Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:15]([Cl:16])=[CH:14][C:7]2[O:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1.Cl.[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:18][O:19][C:20]([CH:11]1[CH2:10][CH2:9][O:8][C:7]2[CH:14]=[C:15]([Cl:16])[C:4]([Cl:3])=[CH:5][C:6]=2[C:12]1=[O:13])=[O:21]
Reactant: O=C1CCCOc2cc(Cl)c(Cl)cc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A suspension of sodiumhydride in parrafin (0.35 g, 60%) was added to 5 ml dimethylcarbonate. To this suspension 7,8-Dichloro-3,4-dihydro-2H-benzo[b]oxepin-5-one (4.3 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. The residue was dissolved in diethyl ether. 7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained by crystallization from this solution in a yield of 40%. LC-MS 2.3 min, 289.0 (MH+), 2.8 min, 289.0 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1

Procedure:
40.56 mg of solid white 3-{4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-chloro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])=O)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:23]1([C:17]2[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[N:18]=2)[C:13]([NH:12][NH2:11])=[O:14])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cc(C(=O)NNC(=O)OCc2ccccc2)cc(C2CCCC2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)NN)cc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 90.5 %

Procedure:
Pd/C (500 mg, 10% Pd) is added to a solution of N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g, 7.42 mmol) in THF (50 mL) and methanol (50 mL). The mixture is stirred at rt under 1 bar of H2 for 25 h. The catalyst is removed by filtration and the filtrate is concentrated and dried under HV to give the title compound (1.58 g) as an off-white solid; LC-MS**: tR=0.51 min, [M+1]+=236.20; 1H NMR (D6-DMSO): δ 1.60-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.08-3.19 (m, 1H), 3.86 (s, 3H), 4.56 (s br, 2H), 6.93 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([OH:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Fc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirring solution of 1-bromo-2-fluorobenzene (2 g, 11.4 mmol) in tetrahydrofuran (30 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (5.0 mL, 12.6 mmol, 2.5 M in hexane). After 30 minutes, 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.97 g, 14.9 mmol) was added in one portion. After 30 minutes, the reaction was quenched with water (2 mL) and was allowed to warm to ambient temperature. After one hour at ambient temperature, the reaction mixture was poured into water (75 mL) and the mixture was extracted with ethyl acetate (2×75 mL). The organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure. The resulting crude product was triturated with hexane (35 mL) for 2 hours, filtered and dried to give the product as a white solid (2.22 g, 65%). 1H NMR (CDCl3) δ 7.45 (m, 1H,), 7.24 (m, 1H), 7.19-7.01 (m, 2H), 4.03 (br s, 2H), 3.23 (m, 2H), 18 (m, 3H), 1.81 (m, 2H), 1.45 (m, 9H). MS (ES+)=296 (MH)+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.O>[F:11][C:4]1[C:3]([CH2:12][C:13]#[N:14])=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: N#CCc1c(F)ccc([N+](=O)[O-])c1F
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Yield: 17.6 %

Procedure:
A solution of (2,6-difluoro-3-nitrophenyl)acetonitrile (4 g, 20.1 mmol) and aniline (1.83 mL, 20.1 mmol) in DMSO (20 mL) was heated at 100° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown oil (959 mg, 18%). 1H NMR 400 MHz 6 (CDCl3): 8.27 (1H, dd, J=9.4, 5.9 Hz), 7.38-7.32 (2H, m), 7.17-7.12 (1H, m), 6.98-6.90 (3H, m), 3.44 (2H, d, J=1.7 Hz).
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([S:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: O=C(O)CCSc1cccc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(SCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethylthio)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethylthio)-2-pyridyl]thiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:17]1[CH2:22][CH2:21][CH:20]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)OB(c2ccc(NC3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.5 g, 2.28 mmol), tetrahydropyran-4-one (0.25 ml, 2.73 mmol) and sodium triacetoxy-borohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred at room temperature for 16 hours. The crude was filtered over diatomaceous earth, washed with DCM and the filtrate was evaporated in vacuo to yield D7 (0.69 g) that was used without further purification.
