Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2].O1CCOCC1>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[N:11]=[N:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: C1COCCO1
Product: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Temperature: 120 °C

Procedure:
3,4-Bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.1 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (0.100 g, 0.15 mmol) and sodium tert-butoxide (0.59 g, 6.1 mmol) were added to dioxane (10.2 ml). The resulting mixture was purged with nitrogen before 4-fluorobenzylamine (78 mg, 6.1 mmol) was added. The mixture was heated at 120° C. for 1 hour under microwave irradiation. Upon cooling the crude mixture was quenched with water and extracted with ethyl acetate before the organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% ethyl acetate/petrol to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[N:8]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1(F)F
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into the solution of 6-bromo-3,3-difluoroindolin-2-one in DMF (5 mL), was added 1M of NaHMDS solution in THF (1.6 mL), after 30 min., (2-(chloromethoxy)ethyl)trimethylsilane (269 mg) was added. After being stirred at rt for 4 h, the reaction mixture was extracted with ethyl acetate and washed with brine, dried and the solvent was removed, the residue was purified by silica gel chromatography to provide 0.46 g of 6-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.35. 1H NMR (400 MHz, Chloroform-d) δ 7.43 (s, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 5.12 (s, 2H), 3.58 (m, 2H), 1.21 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[NH4+].[Cl-]>ClCCl>[CH3:9][O:8][C:7]1[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Yield: 41 %

Procedure:
4-chloro-5-methoxy-2-(4-nitro-phenyl)-pyrimidine (1.50 g, 1.0 eq) was stirred in dichloromethane (10 mL) and a solution of morpholine (0.75 mL, 1.5 eq) in dichloromethane (5 mL) was added dropwise to the mixture at 0° C. After stirring, the resulting solution was reacted overnight at r.t., NH4Cl (aq) was added to the solution and the solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (0.73 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][NH:19][C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)NCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorophenylacetic acid (17 mg, 0.11 mmole) and 4-chlorophenethylamine (15 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this was added catalytic 4-dimethylaminopyridine (DMAP) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 33 mg, 0.11 mmole). The resulting solution was stirred at room temperature overnight. The reaction was then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 7.31-6.92 (m, 8H), 5.48 (bs, 1H), 3.51 (s, 2H), 3.42 (m, 2H), 2.70 (m, 2H).
Reaction SMILES: [NH2-].[Na+].N.[Na].Cl[C:6]([C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH2:7].Cl>CS(C)=O>[C:6]([C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C=C(Cl)C1(C(=O)O)CCCCC1
Agent: Cl
Agent: N
Agent: [NH2-]
Solvent: CS(C)=O
Product: C#CC1(C(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A suspension of sodium amide in liquid ammonia was prepared using 3.5 g of sodium. After evaporating off the ammonia, the sodium amide was dissolved in 40 cm3 of anhydrous dimethylsulphoxide (DMSO). The mixture was stirred under nitrogen for 3 hours and a solution of 6.6 g (0.035 mole) of 1-(1-chlorovinyl)-1-cyclohexyl-carboxylic acid in 30 cm3 of dry DMSO was added slowly. The temperature of the whole was raised to 50° C. in the course of 6 hours and stirring was continued overnight at laboratory temperature. The mixture was poured into a cold solution of 20% hydrochloric acid. The resulting mixture was extracted several times with ether. After evaporating off the solvent, 1-ethynyl-1-cyclohexyl-carboxylic acid was obtained and this crystallized as colourless crystals on the addition of pentane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br.Br>[Fe]>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([C:8]([F:9])([F:10])[F:11])=[CH:3][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Fe]
Agent: Br
Product: Nc1cc(C(F)(F)F)ccc1Br
Reaction time: 2 h

Procedure:
To 161.0 g of m-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35°-40°, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional 2 hours and then distilled in vacuo to give 4-bromo-3-aminobenzotrifluoride.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=CC=C[CH:25]=1.[C:30]([C:32]1[CH:33]=[N:34]C=C(Br)C=1)#[N:31].IC1C=CC=CC=1>>[C:33]([C:32]1[CH:29]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:25]=[N:31][CH:30]=1)#[N:34]
Reactant: N#Cc1cncc(Br)c1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(C#N)c3)c(=O)c2)cc1

