Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][CH2:8][C:10](=[O:11])[CH3:12])(=[O:7])[OH:6]
Reactant: C=CC(C)=O
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CC(=O)CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.4 g of freshly distilled methyl vinyl ketone are added. An exothermic reaction ensues, the reaction temperature rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 50° and60°. After cooling to room temperature, the volatile materials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residue is obtained which is dissolved in 50 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water, the white solid is co-evaporated with water (10×50 ml) and then with absolute ethanol (10×50 ml). Crystallisation of the residue form ethanol yields 3-aminopropyl(3-oxobutyl)phosphinic acid hydrochloride. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(3-oxobutyl)phosphinic acid, m.p. 163°-5° (decomp.), as a white solid.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)C(NN)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:17]([NH:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:23][CH2:22][C:21]1[O:24][C:17]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:27]=[C:26]([Cl:28])[CH:25]=2)=[N:19][N:20]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a suspension of compound 5 (328 mg, 1.0 mmol) in DCM (10 ml) was added compound 6 (150 mg, 1.0 mmol), EDC (288 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and purified by chromatography to give compound 7 as a white solid (230 mg). Yield: 50%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-fluoroaniline to yield 2-[(3-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14]CC)=O)=[CH:6]2.[H-].[Na+].[CH2:19]([O:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20]>C1(C)C=CC=CC=1>[O:14]=[C:12]1[C:7]2=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=3[N:8]2[CH2:24][CH:23]1[C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cn2c(cc3cc(OC)ccc32)C1=O

Procedure:
A stirred solution of ethyl 5-methoxy-indole-2-carboxylate (30 g, 137 mmol) in 1.5 L of toluene under N2 was treated with sodium hydride (6.7 g of 60% in oil, 167 mmol) and ethylacrylate (16.3 ml, 150 mmol). The mixture was heated to reflux. After 3 hours (hr), additional ethyl acrylate (3 ml) and sodium hydride (3.3 g) were added. After a total of 8 hr, the starting material was consumed completely and the mixture was quenched with ethanol and treated with water and dilute HCl and methylene chloride. The organic layer was washed with brine, dried and concentrated to give 2,3-dihydro-1-oxo-7-methoxy-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>O.NN>[Cl:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Agent: NN
Solvent: O
Product: N#Cc1ccc(N)cc1Cl
Temperature: 0 °C
Yield: 598.3 %

Procedure:
A portion of 2-chloro-4-nitrobenzonitrile (5 g, 0.027 m) was heated with hydrazine monohydrate (110 ml) until the reaction began. Another portion of 2-chloro-4-nitrobenzonitrile (35 g, 0.192 m) was added in predetermined amounts. Once the evolution of nitrogen gas ceased, the reaction mixture was refluxed approximately thirty minutes, and then poured into stirred ice water. The precipitate was filtered and the solid was crystallized from water to yield 2-chloro-4-aminobenzonitrile (25 g, 78%, mp 117° C.).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[N:5]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH2:4][CH2:3][S:23]1
Reactant: CCC(C)C[NH2+]CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: CCC(C)CN1CCSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
N-(2-Hydroxyethyl)-N-(2-methylbutyl)amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-methylbutyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:3]=1N.N([O-])=O.[Na+].[I-:15].[K+].S(=O)(O)[O-].[Na+]>Cl.O.ClCCl>[Cl:1][C:2]1[C:3]([I:15])=[C:5]([S:9][CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(Cl)c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: O
Solvent: ClCCl
Product: CSc1cccc(Cl)c1I
Yield: 54.5 %