Reaction SMILES: [Na].C(O[C:5](=[O:14])[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C.O>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[C:5]([OH:14])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[N:25]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COc1cccc(NN)c1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(O)n(-c2cccc(OC)c2)n1
Temperature: 100 °C

Procedure:
To a solution of 1.2 g of 2-Oxo-succinic acid diethyl ester monosodium salt in 10 ml acetic acid, 900 mg of (3-Methoxy-phenyl)-hydrazine hydrochloride was added and the reaction mixture was heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH3:20]I.O>O1CCCC1>[CH3:20][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[N:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CI
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g of sodium hydride (50% dispersion in oil) in 300 ml of anhydrous tetrahydrofuran under argon was added 14.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide. The solution was stirred for 0.5 hours, then 3.9 ml of methyl iodide was added. After stirring for 2 hours, the solution was poured onto 400 ml of water and extracted with 100 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and chromatographed on hydrated magnesium silicate with dichloromethane-methanol (98:2) as eluant. The fractions containing the desired product were combined, concentrated in vacuo and recrystalized from acetone-hexane to give 14.1 g of cream crystals, mp 109°-112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
At room temperature, 10.9 g of 4-pyridylcarbinol (100 mmol) was treated with 60 mL of DCM followed by 21 mL (150 mmol) of triethylamine. After being cooled to 10° C., 18 g (120 mmol) of t-butyldimethylsilyl chloride (dissolved in 20 mL DCM) was added dropwise. The resulting reaction mixture was warmed to room temperature slowly and stirred overnight. Subsequently, it was filtered over a pad of celite, rinsed with ether. Volatiles were removed and the residue was taken up in hexane and filtered over celite again, washed with hexane/ether, and the solvents removed by rotoevaporation. This was repeated twice. Pumping under high vac of the residue thus obtained provided 22 g (99%) of the desired product as a light brown oil, mass spectrum (CI) m/e=224 (M+1)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=O)([O-:13])=[O:12].N>>[N+:11]([C:14]1[CH:15]=[C:16]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:20]=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=[N+]([O-])c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-nitrobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CDCl3) δ 7.44-7.55 (m, 1 H), 7.82 (t, J=8.3 Hz, 1 H), 8.43-8.60 (m, 3 H), 8.80 (dd, J=4.7, 1.7 Hz, 1 H), 9.07-9.13 (m, 1 H), 9.42 (d, J=2.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 269 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](O)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([Cl:20])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (29.5 g) and thionyl chloride (18 ml) in dry toluene (900 ml) were stirred and heated under reflux for 1 hour. The solution was cooled and the solid that separated was collected. It had m.p. 186.5°-188.5° (98%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.[CH3:26][N:27]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1)[CH3:28]>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:27]([CH3:28])[CH3:26])[CH2:31][CH2:32]1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl)-methanone (267 mg, 1.0 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (270 mg, 1.0 mmol) to afford the desired product (150 mg, 39%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.85 (br s, 1H), 9.19 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 4.97 (br s, 1H), 2.72-2.62 (m, 1H), 2.31-2.24 (m, 2H), 2.22 (s, 6H), 2.13 (d, J=7.2 Hz, 2H), 1.96-1.89 (m, 2H), 1.55-1.46 (m, 1 H), 1.36 (qd, J=12.4, 3.3 Hz, 2H), 1.28-1.22 (m, 2H), 1.21-1.09 (m, 2H), 1.08-1.02 (m, 2H); ESI MS m/z 387 [M+H].+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[C:12](=[O:15])[CH2:13][Cl:14].[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH:12]([OH:15])[CH2:13][Cl:14]
Reactant: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2cc(C(O)CCl)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A reactor is loaded with 200 g (0.82 mol) of 6-chloro-5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one, in 1 L of ethanol. The reaction mixture is added with 15.5 g (0.41 mol) of sodium borohydride in portions, under strong stirring, at room temperature. The temperature is kept at 15-20° C. during the addition, after that the mixture is left under stirring for about 15 h at room temperature. The mixture is then added with 250 ml of glacial acetic acid and refluxed (approx. 85° C.) for 1 hr 30 min, then 200 ml of acetic acid are added and the mixture is refluxed a further 30 min, then cooled to 20° C. The suspension is filtered and washed with ethanol and heptane. The solid product is dried under vacuum at a temperature of 60° C., to obtain 177 g (88% molar yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[Br:22]Br.O>O1CCOCC1>[Br:22][C:10]1[C:9]([S:15]([C:18]([F:19])([F:21])[F:20])(=[O:16])=[O:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: BrBr