Procedure:
4-[3-(5'-Cyano-2-oxo-2H-[1,3']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 3-cyano-5-bromopyridine for the iodobenzene in Step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
To a stirred solution of ethyl 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (0.93 g) in tetrahydrofuran (15 mL) and methanol (15 mL) was added a solution of potassium hydroxide (85%, 0.50 g) in water (10 mL). The mixture was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (783 mg, 91%) as pale yellow crystals. MS 362 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:5]=1[O:6][N:7]=C(OCC)C)([O-:3])=[O:2].Cl(O)(=O)(=O)=O>O1CCOCC1>[N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:5]=1[O:6][NH2:7])([O-:3])=[O:2]
Reactant: CCOC(C)=NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 190 %

Procedure:
To a suspension of 2.0 g (0.0074 mole) of ethyl N-(2,4-dinitrophenoxy)acetimidate in 10 mL of dioxane, cooled in an ice/water bath, was added dropwise 3 mL of 70% perchloric acid during a 10 minute period. The reaction mixture was stirred at 0°-5° C. for five hours and then was poured into 100 mL of ice water. This mixture was extracted three times with 40 mL of methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 2.8 g of a brown oil. This oil was dissolved in 20 mL of diethyl ether, and 30 mL of petroleum ether was added to the solution, causing a precipitate to form. This precipitate was recovered by filtration. After being washed with petroleum ether and dried, 0.75 g of O-(2,4-dinitrophenyl)hydroxylamine was recovered as a yellow powder. The NMR spectrum was consistent with the proposed structure. This method is described by Y. Tamura et al., J. Org. Chem., 38, 1239 (1973).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(C(OCC)=O)[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.65 g of 5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 10 ml of methanol containing 0.2 g of sodium hydroxide is stirred for 3 h at room temperature and 5 ml of 1N hydrochloric acid is added. The reaction mixture is refluxed for 1 h, cooled and evaporated. The residue is partitioned between water and ethyl acetate. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1>ClCCl>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH3:60])[C:8]([C:5]5[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[O:10])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nn(C)c(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A mixture of 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid (71 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was treated with triphenylphosphine (145 mg, 0.55 mmol) and N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 10 min. At this time, the reaction was treated with a solution of 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (400 mg, 0.92 mmol) in dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The water layer was re-extracted with dichloromethane (2×50 mL). The organic layers were combined and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in vacuo for 24 h to afford 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (169 mg, 65%) as a white solid: (ES)+-HRMS m/e calcd for C31H32N7O3F (M+H)+ 570.2623, found 570.2619.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([Cl:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) (0.2 g, 0.53 mmol) was dissolved in DCM (10 ml) and treated with oxalyl chloride (1.5 g, 12 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 14 hours and the solvent was then removed in vacuo. The crude material was dissolved in toluene and evaporated. Crude 2,4-bis-benzyloxy-5-isopropyl-benzoyl chloride was obtained as an oil (200 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[BH4-].[Na+].[OH-].[K+].C(OCC)(=O)C>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
10 g of 2-bromo-1-(3-nitro-phenyl)-ethanone is dissolved in 200 ml of ethanol, mixed with 1.55 g of sodium borohydride and stirred for 1 hour at room temperature. 2.1 g of potassium hydroxide is added, and it is stirred for another 15 hours at room temperature. 1000 ml of ethyl acetate is added, and it is washed twice with 300 ml of semi-saturated ammonium chloride solution and once with 100 ml of water. The organic phase is dried on sodium sulfate. After purification by chromatography on silica gel, 7.48 g of the title compound is obtained.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH:10]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([N:25]1[CH2:39][C:28]2=[C:29]3[N:34]([N:35]=[C:27]2[CH2:26]1)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]3)=[O:24])=O)(C)(C)C.O>O1CCOCC1>[Cl:37][C:32]1[C:31]([CH3:38])=[N:30][C:29]2[N:34]([N:35]=[C:27]3[CH2:26][N:25]([C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH:10]4[CH2:11][O:12][CH2:13][CH2:14][NH:9]4)=[O:24])[CH2:39][C:28]3=2)[C:33]=1[CH3:36]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1COCCN1C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1COCCN1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (3.2 mL; 12.7 mmol; 10 eq.) was added to a suspension of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (690 mg; 1.27 mmol; 1 eq.) in 1,4-dioxane (10 mL) followed by WATER (130 μL) and the resulting mixture was stirred at room temperature for 16 hours. After concentration in vacuo, the residue was partitioned between DCM and 1M NaOH and the aqueous layer was extracted with DCM. The combined organic phase was dried over sodium sulfate and concentrated in vacuo. Crystallization from EA afforded the title compound (240 mg, 43%) as a yellow solid. 1H NMR (CDCl3) δ 7.44-7.30 (m, 2H), 7.13-7.01 (m, 1H), 6.96 (dd, J=8.2, 4.0 Hz, 1H), 5.07-4.96 (m, 2H), 4.68-4.55 (m, 2H), 4.03-3.89 (m, 2H), 3.85-3.76 (m, 1H), 3.76-3.66 (m, 1H), 3.51-3.39 (m, 1H), 3.31 (t, J=10.0 Hz, 1H), 3.25-3.12 (m, 1H), 2.95-2.76 (m, 5H), 2.69 (s, 1.1H), 2.61 (s, 1.9H), 1.94 (brs, 1H). HPLC (max plot) 94.4%, Rt 2.72 min. UPLC/MS: (MS+) 442.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:2]([NH:3][N:4]1[CH2:8][C:9]([CH3:10])=[N:14][NH:13][C:5]1=[O:7])(=[O:6])[CH3:1]
Reactant: CC(=O)Cn1nc(C)oc1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NN1CC(C)=NNC1=O

