Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:15][NH2:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[NH:16][N:15]=[CH:4]2
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2cn[nH]c12
Yield: 93 %

Procedure:
A solution of 2-fluoro-3-trifluoromethylbenzaldehyde (5 g, 26 mmol)), hydrazine hydrate (8.3 mL, 260 mmol) and DMAP (3.17 g, 26 mmol.) in 10 mL pyridine was heated at 100° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The organic phase was concentrated in vacuo to give 4.5 g of product. The crude product was recrystallized from Et2O/hexane to give the title compound (3.6 g, white solid, mp 90° C.).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>CCCCCC.O1CCCC1>[Cl:24][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc(F)c1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 1.6N n-butyl lithium in hexane (294 ml) was added to 71 ml of tetramethyl ethylene diamine (TMEDA) in tetrahydrofuran at -70° C. under an inert atmosphere. 3-Fluorobenzoic acid (30 g) in tetrahydrofuran was added and the mixture was stirred for one hour. Hexachloroethane (111.5 g) was added and the reaction mixture was stirred for two hours at -70° C. The reaction mixture was allowed to warm to 10° C. and acidified (to pH 1) with 3M hydrochloric acid solution, extracted with diethyl ether, dried (anhydrous magnesium sulphate) and concentrated to give a solid that was recrystallised from heptane/ethyl acetate to give 2-chloro-3-fluorobenzoic acid (26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C1COCC1>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(N)c(Nc2ccccc2)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#N)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
A mixture of 4-amino-3-phenylaminobenzonitrile (490 mg, 2.34 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (490 mg, 2.57 mol), HOAt (380 mg, 2.79 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (540 mg, 2.81 mol) and 4-methylmorpholine (560 μL, 5.15 mmol) in THF (5 mL) was stirred at RT for 48 h under an argon atmosphere. The crude reaction mixture was then partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in DCM) affording [(S)-1-(4-Cyano-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a cream foam (800 mg, 89%). LCMS: RT 3.62 min [M+H]+ 381.2.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][C:39](Cl)=[O:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:39]([CH2:38][CH2:37][C:36]([CH3:43])([CH3:42])[CH3:35])=[O:40])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: CC(C)(C)CCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CCC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is interacted with 3,3-dimethylbutanecarbonyl chloride there is obtained 3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)c2c(-c3ccccc3)noc2C)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), ethyl isonipecotate (33.8 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C19H22N2O4: 342.1580, found 342.1578.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([NH:19][OH:20])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Si]([N:25]=[C:26]=[O:27])(C)(C)C.CCO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([N:19]([OH:20])[C:26]([NH2:25])=[O:27])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)N(O)C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a stirred solution of N-[3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopenten-1-yl]-N-hydroxylamine (1.35 g; 4.64 mM) in THF (13 ml) was added TMSNCO (0.755 g; 5.56 mM) at room temperature under N2. After stirring for 1 hr, EtOH (20 ml) was added. Volatiles were removed, and the resulting residue was recrystallized from ethyl acetate-EtOH (20 ml-120 ml) to provide 0.5 g of the title compound as a colorless solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1ccco1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccco3)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of 2-furylmethyl amine and 3.5 of triethyl amine and worked up. Melting point: 154° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CNCCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.4 g, 1.13 mmol) in dichloromethane (5.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification. ESI-MS m/z: 254 (M+1), UV retention time: 1.01 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH2:7][CH2:8][C:9]1=[O:12]
Reactant: O=C1CCc2cccc(F)c2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCN1C(=O)CCc2cccc(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Fluoro-3,4-dihydroquinolin-2(1H)-one (2.31 g, 13.98 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (4.03 g, 27.9 mmol) and potassium carbonate (11.78 g, 85.3 mmol) were combined in a round bottom flask containing a stirbar. The flask was purged with argon and DMF was added. The white suspension was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate and washed with water (5×), then brine (2×). The organic phase was then dried, filtered and concentrated, then chromatographed on silica gel using EtOAc eluent. Yield: 2.86 g, 86%. 1H NMR 7.0 Hz), 4.09 (t, 2H, J=7.0 Hz), 6.98 (m, 3H). ESI-MS: 237 (MH+, 29), 192 (100). (CDCl3) δ 2.24, (s, 6H), 2.51 (t, 2H, J=7.0 Hz), 2.59 (t, 2H, J=7.0 Hz), 2.87 (t, 2H, J=
