-3,6-dioxaoctanoic acid, 546 mg (9.73 mmol) isobutylene, and 4.3 μL of 95-98% H2SO4 was stirred at r.t. for 3 days. For workup the reaction solution was diluted with dichloromethane and washed with sat. bicarbonate solution. After drying over sodium sulfate the solvent was removed and the residue obtained purified by chromatography on silica gel with a cHex/EtOAc gradient providing 145 mg (84.4%) of the title compound. ESI MS: 464.12 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:18]([O-])=[O:19].[Na+]>Cl.C(O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:18]=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NCCc2ccc(Cl)nc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N(CCc2ccc(Cl)nc2)N=O)cc1
Temperature: 25 °C

Procedure:
A 250 mL reaction flask was charged with N-(2-(6-chloropyridin-3-yl)ethyl)-4-methylaniline (5 g, 20.3 mmol; Example 117B) in 1 N HCl (22 mL) and ethanol (20 mL). The mixture was stirred at room temperature until complete dissolution was obtained (˜2 hours). The reaction then was cooled in an ice bath and a solution of sodium nitrite (1.55 g, 22.47 mmol; Aldrich) in water (10 mL) was added dropwise with stirring. After the addition was complete, the reaction mixture was allowed to warm briefly to room temperature, then it was cooled again in an ice bath before filtering. The filter cake was washed with water several times and then dried to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.38 (s, 3H), 2.88 (t, J=7 Hz, 1H), 4.34 (t, J=7 Hz 2H), 7.25-7.39 (m, 5H), 7.63 (dd, J=8, 2 Hz, 1H), 8.11 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCc1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCc3cccnc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-3-ylmethanamine according to general procedure 1 providing the intermediate (88 mg, 45%) as a white solid: Rf=0.66 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=1.9 Hz, 1H), 7.99-7.97 (m, 1H), 7.85-7.82 (m, 1H), 7.59 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 4.57 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-])=O)=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1>CCO.[Pd]>[NH2:20][C:19]1[C:2]([OH:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Yield: 100 %

Procedure:
1,1-Dimethylethyl 7-hydroxy-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (8.2 g) was hydrogenated for 4 h under atmospheric pressure and 25° C. in the presence of 10% Pd/C (1.4 g) in EtOH (200 ml). The catalyst was removed by filtration and volatiles evaporated to provide the title compound as a grey solid (7.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([C:42](=[O:43])[N:44]([CH3:45])[CH3:46])[CH2:40][CH2:41]4)=[O:25])[NH:13][C:12]43[CH2:27][CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Reactant: CN(C)C(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)[C@@H]2NC3(CCC(C)(C)CC3)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccnc(Cl)c2F)CC1

Procedure:
The compound (29 mg, 0.06 mmol) obtained in Step 1 of Example 17 and trans-4-amino-N,N-dimethylcyclohexanecarboxamide hydrochloride (WO2008/068171) (17 mg, 0.08 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 36 mg (100%) of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br[CH2:16][C:17]([NH2:19])=[O:18]>>[Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][N:13]([CH2:16][C:17]([NH2:19])=[O:18])[CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cccc2c1C[C@@H]1CNCCN21
Reactant: NC(=O)CBr
Product: NC(=O)CN1CCN2c3cccc(Br)c3C[C@@H]2C1

Procedure:
The title compound, MS: m/e=310.1 (M+H+) was prepared in accordance with the general method of example 6 from (10aR)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and 2-bromoacetamide.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][CH:17]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1c[nH]c2ccccc12
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[N:34]=1)[C:30]#[N:31]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[N:34]=3)[C:30]#[N:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1cc(C#N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from step 3 of Example 5 (59 mg, 0.21 mmol) was dissolved in DMSO (1.0 ml). K2CO3 (86 mg, 0.62 mmol) and 2-chloro-6-methylisonicotinonitrile (31 mg, 0.21 mmol) from step 2 of this example were added and the mixture stirred at 150° C. overnight. The mixture was cooled to RT, diluted with water (30 ml), and extracted with EtOAc (3×30 ml). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 20% EtOAc:Hexanes to give the titled compound. LRMS calc: 396.18; obs: 397.27 (M+1).
Reaction SMILES: C([NH:8][NH:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:23]=[CH:22][N:21]3[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:25][N:26]=[C:20]3[CH:19]=2)[CH:12]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[N:21]2[CH:22]=[CH:23][C:18]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=3[CH3:17])[C:10]([NH:9][NH2:8])=[O:34])=[CH:19][C:20]2=[N:26][N:25]=1
Reactant: Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NN)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Reaction time: 1.5 h

Procedure:
A solution of N′-boc-3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzohydrazide (300 mg, 0.63 mmol) in 3.0 mL of DCM at RT was treated with 2.0 mL of TFA. After 1.5 h of stirring, the volatiles were evaporated. The residue was dissolved in DCM, washed with 1 N NaOH followed by brine. The DCM layer was dried and concentrated to afford the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[N+:24]([O-])=O)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=[O:7])(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([NH:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][C:17]2[C:18](=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[NH:24][C:6]1=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(C)c1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(C)=O)Cc2cccc(C)c2NC1=O

