Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][CH:15]=1.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([F:13])[C:15]([B:23]([OH:28])[OH:24])=[CH:16][CH:17]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)c1cccc(F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)c1ccc(B(O)O)c(F)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]([C:21]([O:23][CH3:24])=[O:22])[C:4]1=[O:25])[CH3:2].[CH2:26](N1C2C(=CC(C(=O)C3C=CC(F)=CC=3)=CC=2)C(C(OC)=O)C1=O)C.C(N1C2C(=CC(C(=O)C3C=CC(C)=CC=3)=CC=2)C(C(OC)=O)C1=O)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]([C:21]([O:23][CH2:24][CH3:26])=[O:22])[C:4]1=[O:25])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(F)cc3)ccc21
Agent: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(C)cc3)ccc21
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21

Procedure:
In a similar manner were prepared methyl 1-ethyl-5-(4-chlorobenzoyl)oxindole-3-carboxylate, m.p. 115°-118° C.; methyl 1-ethyl-5-(4-fluorobenzoyl)oxindole-3-carboxylate, m.p. 90°-100° C. (dec.); and methyl 1-ethyl-5-(4-methylbenzoyl)oxindole-3carboxylate, m.p. 110°-115° C.
Reaction SMILES: I.[CH2:2]([N:9]1[CH2:13][C:12](=[O:14])[N:11]=[C:10]1SC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[ClH:42]>C(O)C>[ClH:42].[ClH:42].[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][NH:31][C:10]2[N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:13][C:12](=[O:14])[N:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC1=NC(=O)CN1Cc1ccccc1
Agent: Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(NCCCOc2cccc(CN3CCCCC3)c2)=N1

Procedure:
1-Benzyl-2-methylthio-2-imidazolin-4-one hydroiodide (2.09 g) from the previous stage, 3-(3-piperidinomethylphenoxy)propylamine (1.49 g) and triethylamine (1.27 g) were refluxed in ethanol (35 ml) for 7 hours with stirring. The solution was allowed to cool overnight and evaporated under reduced pressure to give a residue. This residue was dissolved in 2N hydrochloric acid (30 ml), and extracted with chloroform (3×20 ml). The aqueous layer was taken to pH 10 with 2N sodium hydroxide and extracted with chloroform (3×30 ml). The latter chloroform extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was washed thoroughly with cold diethyl ether and treated with dilute ethanolic HCL. Excess solvent was evaporated and the residue recrystallised from isopropanolacetone to afford 2-[3-(3-piperidinomethylphenoxy)propylamino]-1-benzylimidazolin-4-one dihydrochloride, m.p. 95°-98° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[C:12]([O:16][C:17]([N:19]1[CH2:36][CH2:35][N:22]2[C:23](=O)[C:24]3[C:29]([C@@H:21]2[CH2:20]1)=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:36][CH2:35][N:22]2[CH2:23][C:24]3[C:29]([C@@H:21]2[CH2:20]1)=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cccc3C(F)(F)F)[C@@H]2C1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2Cc3c(cccc3C(F)(F)F)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a stirring solution of lithium aluminum hydride (1.12 mL, 1.12 mmol; 1.0 M in THF) in dry tetrahydrofuran (1.2 mL) at 0° C. was added dropwise sulfuric acid (0.50 mL, 0.50 mmol; 1.0 M in THF). After 1 h, N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (100 mg, 0.28 mmol) was added dropwise as a solution in tetrahydrofuran (1.2 mL). The reaction was slowly allowed to warm to room temperature over a period of 1 h and was then quenched by the addition of water (2 mL) and 1N aqueous sodium hydroxide (0.30 mL). The mixture was extracted with ethyl acetate (×3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting pale yellow residue was purified by radial chromatography (30-50% ethyl acetate in hexanes) to afford N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole (37 mg, 39%) as a clear residue. MS (ESI) 343.4 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([C:11]3[N:12]([CH3:20])[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=3)=[N:10][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:16]([C:14]1[CH:15]=[C:11]([C:9]2[NH:8][C:5]3[CH:6]=[N:7][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])=[CH:3][C:4]=3[N:10]=2)[N:12]([CH3:20])[N:13]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cn1nc(C(C)(C)C)cc1-c1nc2cc(Br)ncc2[nH]1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1nc(C(C)(C)C)cc1-c1nc2cc(-c3ccccc3Cl)ncc2[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 6-bromo-2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine (50 mg, 0.15 mmol, prepared as described in the previous step), 2-chlorophenylboronic acid (47 mg, 0.30 mmol), 2M Na2CO3 (0.60 mL, 1.2 mmol) and DME (1 mL) was stirred at 90° C. for 18 h. The resulting mixture was allowed to cool to room temperature and organic layer was separated. The organic layer was purified by direct application to silica preparative TLC plates (2000 micron) and eluted with 3:7 EtOAc-hexanes to yield 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-6-(2-chloro-phenyl)-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Br:19][CH2:18][C:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: CCOC(=O)c1cn(-c2ncccc2F)nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cn(-c2ncccc2F)nc1CBr
Yield: 39.5 %