Procedure:
2-Chloro-6-methylthioaniline (15.0 g, 87 mmol) was dissolved in 200 mL of concentrated hydrochloric acid and the resulting solution was cooled to 0° C. to -10° C. with a dry ice/methanol bath. A solution of 8.9 g (130 mmol) of sodium nitrite in 30 mL of water was added dropwise with stirring and cooling to maintain the temperature below 0° C. The solution was then stirred for 20 min at 0C. A mixture of 22 g (130 mmol) of potassium iodide dissolved in 300 mL of water and 200 mL of dichloromethane was prepared and the solution prepared above was added to it in portions with stirring. The mixture was allowed to react for 20 min at ambient temperature. A small amount of aqueous sodium bisulfite solution was added and then the phases were separated. The organic phase was washed twice with 2N aqueous hydrochloric acid and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was crystallized with heptane and chromatographed on silica eluting with an 85:15 mixture of hexane and dichloromethane to obtain 13.5 g of the title compound as a crystalline, low melting yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[CH2:12](O)[CH3:13]>>[NH:1]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([O:10][CH2:12][CH3:13])=[O:9]
Reactant: CCO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H]1CCC(=O)N1

Procedure:
A mixture of ethanol and glutamic acid was initially charged in a stirred vessel (A). The fraction of glutamic acid was 0.1% of the ethanol fraction. The mixture was conveyed continuously through the reactor (C) at a pressure of 72 bar by a suitable pump (B). The tubular reactor (C) was heated to a temperature of 260° C. by the heater (D). A carrier stream of pure ethanol from the reservoir (F) was heated to the same temperature using the preheater (G). At the mixing point (H), the carrier stream was mixed with the reactant stream (ratio 50/50) and fed to the reactor (C). The preheating temperature selected was so high that there was already reaction temperature at the mixing point, so that the temperature gradient in the reactor (C) was sufficiently small to prevent carbonization at the wall. The residence time in the tubular reactor (C) was 40 sec. With the aid of the control valve (E), the pressure was kept at the target value mentioned. At the outlet of the system, the reacted solution was introduced into 1 molar HCl. According to HPLC, 50% product yield (ethyl pyroglutamate) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:25](OC)([CH2:28][CH3:29])[CH2:26][CH3:27]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:16][C:25]1([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: CCC(CC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(CC)(CC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 75.4 %

Procedure:
A solution of 2.5 g of ethyl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 1.12 g of 3,3-dimethoxypentane and 25 mg of pyridinium p-toluene-sulphonate in 25 cm3 of toluene is stirred for 3 hours at a temperature in the region of 20° C. The reaction mixture is heated to boiling and the distillate is collected in a graduated vessel. After 20 cm3 of distillate have been collected, a solution of 1.12 g of 3,3-dimethoxypentane and 25 mg of pyridinium p-toluenesulphonate in 10 cm3 of toluene is added to the reaction medium and the mixture is heated to reflux of the toluene for 5 hours. The reaction medium is cooled to a temperature in the region of 20° C. and 10 cm3 of saturated aqueous sodium hydrogen carbonate solution are then added. The aqueous phase is separated after settling has taken place and then extracted with 2 times 10 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 2.3 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2,2-diethyl-4-phenyl-5-oxazolidinecarboxylate are thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O)[CH3:2].[BH3-]C#[N:15].[Na+]>C(O)(C)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH2:15])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCc1cccc2c1CCC2=O
Agent: [Na+]
Solvent: CC(C)O
Product: CCc1cccc2c1CCC2N