Reactant: N#Cc1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of 5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole-2-carbonitrile (0.87 g, 0.0026 mol) in dioxane is cooled, treated with bromine (0.46 g, 0.00286 mol), stirred at room temperature for two hours, treated with additional bromine (0.21 g, 0.0013 mol), stirred overnight at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water, saturated sodium meta-bisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a tan solid (0.27 g, mp 170°-185° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: C(N)C1C=CC=CC=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31](OC)=[O:32])[C:24]2=[O:38])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31]([NH:16][CH2:15][C:12]3[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=3)=[O:32])[C:24]2=[O:38])=[CH:39][CH:40]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccncc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 42 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with pyridin-4-ylmethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide was obtained as a colorless solid in 42% yield: mp 205-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.33 (t, J=6.0 Hz, 1H), 8.62 (s, 1H), 8.49-8.47 (m, 2H), 8.39 (d, J=5.4 Hz, 1H), 7.37-7.26 (m, 5H), 7.18-7.13 (m, 2H), 4.47 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 3.94 (t, J=7.5 Hz, 2H), 3.38-3.32 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.9, 160.4, 156.8, 153.6, 150.1, 148.6, 143.1, 133.6, 133.6, 130.4, 130.3, 122.6, 116.0, 115.7, 115.2, 110.4, 46.6, 42.3, 41.6, 41.2; MS (ES+) m/z 406.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:16][O:17][C:33]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(CO)Cc2ccc(Cl)cc2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OCC2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-[1-(4-Chloro-benzyl)-2-hydroxy-ehtylamino]-piperidine-1-carboxylic acid tert-butyl ester, the intermediate alcohol was dissolved in 15 mL of methylene chloride. Triethylamine (0.423 g, 0.00418 mol, 583 uL 1.2 equiv) was added followed by portionwise addition of carbonyl diimidazole (0.68 g, 0.00418 mol, 1.2 equiv). The mixture was stirred at room temperature and then quenched with water (15 mL). The organic layers were separated and the remaining aqueous layer was extracted with methylene chloride (3×15 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford 4-[4-(4-chloro-benzyl)-2-oxo-oxazolidin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.1 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:19][C:20]([NH2:22])=[NH:21]>CO>[NH2:21][C:20]([NH2:22])=[N:19][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: CCOc1cc(C)c(C(=O)OC)cc1S(C)(=O)=O
Solvent: CO
Product: CCOc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
A solution of 1.4 g of methyl 2-methyl-4-ethoxy-5-methylsulfonylbenzoate (obtainable by reaction of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium ethoxide and subsequent esterification) and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours and the solvent is then removed. The residue is treated with water, and the crystallizate which remains is filtered off with suction and treated with dilute sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonylbenzamide is obtained, m.p. 201°-203°.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].[CH:8]1([C:11]2[N:15]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:14]=[CH:13][C:12]=2[C:26](Cl)=[O:27])[CH2:10][CH2:9]1>O1CCCC1>[CH:8]1([C:11]2[N:15]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:14]=[CH:13][C:12]=2[C:26]([NH:4][C:3]([NH2:5])=[NH:2])=[O:27])[CH2:10][CH2:9]1
Reactant: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining guanidine hydrochloride and sodium hydroxide with a suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine; and
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:4]1=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[ClH:1].[C:31]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:8][C:7]2[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:4]1=[O:30])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@H]2Cc3c(cccc3[N+](=O)[O-])N(CCN(C)C)C(=O)[C@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@H]2Cc3c(cccc3[N+](=O)[O-])N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
A stirred suspension of the hydrochloride salt of (cis)-3-(hydroxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-nitro-2H-1-benzazepin-2-one, monohydrochloride (approximately 1.93 mmol) in 30 ml of acetic anhydride was heated to 100° C. (oil bath) and the resulting solution heated at 110°-120° C. for 4.5 hours. After removing the bulk of acetic anhydride on a rotary evaporator at 0.2 mm, the solid residue (2 g) was rubbed under 10 ml of ethyl acetate and diluted portionwise with 20 ml of ether. After cooling overnight, the colorless solid was filtered under argon, washed with ether and dried in vacuo; yield, 0.84 g; melting point 198°-200° C. (dec.), s. 192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]34)[CH:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(F)c3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (125 mg, 0.28 mmol) and corresponding 3-fluorophenylboronic acid (77 mg, 0.56 mmol), to afford after chromatographic purification the title compound (48 mg, 44%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.20–7.40 (m, 2H), 7.10–7.20 (m, 3H), 6.80–7.00 (m, 1H), 3.80–3.90 (m, 1H), 3.60–3.80 (m, 1H), 3.10–3.50 (m, 7H), 2.80–3.00 (m, 1H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 395 (base, M+H).