Procedure:
To a solution of ethyl 1-(3-fluoro-2-pyridyl)-3-methyl-pyrazole-4-carboxylate (10.2 g, 40.9 mmol) in chlorobenzene (205 mL), N-bromosuccinimide (8 g) is added at room temperature. The reaction mixture is stirred and irradiated under a 100 W lamp at room temperature overnight. Then more N-bromosuccinimide (2 g) is added and after 2 hr., no starting material is detected. Solids are filtered and solvent is evaporated. The crude is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol to give 5.3 g of ethyl 3-(bromomethyl)-1-(3-fluoro-2-pyridyl)pyrazole-4-carboxylate. MS (m/z): 328; 330 (M+1; M+3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH3:19])[C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]CCl>>[Cl:20][C:16]([C:12]1([CH3:19])[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17]
Reactant: ClCCl
Reactant: CC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Product: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0 g, 3.8 mmol) in anhydrous dichloromethane (10 mL) thionyl chloride (0.54 g, 4.56 mmol) was added drop wise at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][NH2:16])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19]>>[CH2:18]([C:19]1[N:5]2[C:6]3[C:11]([N:12]=[C:3]([O:2][CH3:1])[C:4]2=[N:15][N:16]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=3)[CH3:17]
Reactant: CCOC(CC)(OCC)OCC
Reactant: COc1ccc2nc(NN)c(OC)nc2c1
Product: CCc1nnc2c(OC)nc3cc(OC)ccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 4.0 g. (0.018 mole) of 3,6-dimethoxy-2-hydrazinoquinoxaline, the product of Preparation E(d), and 50 ml. of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting reaction mixture was then cooled to room temperature (~20° C.), and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 3.3 g. (72%) of pure 4,7-dimethoxy-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 184°-188° C. Mass Spectrum: m/e, 258 (P); m/e, 228 (P-30).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>CCO>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:3]=[N:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:35][CH:34]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CNc2nnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazine (example C.26 step 7) (5.76 g, 16 mmol), DIPEA (3.19 mL, 19 mmol) and 4-methoxybenzylamine (2.4 mL, 19 mmol) in EtOH (25 mL) was refluxed for 18 h under argon atmosphere. Cooled to 23 C, the mixture was poured onto water, the precipitated solid was filtered off, washed with water and dried in air at 60° C. on the heating plate to give the title compound as an off-white solid (6.49 g, 98%). MS (ISP) 428.3 [(M+H)+]; mp 101-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[NH2:14].[CH:19](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]2[N:14]=[CH:19][NH:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1N
Reactant: O=CO
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]cnc23)c1

Procedure:
A solution of 3-(3-bromo-5-chlorophenoxy)-4-chlorobenzene-1,2-diamine (400 mg, 1.149 mmol) in 90% formic acid (5 mL) was heated to 100° C. for 1 hour. This mixture was concentrated in vacuo and then partitioned between ethyl acetate (40 mL) and sat. aq. NaHCO3 (40 mL). The organic extract was dried over MgSO4, filtered and concentrated in vacuo to give the desired compound. LRMS (M+1)=358.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:37])[CH2:35][CH3:36])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.4 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and propionyl chloride (69 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 22 h. After heating at 50° C. for another 26 h the resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (206 mg, 89%) as a yellow solid. MS: m/e=405.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:13](=O)[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].B.C1COCC1.CO>C1COCC1.C(OCC)(=O)C>[N+:1]([C:4]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1NCCNc2cccc([N+](=O)[O-])c21
Agent: B
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1CNCCN2
Yield: 12.5 %

Procedure:
6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.20 g, 5.8 mmol) was dissolved in THF (50 mL) and the solution was treated with 1N Borane-THF (2.77 mL, 28.95 mmol). The reaction mixture was then refluxed overnight. Upon cooling, the solution was treated with methanol (50 mL) and was then reduced in vacuo. The residue was taken up in ethyl acetate (40 mL) and was washed with saturated NaHCO3 (100 mL). Organics were extracted with ethyl acetate (3×40 mL) and were then dried over Na2SO4, filtered and reduced. The product was then purified and isolated by flash column chromatography (0% MeOH/DCM-30% MeOH/DCM) to afford 140 mg of 6-Nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine as a yellow oil. LC/MS (ESI)=194.32 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.06 (d, 1H, J=8.08 Hz), 6.86 (d, 1H), J=8.34 Hz), 5.32 (s, 1H), 4.66 (s, 2H), 3.24 (t, 2H, J=5.05 Hz), 3.00 (t, 2H, J=5.05 Hz).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:24][CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][CH2:24][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CCCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 115 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
1-Cyano-4-fluoronaphthalene(1.0 g, 5.84 mmol) and ethyl nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL) and stirred at 115° C. for 20 hours. After cooling to rt ethyl acetate (50 mL) was added and the solution washed with HCl (0.4 M, 2×30 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL). The combined organic layers were washed with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried and evaporated. The crude product was purified by silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane to give the title compound (1.23 g, 68%) as a yellowish oil
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14]Br.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[CH2:14][C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[CH:6]=3)[C:3]2=[O:16])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(OC)c(OC)cc1CBr
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)N(c1ccc(Cl)cc1)C2