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 10 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Following the procedure of J. Org. Chem. 1960, 25, 721) 4-Bromoveratrole (16.28 g, 75.0 mmol) was slowly added to a stirred solution of concentrated nitric acid (122 ml) and acetic acid (365 ml) maintained at 10° C. The reaction mixture was stirred at 15° C. for one hour, then was diluted with water and extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from ethanol to give 1-bromo-4,5-dimethoxy-2-nitro-benzene (13.144 g, 66.9%) as yellow crystals.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:17]([O:18]C(=O)C2C=CC=CC=2)[C@@H:16]([CH2:27][O:28]C(=O)C2C=CC=CC=2)[O:15][C@H:11]1[C:12]([OH:14])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[CH3:70][O:71][C:72]1[CH:79]=[CH:78][C:75]([NH:76][CH3:77])=[CH:74][CH:73]=1>C1COCC1>[OH:9][C@@H:10]1[C@H:17]([OH:18])[C@@H:16]([CH2:27][OH:28])[O:15][CH:11]1[C:12]([N:76]([C:75]1[CH:78]=[CH:79][C:72]([O:71][CH3:70])=[CH:73][CH:74]=1)[CH3:77])=[O:14]
Reactant: O=C(OC[C@H]1O[C@@H](C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CNc1ccc(OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)C2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3,4,6-Tri-O-benzoyl-2,5-anhydro-D-allonic acid (2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon, and triphenylphosphine (2.1 g, 8 mmol) was added to the mixture. The resultant mixture was stirred until the triphenylphosphine was completely dissolved and subsequently 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added. The mixture was stirred at room temperature for 2 hours, after which the 4-methoxy-N-methyl-aniline (0.768 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 mL) and washed twice with 0.1 M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL) and dried (Na2SO4). The solvent was evaporated to dryness and the residue was dissolved in 7M ammonia solution in methanol (250 ml) and stirred for 16 hours at room temperature and then evaporated to dryness. The residue was dissolved in chloroform and applied to a column of silica gel. Elution with a mixture of chloroform methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as an off-white solid (0.77 g, 2.6 mmol, 65%): MS (ES) m/z 320 [M+Na]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]1[CH2:13]OCC1.[CH3:14][CH2:15]N(CC)CC.C[Si](C#C)(C)C>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:9]([C:2]1[CH:7]=[CH:6][C:5]([C:14]#[CH:15])=[CH:4][CH:3]=1)#[CH:13]
Reactant: C1CCOC1
Reactant: Ic1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: ClCCl
Product: C#Cc1ccc(C#C)cc1

Procedure:
Firstly, a mixture of 1,4-diiodobenzene (4 g, 12.1 mmol), PdCl2(PPh3)2 (340 mg, 0.484 mmol) and CuI (92.4 mg, 0.484 mmol), was added with dist. THF (20 mL), dist. Et3N (60 mL) and trimethylsilylacetylene (3.77 mL, 26.7 mmol). The resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 22 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with CH2Cl2. After that, an organic layer was washed with sat. NaCl, and dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1) to obtain 1,4-diethynylbenzene.
Reaction SMILES: C([C@@:4]1([OH:28])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH2:13][O:14]C(=O)C)[O:6][C@H:5]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22](O)[C:21]=2[N:20]=[CH:19]1)(=O)C.S(Cl)([Cl:31])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:31][C:22]1[N:24]=[CH:25][N:26]=[C:27]2[C:21]=1[N:20]=[CH:19][N:18]2[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:28]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 60 %

Procedure:
50 g of 2', 3',5'-O-triacetylinosine was dissolved in 400 ml of chloroform. 30 ml of thionyl chloride and 7.2 ml of dimethylformamide were added, and the solution was refluxed with heating for 2 to 4 hours. The reaction mixture was poured into ice cold water, and the separated chloroform layer was washed with saturated aqueous solution of sodium hydrogencarbonate and brine. After drying over sodium sulfate anhydride, the solvent was distilled off. The residue was dissolved in 20% ammonia methanol solution and the container was sealed. After stirring for 3 to 5 hours, the solution was concentrated under reduced pressure. The precipitated crystalline was separated by filtration and dried to give 6-chloro-9-β-D-ribofuranosyl-9H-purine (yield: 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:16]([O-:18])=[O:17])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
