Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]=[C:10]=[S:11])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Cl)c1N=C=S
Yield: 17.4 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro-4-methylpyridin-3-amine (4.0 g, 28 mmol), thiophosgene (3.2 g, 28 mmol), N-ethyl di-isopropyl amine (5 mL) in DCM (20 mL) to afford 0.900 g of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:21]([O:10][CH2:9][CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:22])[CH2:20][C:19]([CH3:18])=[O:23]
Reactant: C=C1CC(=O)O1
Reactant: OCC=Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC=Cc1ccncc1

Procedure:
495 mg (3.66 mmol)f 3-(pyridine-4-yl)-2-propene-1-ol, 0.61 ml (4.38 mmol) of triethylamine and 0.35 ml (4.54 mmol) of diketene were heated to 70° C. under stirring in 20 ml of toluene for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture at room temperature. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].[O:35]=[C:36]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:38]2(CCNCC2)[CH2:37]1>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:4](=[O:32])[N:3]1[CH2:1][CH2:2][C:38]2([C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36](=[O:35])[CH2:37]2)[CH2:34][CH2:33]1)(=[O:10])=[O:11]
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: O=C1CC2(CCN(C(=O)C(Cc3ccc([N+](=O)[O-])cc3)C(=O)NS(=O)(=O)c3ccc4ccccc4c3)CC2)c2ccccc21
Yield: 23.7 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 6 (4) and 3-oxospiro[indane-1,4′-piperidine] (141 mg). This was purified by silica gel column chromatography to give the title compound (90 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14].[OH-].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>O.C(O)C>[O:28]1[CH2:27][CH:26]1[CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14]
Reactant: ClCC1CO1
Reactant: O=C(Cc1ccc2ccccc2c1O)NCCO[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Cc1ccc2ccccc2c1OCC1CO1)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 40 %

Procedure:
4.600 g (0.015 mole) of 1-hydroxy-N(2-nitroxyethyl)-2-naphthalene acetamide dissolved in a mixture of 4 ml of water, 1.436 g (0.021 mole) of 85% potassium hydroxide and 38 ml of ethanol were added slowly over a solution of 35.490 g (30 ml, 0.383 mole) of epichlorohydrin in 17 ml of ethanol, with temperature control. The mixture was stirred at room temperature for 22 hours. 150 ml of water were added and the mixture was concentrated at reduced pressure at 40° C. The mixture was extracted three times with 70 ml of ethyl acetate and dried over sodium sulphate. It was filtered and the solvent was removed at low pressure. The oil obtained was purified by column chromatography in silica gel (0.060-0.200 mm). 2.354 g (0.006 mole) of 1-(2,3-epoxy)propoxy-N-(2- nitroxyethyl)-2-naphthalene acetamide were obtained on eluting with a mixture of chloroform/methanol: 9/1 and removing the solvent at reduced pressure (m.p. 67°-71° C., Rf =0.41 TLC, silica gel Merck HPTLC-5629, chloroform 80/acetone 20). They were mixed with 8.88 g (12.8 ml, 0.150 mole) of isopropylamine in 80 ml of methanol and heated under reflux for 1 hour under anhydrous conditions. The product was concentrated at reduced pressure at 40° C. The oil obtained was redissolved in 80 ml of ethyl acetate and was extracted three times with 35 ml of 1N HCl. The acid extracts were pooled and were alkalized with the addition of powdered sodium carbonate and a solution of 1N NaOH to pH=12. The solution was treated twice with 50 ml of ethyl acetate. The organic extracts were pooled and washed twice with 25 ml of sodium chloride saturated water. It was dried over anhydrous sodium sulphate, was filtered and was concentrated at reduced pressure to give a residue which was purified by column chromatography on silica gel (0.060-0.200 mm). On eluting with a mixture of chloroform 90/methanol 20 and removing the solvent at reduced pressure until a constant weight, 1.113 g (17%) of an oil which solidified in amorphous form were obtained.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[ClH:31].[NH2:32][C:33]([NH2:35])=[NH:34].C(NC(C)C)(C)C>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:35][C:33](=[NH:32])[NH:34]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17].[ClH:31]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: N=C(N)N
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCOc1cc(C2NC(=N)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,2-diphenylethanone (500 mg, 2.55 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (538.5 mg, 2.55 mmol), guanidine hydrochloride (731 mg, 7.65 mmol), diisopropylamine (1.1 mL) in ethanol (5 mL) was refluxed at 80° C. for 60 h. The mixture was evaporated under reduced pressure and the residue was treated with a mixture of saturated aqueous sodium bisulfite solution (50 mL), dichloromethane (100 mL) and isopropanol (30 mL), and the resulting mixture was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was extracted with a mixture of dichloromethane and isopropanol (3:1, 50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and purified by preparative HPLC. The product containing fractions were treated with HCl/MeOH (2 mL, 2 N) and concentrated in vacuo to give Compound 112 as an HCl salt (280 mg, yield 25.45%). 1H NMR (DMSO-d6 400 MHZ): δ 10.48 (s, 1H), 10.27 (s, 1H), 9.35 (s, 1H), 7.59 (s, 2H), 7.53 (s, 1H), 7.52-7.31 (m, 5H), 7.26 (d, J=2.0 Hz, 1H), 7.12-7.10 (m, 3H), 6.92-6.90 (m, 2H), 5.57 (d, J=3.2 Hz, 1H), 4.1-4.06 (q, J=7.2 Hz, 2H), 1.36-1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 431.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(Cl)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(Cl)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.O>[N+:17]([C:6]1[CH:7]=[C:8]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:5]=1[C:2]#[N:3])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(F)(F)(F)(F)F)ccc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 1.25 h
Yield: 95.1 %