Procedure:
A solution of 2-bromomethyl-4,5-dimethoxy-benzoic acid methyl ester (2.9 g), 4-chloroaniline (1.28 g) and triethylamine (1.4 ml) was refluxed in toluene for six hours. The reaction mixture was stirred in an ice bath, filtered and washed with 1 M hydrochloric acid and water.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]=[C:28]3[CH:31]([CH3:33])[CH3:32])=[CH:23][CH:22]=2)[CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]2)[CH2:5][OH:6].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH:31]([C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([CH:20]=[CH:19][C:9]3[CH:10]=[C:11]4[C:16](=[C:7]([CH:4]5[CH2:3][CH2:2][O:6][CH2:5]5)[CH:8]=3)[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]4)[CH:30]=2)[CH2:25][CH2:26][N:27]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(C(CO)CCO)c4cc(C#N)ccc4c3)cc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C1=NCCc2ccc(C=Cc3cc(C4CCOC4)c4cc(C#N)ccc4c3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 7A (140 mg, 0.52 mmol) in dichloromethane (3 mL) at 0° C. was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF3.OEt2 (0.096 mL, 0.78 mmol), warmed to room temperature, stirred for 4 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[SH2:9]>C(N(CC)CC)C>[NH2:6][C:5](=[S:9])[CH2:4][C:3]([N:2]([CH3:8])[CH3:1])=[O:7]
Reactant: S
Reactant: CN(C)C(=O)CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CC(N)=S
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A reaction mixture was prepared from 22.4 g. of N,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml. of triethylamine. The reaction mixture was placed in an autoclave and the autoclave shaken at about 55° C. for about 12 hours. The reaction mixture was taken from the autoclave and the volatile constituents removed by evaporation. Ethanol was added to the residue, thus producing a crystalline solid. The solid was filtered and the filter cake washed with cold ethanol. Twenty-one grams of 3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at 111°-114° C. The compound had the following nmr (CDCl3 +DMSOd6)δ: 3.07 (doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:27]([OH:29])[CH3:28])[C:15]([NH:17][NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[OH:29][C@H:27]([CH3:28])[C@@H:14]([NH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[O:16][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:18][N:17]=1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)c1nnc(-c2ccccc2)o1
Reaction time: 1.25 h
Yield: 0.3 %

Procedure:
To a solution of N′-((2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (846 mg, 2.18 mmol) in anhydrous THF (90 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (2.97 g, 6.53 mmol) followed by p-TSCl (498 mg, 2.60 mmol) and the mixture was stirred for 75 min. The mixture was filtered under suction and the residue washed with acetone (3×100 mL) followed by MeOH (3×150 mL). The filtrate was concentrated under reduced pressure to provide a off white solid, which was purified by flash chromatography over silica gel (25-40% EtOAc in hexanes) to provided the title compound as a yellow solid (2.1 mg, 0.3%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.19 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.0 Hz, 1H), 7.63-7.53 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 1H), 5.41 (d, J=9.4 Hz, 1H), 4.95 (d, J=2.9 Hz, 1H), 4.75-4.64 (m, 1H), 1.50 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.CCN(CC)CC.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a mixture of 10.0 g (37.9 mmol) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of Et3N in 200 mL of dry THF at room temperature and under a nitrogen atmosphere was added 33.0 g of piperazine. The mixture was stirred at room temperature for 22.5 hours and then refluxed for 5.5 hours. It was then cooled to room temperature, poured into 250 mL of 5% aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (2→5% MeOH saturated with NH4OH in CH2Cl2) to yield the title compound as a glass.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24](O)=[O:25])[C:22]=1[C:30](O)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:30](=[O:31])[C:22]5=[C:21]([F:20])[CH:29]=[CH:28][CH:27]=[C:23]5[C:24]4=[O:25])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C(O)c1cccc(F)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1c2cccc(F)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.37 gm, 8.98 mmoles), 3-fluorophthalic acid (1.82 in, 9.9 moles) and dicyclohexylcarbodiimide (DCC, 5.5 gm, 26.7 mmoles, 2.6 eq) in dichloromethane (DCM, 250 ml) was stirred at room temperature for 18 hrs. The solids were filtered off. The organic solution was concentrated down. The residue was purified on a flash chromatography column (SiO2, 50 in; eluted with 1% CH3OH:99% DCM, 1.4 liter; 2-6% CH3OH:DCM, liter). The desired product thus obtained weighed 2.64 gm (71%) as an off-white solid. Recrystallization from hot ethanol gave 1.41 gm of white crystals, m.p.=142°-143° C.