Procedure:
4-Ethyl-indan-1-one (5.00 g, 31.21 mmol), NaBH3CN (13.70 g, 0.22 mol) and NH4OAc (72.00 g, 0.93 mol) in isopropanol were reacted according to the protocols as outlined in general procedure B to give the desired amine.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH:8]1[CH2:11][CH:10]([S:12][C:13]2[CH:18]=[CH:17][C:16](/[C:19](/[C:26]3[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH3:34])=[CH:28][CH:27]=3)=[CH:20]\[CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O>[CH:21]1(/[CH:20]=[C:19](/[C:26]2[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH3:34])=[CH:28][CH:27]=2)\[C:16]2[CH:15]=[CH:14][C:13]([S:12][CH:10]3[CH2:11][N:8]([CH2:1][CH3:2])[CH2:9]3)=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC=O
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC3CNC3)cc2)ccc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN1CC(Sc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(OC)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
90% acetaldehyde (31 μL) and acetic acid were added to a solution of 6-{(E)-1-[4-(azetidin-3-ylsulfanyl)phenyl]-2-cyclopentylethenyl}-2-methoxy-3-methylpyridine in chloroform (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled and sodium triacetoxyborohydride (206 mg) was added, after which the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→93:7) to give 6-[(E)-2-cyclopentyl-1-{4-[(1-ethylazetidin-3-yl)sulfanyl]phenyl}ethenyl]-2-methoxy-3-methylpyridine as a colorless oil (78 mg, 58%).
Reaction SMILES: C([O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]2[C:24]3[C:19](=[N:20][C:21]([NH2:25])=[N:22][CH:23]=3)[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[Cl:27])C1C=CC=CC=1>Br.O>[NH2:25][C:21]1[N:20]=[C:19]2[N:18]([CH3:26])[N:17]=[C:16]([C:12]3[CH:13]=[C:14]([Cl:15])[C:9]([OH:8])=[C:10]([Cl:27])[CH:11]=3)[C:24]2=[CH:23][N:22]=1
Reactant: Cn1nc(-c2cc(Cl)c(OCc3ccccc3)c(Cl)c2)c2cnc(N)nc21
Agent: Br
Solvent: O
Product: Cn1nc(-c2cc(Cl)c(O)c(Cl)c2)c2cnc(N)nc21
Temperature: 120 °C

Procedure:
3-(4-Benzyloxy-3,5-dichloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (0.2 g, 0.500 mmol) is dissolved in 48% HBr in water (20 ml) and heated to 120° C. for 1 hour. The reaction mixture is cooled to room temperature and the resulting precipitate is collected by filtration and re-crystallised from EtOH to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Reactant: COC(=O)CCCCCCCCBr
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCCC(=O)OC
Yield: 71 %

Procedure:
Using the procedure of example 122, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 9-bromononanoate giving the title compound, in 71% yield, as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC4CC4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC4CC4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-cyclopropylmethylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (125 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (68 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified with silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-cyclopropylmethylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (65.9 mg) (Compound 348) as yellow amorphous.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([OH:37])(=[S:36])[CH3:35].[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46](O)[C:47]([O:49][CH:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])=[CH:41][CH:40]=1>O1CCCC1>[C:34]([S:36][CH:46]([CH2:45][C:42]1[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=1)[C:47]([O:49][CH:50]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:48])(=[O:37])[CH3:35]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(O)Cc1ccc(F)cc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC(Cc1ccc(F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 76 %

