Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10][C@H:11]([C@@H:28](O)[CH3:29])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10]/[C:11](/[C:12]2[O:13][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=3)=[N:15][N:14]=2)=[CH:28]\[CH3:29])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C(F)(F)F)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: C/C=C(\Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C(F)(F)F)cc2)o1
Reaction time: 1 h

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(trifluoromethyl)benzohydrazide (1.0 g, 2.20 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) (3.0 g, 6.60 mmol) followed by para-toluenesulfonyl chloride (419 mg, 2.20 mmol) and the mixture was stirred for one hour. The mixture was filtered under suction and the residue washed with acetone (2×100 mL) followed by Methanol (2×150 mL). The filtrate was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provided (Z)-2-chloro-3-methyl-4-(1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzonitrile, the less polar component as a colourless solid (122 mg, 13%) and 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile, the more polar component as a yellow oil (336 mg, 35%): Less polar compound; 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.27 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.13 (br s, 1H), 7.04 (q, J=7.2 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 2.47 (s, 3H), 1.91 (d, J=7.0 Hz, 3H): More polar compound; 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.22 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.70 (d, J=8.6 Hz, 1H), 5.16 (dd, J=3.5, 8.6 Hz, 1H), 4.86 (br d, J=4.3 Hz, 1H), 4.70-4.61 (m, 1H), 2.40 (s, 3H), 1.43 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][O:10][CH3:11])=[N+:6]([O-])[CH:7]=1.[CH2:12]([N:14](CC)CC)C.C[Si](C#N)(C)C.O>C(#N)C>[Br:1][C:2]1[C:7]([C:12]#[N:14])=[N:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COCc1ccc(Br)c[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: CC#N
Product: COCc1ccc(Br)c(C#N)n1
Yield: 58.2 %

Procedure:
A solution of 5-bromo-2-methoxymethyl-pyridine-1-oxide (5.0 g, 22.7 mmol), triethylamine (12.7 ml, 91 mmol) and trimethylsilyl cyanide (9.1 ml, 68.2 mmol) in acetonitrile (10 ml) was heated in a sealed tube to 120° C. for 18 hours. After completion of the reaction, water was added to the reaction mixture and acetonitrile was removed. The crude material was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 3.0 g (58%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: Nc1cccc(S(N)(=O)=O)c1
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 3-nitrobenzene sulfonamide (5 mmol) dissolved in argon (Ar) saturated MeOH was suspended 200 mg of 10% Pd/C. A balloon of H2 gas was connected via a needle to the reaction mixture which was left to stir for 5 h. The solution was purged with Ar again and filtered through celite to remove the Pd/C. The solution was evaporated to give 3-aminobenzene sulfonamide (95%) which was used without further purification at the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17](I)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[NH:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:20]2[CH2:26][CH2:25][CH2:24][C@H:21]2[CH2:22][OH:23])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6]
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(I)c2)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@H]3CO)c2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 3-bromo-5-iodo-N-((6-methylpyridin-3-yl)methyl)benzamide (250 mg, 0.58 mmol), L-prolinol (88 mg, 0.87 mmol), potassium carbonate (160 mg, 1.2 mmol), L-proline (13 mg, 0.12 mmol), and copper(I) iodide (11 mg, 0.058 mmol) in dimethyl sulfoxide (2 mL) under nitrogen was stirred at 90° C. for 10 h. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (EtOAc/hexane: 0-100%) to afford a white foam.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[NH:3])[NH2:2].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH:26]([C:32](OCC)=[O:33])[C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:26]1[C:32]([OH:33])=[N:3][C:1]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:2][C:27]=1[OH:28]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(O)n2)CC1
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 4-carbamimidoylpiperidine-1-carboxylate (35 g, 153.98 mmol, 1.00 equiv) and 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate (49.7 g, 169.43 mmol, 1.10 equiv) in toluene (500 ml) was heated overnight at 120° C. in an oil bath under nitrogen. After cooled to room temperature, the solid was collected by filtration. 45 g of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4,6-dihydroxypyrimidin-2-yl]piperidine-1-carboxylate was obtained as a light yellow solid. MS m/z [M+H]+ (ESI): 429.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH:5]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:32][CH2:33]3)[C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1
Reactant: Fc1ccc(C(CCCCl)c2ccccc2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 7.85 parts of 1-chloro-4-(4-fluorophenyl)-4-phenylbutane, 6.3 parts of 5-chloro-1-(4-piperidyl)-2-benzimidazolinone, 6.35 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature and water is added. The organic layer is separated, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1-{1-[4-(4-fluorophenyl)-4-phenyl-butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 182.9° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3=[O:30])=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:30])=[CH:31][CH:32]=2)=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Agent: Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCNCC2=O)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in 9 mL of DMF at 45° C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg of tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCl was subsequently added to crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate and concentrated to give the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[C:8](=[O:13])([O:10][CH2:11][CH3:12])[NH2:9].P(Cl)(Cl)(Cl)=O>O>[C:3]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])(=[O:5])[CH2:2][C:1]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])=[O:7]
Reactant: O=C(O)CC(=O)O
Reactant: CCOC(N)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Temperature: 80 °C
Yield: 43.1 %