841 g of 3-fluorobenzoic acid were placed in 3261 g of 100% strength by weight sulphuric acid and the mixture was cooled to +10° C. 1147 g of nitrating acid comprising 67% by weight of 100% strength by weight sulphuric acid and 33% by weight of 100% strength by weight nitric acid were then added. After the reaction was completed, the mixture contained approximately 1.65% by weight of wrong isomers. The mixture was added to 10 1 of water and then cooled to room temperature. The solid product precipitated out was filtered off and then washed 3 times, each time with 2 1 of water, and dried. 957.8 g of 5-fluoro-2-nitro-benzoic acid (calculated as 100% pure product) were obtained, which corresponds to 86.3% of theory. The product contained 0.17% by weight of 3-fluoro-2-nitro-benzoic acid.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]([CH2:17][C:16]1[CH:27]=[CH:28][C:13]([O:12][CH2:11][CH2:10][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:14][CH:15]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Example 30 is dissolved in 5 ml of methanol and 3 ml of THF. The mixture is cooled to 0° C. and 0.44 ml of a 2M sodium hydroxide solution is added dropwise. After stirring for 1 hour 30 minutes at ambient temperature, the solvents are removed by evaporation under reduced pressure and the resulting residue is taken up in water and extracted with ethyl acetate. The aqueous phase is acidified with a 2M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered, and evaporated under reduced pressure. The resulting residue is taken up in a minimum of ethyl acetate and precipitated with pentane to yield the title product after filtration.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].CCN(CC)CC.[NH2:27][CH2:28][CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:27][CH2:28][CH2:29][C:30]2[N:34]=[CH:33][NH:32][CH:31]=2)[N:14]=1)[C:11]#[N:12]
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Reactant: NCCc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC(c1ccnc(NCCc2c[nH]cn2)n1)c1nc2ccccc2s1
Temperature: 70 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
To a suspension of 1 (0.1 g, 0.35 mmol) in dry EtOH (3 ml) was added Et3N (0.05 ml, 0.35 mmol) and histamine (0.078 g, 0.70 mmol). After sonication, the yellow solution was shaken at 70° C. for 3 days. The yellow precipitate formed was filtered off and washed with H2O (2×) then EtOH (3×) and dried under vacuum at 40° C., affording 47 mg (37%) of the title compound as a bright yellow powder: mp 257-258° C., 10 was taken up in a mixture of DCM/TFA. The yellow fluffy solid formed by addition of ether was filtered off, washed with ether (3×) then dried under vacuum at 40° C., affording 36 mg (29%) of the title compound as a yellow powder: mp 247-249° C., MS: 362.0 (M+1); HPLC (Conditions a, 265 nm): 98%, rt. 2.87 min; 1H NMR (DMSO-d6): δ 14.25 (br s, 2H, exchangeable), 11.05 (br s, 1H, exchangeable), 9.03 (s, 1H), 7.94-7.87 (m, 1H), 7.74-7.71 (m, 2H), 7.57-7.52 (m, 2H), 7.42-7.37 (m, 1H), 7.24-7.19 (m, 1H), 6.40 (d, J=7.1 Hz, 1H), 3.97-3.55 (m, 3H), 3.11-3.05 (m, 2H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (543 mg) in dry chloroform (4.6 mL) was cooled to 0° C. and NBS (334 mg) was added. The mixture was stirred at room temperature for 10 mins. The reaction was taken up in DCM (30 mL) and was washed with water (30 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a viscous brown residue (627 mg) which was used crude in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:9][C:7](=[O:8])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[C:4](=[O:5])[CH2:3]1.P(OCC)(OCC)[O:28]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C=NC(N2CCN(CCCCN3C(=O)CC4(CCCC4)CC3=O)CC2)=NC=1>C1COCC1>[CH3:1][C:2]1([CH3:26])[CH:3]([OH:28])[C:4](=[O:5])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[C:7](=[O:8])[CH2:9]1
Reactant: CCOP(OCC)OCC
Reactant: CC1(C)CC(=O)N(CCCCN2CCN(c3ncccn3)CC2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(CCCCN2CCN(c3ncccn3)CC2)C(=O)C1O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Gepirone (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione) (10.0 g, 27.8 mmol) was charged to a 500 mL flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (250 mL, 25 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (28.9 g, 174 mmol, 29.8 mL, 6.25 eq) was added and the mixture was cooled to −65 to −80° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (27.8 mL, 27.8 mmol, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of gepirone. Additional gepirone in THF (25 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 3.24% excess of gepirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (40.0 mL) was added followed by 1M hydrochloric acid (45.0 mL) and the solution was warmed to ambient temperature. The pH (9.48 at 20.6° C.) was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4 (pH=6.95 at 22.7° C.). The phases were separated and the organic phase was washed twice with 25 wt % brine (40.0 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to ambient temperature to crystallize the reaction product. The crystalline slurry was then filtered and the wet cake was washed twice with isopropyl alcohol (15.0 mL) and dried to provide 3-hydroxygepirone (9.32 g, 89%), mp 128° C.