Procedure:
Copper (I) cyanide (5.05 g) was added to a stirred solution of 4-bromo-3-nitro- phenylsulphur pentafluoride (18.5 g) in N,N- dimethylformamide and heated at 140° C. for 4 hours. A mixture of ferric chloride (20.0 g),concentrated hydrochloric acid and water was added at 105° C. and heating continued for 1.25 hours. The cooled mixture was diluted with water, extracted (ether) and the organic phase washed (water), dried (magnesium sulphate) and evaporated to give 2-nitro-4-pentafluorosulphanylbenzonitrile (14.7 g), m.p.57-59° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][CH:49]3CCN(C(OC(C)(C)C)=O)CC3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:88]([CH2:91][CH3:92])[CH2:89][CH3:90]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:29]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][CH:49]6[CH2:90][CH2:89][NH:88][CH2:91][CH2:92]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:30])[N:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (80 mg, 0.177 mmol), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (74 mg, 0.177 mmol), HBTU (o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (80 mg, 0.212 mmol) and Et3N (0.12 mL, 0.884 mmol) in DCM was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred for 2 h. Solvent was evaporated under a stream of nitrogen and then the residue was purified with a Gilson HPLC (with 1% TFA in the solvent), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, product converted to the free base with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide as a solid (14 mg, 11.1%). LC-MS m/z 716 (M+H)+, 1.58 min (ret time).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:17]2[NH:16][C:15](=[O:27])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:20][CH2:19][C:18]=2[CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Yield: 81 %

Procedure:
A mixture of 21.6 g (59.2 mmol) 3-(1-benzyl-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.5 g palladium on charcoal (10%) in 300 mL methanol was hydrogenated in a 3 bar hydrogen atmosphere at 50° C. until the reaction was complete. The catalyst was removed by suction filtering and the mother liquor was concentrated by rotary evaporation. The residue was triturated with 150 mL DIPE, suction filtered, washed with 100 mL DIPE and dried at 40° C. in the CAD. 13.2 g of the desired product was obtained.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]2([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[CH2:6][CH2:5]2)[O:18][CH2:17][CH2:16][O:3]1
Reactant: CC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(C2(c3ccc([N+](=O)[O-])cc3)CC2)OCCO1

Procedure:
A solution of 4-(1-acetylcyclopropan-1-yl)nitrobenzene (2.40 g), ethylene glycol (6.5 mL), and pyridinium p-toluenesulfonate (1.47 g) in benzene (120 mL) was heated under reflux with Dean-Stark apparatus for 15 hours. After cooling, dilution with saturated sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:1) of the residue gave 4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)nitrobenzene (2.83 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][N:23]=[CH:22]5)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(#N)C>[C:36]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:8]([C:7]5[C:2]([F:1])=[C:3]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH:4]=[CH:5][C:6]=5[F:28])=[O:9])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1)(=[O:38])[CH3:37]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc5[nH]ncc5c4)cc23)c1F
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc5c(cnn5C(C)=O)c4)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a round bottom flask, propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-0001, 0.020 g, 0.040 mmol) is combined with acetic anhydride (0.023 mL, 0.24 mmol) and 4 mL of acetonitrile. The reaction is stirred at room temperature for 3 hours, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of 20-100% ethyl acetate (with 2% acetic acid) in hexanes. Appropriate fractions are combined and concentrated under vacuum, and the resulting solid is further washed with a mixture of ethyl acetate:hexanes to provide the desired compound. MS (ESI) [M+H+]+=538.0.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11]([NH2:13])=O.O>O=P(Cl)(Cl)Cl>[Br:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11]#[N:13]
Reactant: NC(=O)c1c([N+](=O)[O-])ccc(F)c1Br
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 75 °C
Yield: 63.8 %

Procedure:
Triethylamine (2.53 mL, 18.2 mmol) was added to a suspension of 2-bromo-3-fluoro-6-nitrobenzamide (Example 6e) (1.60 g, 6.08 mmol) in POCl3 (32 mL), and the mixture was heated at 75° C. for 1.5 h. The mixture was carefully poured into a mixture of ice and water (400 mL) and extracted twice with CH2Cl2. The combined extract was dried MgSO4, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with solvent gradient 0% to 100% EtOAc in hexanes, to give 2-bromo-3-fluoro-6-nitrobenzonitrile 0.95 g, (64%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][CH2:15]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CN(Cc2ccccc2)CCO1
Solvent: ClC(Cl)Cl
Product: ClCCC1CN(Cc2ccccc2)CCO1
Yield: 121.1 %