Procedure:
With a mortar and pestle 10.40 g (0.100 mole) of malonic acid and 18.00 g (0.210 mole) of ethyl carbamate were ground to a fine powder. This powder was placed in a flask, and 16.0 mL (0.167 mole) of phosphorus oxychloride was added. This mixture was heated at 80° C. until the evolution of gas ceased. After this reaction mixture had cooled to ambient temperature, 210 mL of water was added. When the stiff glassy mixture became fluid, it was extracted with ethyl acetate. The combined extracts were washed in succession with saturated aqueous solutions of sodium bicarbonate and sodium chloride and were then dried over anhydrous magnesium sulfate and filtered. The solution was filtered through a short column of silica gel, which was eluted with ethyl acetate. The solvent was then evaporated under reduced pressure, leaving a crystalline mass of malonyldiurethane weighing 10.62 g. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:46])([CH3:45])[NH:37][S:38]([CH2:41][CH2:42][CH2:43][Cl:44])(=O)=[O:39]>>[CH3:35][Si:36]([CH3:46])([CH3:45])[N:37]=[S:38]([Cl:1])([CH2:41][CH2:42][CH2:43][Cl:44])=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)NS(=O)(=O)CCCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)CCCCl

Procedure:
The reactants used in the foregoing general procedure were hexachloroethane (0.0902 mol, 21.79 g), triphenylphosphine (0.0911 mol, 24.14 g), triethylamine (0.0902 mol, 12.8 mL), N-trimethylsilyl sulfonamide (3e) (0.0902 mol, 20.66 g). The identity of the reaction product was confirmed by the presence of signals at the following shifts in the 1H NMR spectrum: 90 MHz (CHCl3): 0.05 (s, 9H), 2.12 (m, 2H, SCH2CH2), 3.38 (t, 2H, SCH2), 3.45 (t, 2H, ClCH2).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=4)=[N:13][CH:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:22][C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][N:3]([CH:27]3[CH2:28][O:25][CH2:26]3)[CH2:4]4)=[CH:14][N:13]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CNC4)cn2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CN(C3COC3)C4)cn2)c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
A mixture of 152d (676 mg, 1.7 mmol), oxetan-3-one (251 mg, 3.5 mmol), NaBH3CN (274 mg, 4.4 mmol), and zinc chloride (592 mg, 4.4 mmol) in methanol (30 mL) was stirred at 50° C. for 5 hours. water was added and the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane three times. The combined extract was concentrated under reduced pressure to afford crude 152e as a yellow solid (650 mg, 84%), which was used in the next step without further purification. MS-ESI: [M+H]+ 446.2.
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:18]([F:21])([F:20])[F:19])[O:11][C:10]2[CH:12]=[CH:13][C:14](C=O)=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][CH:2]([C:7]1([C:18]([F:21])([F:19])[F:20])[O:11][C:10]2[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:9]=2[O:8]1)[C:3]([F:4])([F:5])[F:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
50 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-(trifluoromethyl)-5-formyl-1,3-benzodioxole were dissolved 500 ml of methylene chloride, and 53 g of 70% strength by weight m-chloroperbenzoic acid were added. The mixture was stirred under reflux for 6 hours. It was then cooled, and the precipitate which had separated out was filtered off. The filtrate was washed with 5% strength by weight aqueous sodium hydrogen sulphide solution and with saturated aqueous sodiumbicarbonate solution and concentrated on a rotary evaporator. The residue which remained was dissolved in 300 ml of diethyl ether, and 100 ml of 1N sodium hydroxide solution were added at room temperature. When the reaction had ended, the phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried with magnesium sulphate and subjected to fractional distillation in vacuo. The yield was 26 g (=54% of theory), and the boiling point was 95° C. under 0.07 mbar. 19F-NMR: -68.6 and -81.6 ppm. 1H-NMR: 4.70 ppm.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.8 G. of 1 -acetamido-4-methylthiomethoxy-2-nitrobenzene is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to give 1-amino-4-methylthiomethoxy-2-nitrobenzene as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11](=[NH:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH3:31]N>C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11]([NH:29][CH3:31])=[N:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(=N)NC(=O)N2c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(C(=O)OCc1ccccc1)[C@@H](C)C2
Reaction time: 8 h