Procedure:
10 Grams of diethyl 2-acetylamino-2-(2-nitro-3-methylbenzyl)malonate and 1 g of 10% Pd-C were suspended in 50 ml of acetic acid, and the suspension was catalytically reduced under 3 to 3.5 atmospheric pressure at 60° to 70° C. by hydrogenation. After the hydrogenation was finished, the catalyst was removed by filtration, and the solvent was removed by evaporation. The residue thus obtained was recrystallized from ethanol to obtain 2.7 g of ethyl 3-acetylamino-8-methyl-3,4-dihydrocarbostyril-3-carboxylate. White powdery substance. Melting point: 236.5°-238.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](O)=[O:20])[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCOCC1.O>[CH:27]1([NH:30][C:19]([C:4]2[C:3]([S:22][C:23]([F:24])([F:26])[F:25])=[C:2]([NH2:1])[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=3[Cl:18])[N:5]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: Nc1c(SC(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(SC(F)(F)F)c(C(=O)NC2CC2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio-1H-pyrazole-3-carboxylic acid (0.85 g, 1.83 mmol) and 1,1-dicarbonylimidazole (0.36 g, 2.20 mmol) in dioxane was heated to. 55° C. for 2 hours. Cyclopropylamine (0.20 ml, 2.83 mmol) was then added and stirring continued at 55° C. for 6 hours. The cooled mixture was diluted with water, extracted with ethyl acetate, washed with aqueous potassium hydrogensulfate (5%), dried over magnesium sulfate and evaporated to give the title compound (0.762 g, yield 87%) as off-white crystals, mp 193° C., 1H NMR (CDCl3): 0.64 (m, 2H, cyclopropyl), 0.83 (m, 2H, cyclopropyl), 2,87 (m,1H, cyclopropyl), 4.31 (bs, 2H, NH2), 6.82 (bs,1 H, C(O)NH), and 7.80 (s, 2H, Ar—H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[CH2:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[CH2:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Product: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(-c2ccccc2)cc1
Yield: 29.1 %

Procedure:
Using general procedure E, N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide (200 mg, 0.550 mmol), phenylboronic acid (134 mg, 1.00 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous brown oil (58 mg, 32%). 1H NMR (500 MHz, CDCl3) δ 7.58-7.50 (m, 4H), 7.44-7.37 (m, 4H), 7.31 (t, J=7.0 Hz, 1H), 6.50 (s, 1H), 3.16 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 3H), 2.60 (m, 1H), 2.40-2.20 (m, 3H), 1.47-1.90 (m, 11H) ppm. 13C NMR (125 MHz, CDCl3) δ 170.5, 146.1, 140.7, 139.2, 128.8, 127.2, 127.0 125.2, 55.6, 53.1, 46.8, 46.2, 40.3, 31.7, 29.3, 29.2, 26.0, 24.4, 19.7 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.55 min; (M+1) 363.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([CH3:36])[NH:30][C:29]3=[O:37])[CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([O:1][CH2:2][CH:3]([NH:13][C:14](=[O:38])[C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([CH3:36])[NH:30][C:29]3=[O:37])[CH2:22][C:23]#[CH:24])=[CH:19][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NC(CO)c2cccc([N+](=O)[O-])c2)cc1
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NC(COC(C)=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 4, N-[2-hydroxy-1-(3-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide was reacted with acetic anhydride to give N-[2-acetoxy-1-(3-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (containing 2 equivalents of water) in 56% yield, m.p. 133°-135° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[F-].[K+].C([Si](CC)(CC)[C:22]([F:25])([F:24])[F:23])C>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu]I>[CH3:16][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[C:2]([C:22]([F:25])([F:24])[F:23])[CH:3]=[N:4]1
Reactant: COC(=O)c1cc(-c2c(I)cnn2C)cs1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cc(-c2c(C(F)(F)F)cnn2C)cs1
Temperature: 70 °C
Reaction time: 10 h
Yield: 74 %

Procedure:
To a solution of methyl 4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (470 mg, 1.35 mmol), copper (I) iodide (256 mg, 1.35 mmol) and potassium fluoride (78 mg, 1.35 mmol) in anhydrous DMF/HMPA (2 ml/2 mL) was added triethyl(trifluoromethyl)silane (745 mg, 4.04 mmol). The mixture was heated to 70° C. under N2 in a sealed tube. After 10 h, the reaction was quenched with NH4Cl (sat'd) (2 mL), extracted with ether (5 mL×5) and washed with distilled water (5 mL×5). The combined organic phase was dried over Mg2SO4 and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.29 g, 74%) as a yellow syrup: LC-MS (ES) m/z 291 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O-])=O>[Pd].COCCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
A suspension of N-[3-(3-nitrophenoxy)propyl]phthalimide (1.0 g; 3.1 mmoles) [prepared in Step A] and 10% palladium on carbon (0.2 g) in 100 ml of 2-methoxyethanol was hydrogenated in a Parr Apparatus at ambient temperature for 45 minutes. The reaction mixture was filtered and the filtrate was evaporated to dryness to give 0.91 g of crude product.