Procedure:
To 200 ml of toluene is added 58 g of a solution of 70% RDB in toluene and to the mixture is added dropwise a solution of 26.3 of ethyl 4-benzyl-2-morpholinylacetate in 50 ml of toluene below 10° C. Further, after ice-cooling for 30 minutes, the mixture is stirred at room temperature overnight. After to the reaction mixture is successively added 20 ml of acetone and 100 ml of water, the inorganic substance precipitated is filtered off. The toluene layer is separated from the filtrate and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on silica gel to give 10.1 g of 2-(4-benzyl-2-morpholinyl)ethanol. To a mixture of 2.21 g of 2-(4-benzyl-2-morpholinyl)ethanol in 30 ml of chloroform is added 2.30 g of thionyl chloride and the system refluxed for 2.5 hours. After completion of the reaction, the solvent is concentrated under reduced pressure and to the residue are added water and ether. After neutralizing with potassium carbonate, the ether layer is separated and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 2.90 g of 2-(2-chloroethyl)-4-benzylmorpholine as an oily substance.
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=C[CH:3]=1.[NH:10]1C=CC=N1.[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:17]=1[C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH:27]=O)[CH2:23][CH2:22]1)=[O:19].Cl.COC([C@H]1CC[C@H](N)CC1)=O.[Cl-]>>[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:17]=1[C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:10][C:1]2[C:2]([CH3:3])=[CH:7][CH:6]=[CH:5][N:9]=2)[CH2:23][CH2:22]1)=[O:19]
Reactant: c1cn[nH]c1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: NC(=O)c1ccccc1
Agent: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [Cl-]
Product: Cc1cccnc1NC[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1

Procedure:
The compounds of the following tabulated Examples (Table 1) are prepared by a similar method to that of Example 1 using the appropriate benzamide or pyrazole starting materials (prepared analogously to trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide from trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride and the appropriate benzoly chloride) and the appropriate amine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[C:4]([CH3:8])=[N:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(=O)n(C)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn(C)c(O)c1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
In 22 ml. of dry dioxane is dissolved 2.24 g. of 1,3-dimethyl-5-pyrazolone and then 2.96 g. of calcium hydroxide is added thereto. 3.71 g. of p-nitrobenzoyl chloride is added dropwise thereto while stirring at room temperature. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and then 40 ml. of a 2 N hydrochloric acid solution is added thereto. Crystalline substances thus separated are recovered by filtration and washed with water to give 4.38 g. of crude crystals. This product is recrystallized from methanol to give 3.62 g. of the desired product as pale yellow columns having a melting point of 234°-235° C. Yield 69.3%
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.S([Cl:33])(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1.CCOC(C)=O>[Cl:33][CH:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12]
Reactant: O=C1CCCN1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C(Cl)CCN1c1ccccc1
Reaction time: 0.67 h

Procedure:
1-Phenyl-2-pyrrolidinone (1 g, 6.2 mmol) in THF (60 mL, anhydrous) was cooled to −40° C. and LiHMDS (8 mL, 8 mmol, 1 M soln. in THF) was added. The resulting solution was stirred for 40 min. and tosyl chloride (1.78 g, 9.33 mmol) was then added. After warming the solution to RT over a 14 hour period, H2O added to quench reaction. The solution was then concentrated to provide an oil. Next, the oil was redissovled in EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to an oil once again. Purified via flash column chromatography (4:1 hexane/EtOAc) provided 3-chloro-1-phenylpyrrolidin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].O.[CH3:18]N(C)C=O>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(OCCCCCl)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Hydroxybenzaldehyde (26.4 g) in dimethylformamide (50 mL) is added to sodium hydride (8.64 g of 60% in oil) in dimethylformamide (200 mL). 1-Bromo-3-chloropropane (93.2 g) is added and the mixture stirred at 60° C. for 3 hours. The mixture is poured into water (400 mL) and extracted with diethyl ether (3×150 mL). The extracts are dried over MgSO4, filtered and evaporated to leave an orange oil. The oil is distilled end 40.7 g of the title compound collected at 158°-175° C./0.7 mmHg as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH2:18].[OH-].[Na+].OO>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.48 g, 19.71 mmol) was dissolved in THF (100 mL) and the stirred solution was cooled to 0° C. Borane-dimethylsulfide complex (1.9 mL, 19.7 mmol) was added and the reaction mixture was allowed to warm to RT o/n. After 16 h, water was added dropwise until no bubbling was observed. The stirred mixture was then cooled to 0° C. Aqueous NaOH (5M in H2O, 5.3 mL, 26.6 mmol), then H2O2 (30 wt % in H2O, 6.0 mL, 58.5 mmol) were added dropwise. The reaction was then warmed to 50° C. After 30 min, the mixture was diluted with ethyl ether and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hex) to afford the title compound (2.08 g, 41%).