Procedure:
Triphenylphosphine (3.99 g, 15.2 mmol) was dissolved in dry tetrahydrofuran (78 ml), followed by cooling to 0° C. under cooling with ice. Further, diisopropyl azodicarboxylate (DIAD (2.99 ml, 15.2 mmol)) was dropped thereinto under stirring. Thirty minutes thereafter, a solution of a mixture of thioacetic acid (1.25 ml, 17.8 mmol) with diphenylmethyl 3-(4-fluorophenyl)lactate (4.0 g, 11.4 mmol) obtained in the Synthesis Example F-1 in dry tetrahydrofuran (45 ml) was dropped thereinto. The mixture was allowed to react at 0° C. for 3 hours. Then the ice bath was removed and the reaction mixture was warmed to room temperature and allowed to react at this temperature overnight. Next, this reaction mixture was concentrated under reduced pressure. The residue thus obtained was separated by silica gel column chromatography (hexane:ethyl acetate=6:1) to thereby give a crude product (4.7 g). This crude product was recrystallized from diisopropyl ether and hexane (20 ml-30 ml). The solid thus precipitated was removed by filtration and the filtrate was concentrated under reduced pressure to thereby give the title compound (3.54 g, 76%) as an oily product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:26][CH2:25][CH2:24][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NCCN1CCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
A mixture of 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid (500 mg, 1.99 mmol), 2-Pyrrolidin-1-yl-ethylamine (0.28 mL, 2.19 mmol), EDC (459 mg, 2.39 mmol), HOBt (323 mg, 2.39 mmol) and triethylamine (0.40 mL, 2.99 mmol) in DMF (10 mL) was stirred at ambient temperature for 15 h. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) and NaHCO3 (25 mL). The aqueous mixture was extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the title compound (421 mg, 61%). m/z (M+1) 348.23.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[N:8]=[C:7]2[NH:25][C:26]1[N:27](C(C)(C)C)[N:28]=[C:29]([CH3:31])[CH:30]=1)([O-])=O.[N+](C1C=C2C(C(NC3N(C(C)(C)C)N=C(C)C=3)=N[N:45](C3C=CC(C(C)(C)C)=CC=3)[C:46]2=[O:49])=CC=1)([O-])=O.BrC1C2C(=CC=C([N+]([O-])=O)C=2)C(=O)N(C2C=CC(C(C)(C)C)=CC=2)N=1.BrC1C2C(=CC([N+]([O-])=O)=CC=2)C(=O)N(C2C=CC(C(C)(C)C)=CC=2)N=1.C(N1C(N)=CC(C)=N1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl.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]>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:9]2[C:10](=[O:14])[C:11]3[C:6](=[CH:5][CH:4]=[C:13]([NH:45][CH:46]=[O:49])[CH:12]=3)[C:7]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:8]2)=[CH:20][CH:19]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)n(C(C)(C)C)n1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc([N+](=O)[O-])cc23)n(C(C)(C)C)n1
Agent: [Pd]
Agent: CC(C)(C)c1ccc(-n2nc(Br)c3cc([N+](=O)[O-])ccc3c2=O)cc1
Agent: CC(C)(C)c1ccc(-n2nc(Br)c3ccc([N+](=O)[O-])cc3c2=O)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(NC=O)ccc23)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one and 7-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one: 4.56 g of a 1:1 mixture of 4-Bromo-2-(4-tert-butyl-phenyl)-6-nitro-2H-phthalazin-1-one and 4-Bromo-2-(4-tert-butyl-phenyl)-7-nitro-2H-phthalazin-1-one in 45 ml dry dioxane were reacted with 2.605 g 1-(tert.butyl)-3-methyl-1H-pyrazole-5-ylamine, 5.526 g cesium carbonate, 311 mg tris-(dibenzylideneacetone)-dipalladium and 393 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene under nitrogen at 80 C. After 2 hrs HPLC indicated complete conversion and the mixture was cooled to RT, diluted with 150 ml DCM and washed twice with diluted HCl. The organic phase was dried and evaporated and the residue chromatographed on silica eluting first heptane and subsequently with heptane/EtOAc 8:2. The first eluting product was the 6-nitro isomer (1.82 g), the second eluting product was the 7-nitro isomer (2.05 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[C:6](=[N:9]/[H])/[NH:7][OH:8])=[CH:4][CH:3]=1.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:9]=[C:33]([CH2:32][N:15]3[CH2:16][CH2:17][CH2:18][C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[O:13])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: [H]/N=C(\NO)c1ccc(F)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: O=C1N(Cc2nc(-c3ccc(F)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of (Z)-4-fluoro-N-hydroxybenzimidamide (0.025 g, 0.162 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.162 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.046 g, 0.242 mmol) was stirred in 1,2-dichloroethane (0.5 mL) at room temperature. After stirring for 1 hour, the reaction was heated to 85° C. and stirred overnight. The reaction was cooled, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.09-8.15 (m, 2H), 7.24-7.34 (m, 10H), 7.16-7.24 (m, 2H), 4.91 (s, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.68-2.73 (m, 2H), 1.87-1.96 (m, 2H); MS (ESI+) m/z 428 (M+H)+.