Procedure:
To a flask containing benzyl (5R,7S)-4-amino-1-(3-fluorophenyl)-7-methyl-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (343 mg, 0.86 mmol; Intermediate 11-6) was added methylamine (2.0 M THF, 4.3 mL, 8.6 mmol). The vessel was sealed and placed in a 70° C. oil bath and stirred overnight. The reaction was diluted with aqueous NaHCO3 and extracted with EtOAc (three times). The combined organic layers were washed with brine, isolated and subsequently dried over Na2SO4. Evaporation of solvent and further drying under vacuum gave crude product that was used in the next step.
Reaction SMILES: [NH2:1][C:2]1([CH3:27])[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:20][CH2:19]3)=[C:9](F)[C:8]=2[F:26])[CH2:3]1.[NH3:28]>>[NH2:28][C:9]1[C:8]([F:26])=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([NH2:1])([CH3:27])[CH2:3]2)[C:16]([F:17])=[C:15]2[C:10]=1[C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]2[CH:18]1[CH2:19][CH2:20]1
Reactant: CC1(N)CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: N
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 100 °C

Procedure:
A mixture of 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg) and 28% aqueous ammonia (15 ml) was heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The resulting crystals were treated in the same manner as described in Example 10 (1) to give 5-amino7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (93 mg), m.p. 271°-273° C (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:19][CH:18]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:34][NH2:35]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[CH:19][CH:18]=4)[NH:35][N:34]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1ccc2[nH]ccc2c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: C(=C/c1cc(/C=C/c2ccc3[nH]ccc3c2)n[nH]1)\c1ccc(OCc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
In 0.34 mL of acetic acid was dissolved 15 mg (35 μmol) of (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione. To this solution was added 34 μL (0.70 mmol) of hydrazine monohydrate at room temperature and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol). The resulting solid was washed with an organic solvent to give 3.5 mg (24% yield) of the title compound as a pale yellowish white powder with the following properties.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.Cl>CCOCC>[C:17]1([CH2:16][N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[C:1]#[N:2])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC1CCCCC1N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: N#CC1CCCCC1N(Cc1ccccc1)Cc1ccccc1

Procedure:
To 100 mL of ether is added 10 g (0.2 mol) of sodium cyanide and 37.3 g (0.1 mol) of 2-[bis(phenylmethyl)amino]-cyclohexanol methanesulfonate. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add 1N HCl until gas evolution ceases. Remove the solvent in vacuo and add saturated aqueous sodium bicarbonate and 100 mL methylene chloride. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2)#[CH:2].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]O)[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)[CH:7]=[CH:6]2)#[CH:2]
Reactant: C#Cc1ccc2cc(O)ccc2c1
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#Cc1ccc2cc(OCCCN3CCOCC3)ccc2c1
Reaction time: 1 h

Procedure:
To a mixture of compound 110B (57 mg, 0.34 mmol), 3-morpholinopropan-1-ol (98 mg, 0.68 mmol) and triphenylphosphine (133 mg, 0.508 mmol) in THF (1.5 ml) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (117 mg, 0.508 mmol). The reaction mixture was stirred for 1 h and insoluble material was filtered off The filtrate was concentrated and the residue was purified by reverse phase HPLC (gradient: 0-55% acetonitrile in 0.1% TFA water/40 min) to provide compound 110C: LCMS (APCI) 296 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[C:4]([Cl:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH2:27].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:4]1[CH:3]=[C:2]([NH:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])[CH:7]=[CH:6][C:5]=1[C:8]([C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[F:17])=[O:9]
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Br)cc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
Compound 511 (200 mg, 0.6 mmol) was dissolved in dry 1,4-dioxane (5 mL) in a reaction vial under an argon atmosphere. 2,4-Difluoro-phenylamine (78 mg, 62 μL, 0.6 mmol) was added and dissolved in the solvent. Rac-BINAP (17 mg, 0.028 mmol), Pd2(dba)3 (17 mg, 0.018 mmol) and Cs2CO3 (277 mg, 0.85 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for 40 min. In a microwave oven. The reaction mixture was allowed to cool to RT, filtered through Celite and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:7 to 1:3) as the eluent to afford the title compound as a yellow solid.