Procedure:
312 g of 2,3-dihydro-5-methyl-2-oxo-1,3,4-oxadiazol-3-ylacetone in 4 l of ethanol are stirred together with 200 g of hydrazine hydrate for 16 hours at 35° C. The solvent and the excess of hydrazine hydrate are evaporated in vacuo, and the residue is recrystallised from isopropanol to give 148 g (87% of the theoretical amount) of the title compound having a melting point of 197°-199° C.
Reaction SMILES: C(OC([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][N:14]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[S:18]1)=[O:16])=O)(C)(C)C>C(O)=O>[CH2:10]([NH:11][CH2:12][CH2:13][N:14]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[S:18]1)=[O:16])[CH2:9][CH3:8]
Reactant: CCCCCCN(CCNCCCC(=O)OC(C)(C)C)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Solvent: O=CO
Product: CCCCCCN(CCNCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Yield: 82.7 %

Procedure:
In 4.3 ml of 99% formic acid was stirred 600 mg of N-2-(N-t-butoxycarbonylpropylamino)ethyl-N-hexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide for 5 hours. The reaction solution, after concentration under reduced pressure, was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 406 mg of N-2-(propylamino)ethyl-N-hexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:4]([C:11]([OH:13])=[O:12])[NH:3]1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:4]([C:11]([O:13][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:12])[NH:3]1
Reactant: O=C1NC(C(=O)O)C2CCCCC12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C1NC(=O)C2CCCCC21
Reaction time: 60 h

Procedure:
The intermediate t-butyl octahydro-3-oxo-1H-isoindole-1-carboxylate is prepared from octahydro-3-oxo-1H-isoindole-carboxylic acid (Example 5) as follows. A mixture of 10 g of this acid and 0.4 ml of 70% perchloric acid in 150 ml of t-butyl acetate is allowed to stand for 2.5 days. An additional 50 ml of t-butyl acetate is added and the reaction is allowed to continue for 15 days. The solution is filtered and poured onto 14 g of 50% sodium hydroxide solution and ice. The product is extracted into ether. Drying and concentration gives a residue which when triturated with hexane gives material, mp 143°-149° C., suitable for further use.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]([CH2:58][CH3:59])([CH2:56][CH3:57])[CH2:54][OH:55].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:56]([C:53]([NH:52][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH2:54][OH:55])[CH2:58][CH3:59])[CH3:57]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CCC(N)(CC)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)(CO)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
To a solution of 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c, 20 mg, 77 μmol) in DMF (1.5 mL) was added HATU (32 mg, 84 μmol) and DIPEA (15 μl, 84 μmol). The reaction mixture was stirred at roomtemperature for 20 minutes followed by addition of 2-amino-2-ethylbutan-1-ol (CAN 19792-52-0, 10 mg, 84 μmol). The reaction was stirred at room temperature overnight and was poured into 15 mL of a saturated aqueous solution of sodium bicarbonate. The solution was extracted three times with 10 mL dichloromethane. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica, eluting with a heptane/ethylacetate gradient to yield the titled compound (16 mg, 58%) as white solid. MS (ESI, m/z): 361.1 (M+H+).