Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(Cl)Cl.[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1.C(N(CC)CC)C>O>[CH3:8][N:9]1[CH2:10][CH2:11][CH2:12][N:13]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:33])([F:34])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:1]1=[O:2]
Reactant: CNCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
Phosgene (294 μl, 0.559 mmol) was added at 0° C. to an anhydrous methylene chloride solution (2 ml) that contained the 7-(3-methylaminopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (70 mg, 0.186 mmol) obtained in step B. The obtained mixture was stirred for 10 minutes. Thereafter, triethylamine (156 μl, 0.112 mmol) was added to the reaction solution, and the obtained mixture was then stirred for 30 minutes. Thereafter, water was added to the reaction solution. An organic layer was separated, and a water layer was then extracted with methylene chloride. The organic layer was mixed with the extract. The obtained mixture was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (methylene chloride:methanol=40:1), so as to obtain 7-(3-methyl-2-oxotetrahydropyrimidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.2 mg, 14%).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[C:28]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][CH3:26])[CH2:21][CH2:20]3)[C:15]2=[O:27])=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[C:28]([Cl:30])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([O:25][CH3:26])[CH2:21][CH2:20]2)[C:15]1=[O:27]
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1

Procedure:
Stir (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-methoxy-cyclohexyl)-pyrrolidin-2-one (2.59 g, 5.61 mmol) and palladium hydroxide (20% on carbon) (0.300 g, 10% by weight) in 100 ml of ethyl acetate. Bubble hydrogen gas through the solution while stirring at room temperature for 5 minutes. Stir the mixture under the hydrogen gas atmosphere for 5 hours. Filter through Celite® and concentrate under vacuum to recover 2.08 g of the title compound (99%). MS (m/z): 372 (M+).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:22]([O-:24])=[O:23])[CH:12]=2)[N:7]=1)(=O)[CH3:2].O.N>>[CH3:2][C:1]1[N:7]2[C:8]3[C:13]([C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:15][C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([N+:22]([O-:24])=[O:23])=[CH:10][CH:9]=3
Reactant: CC(=O)NNc1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1
Agent: N
Solvent: O
Product: Cc1nnc2nc(-c3ccccc3)c3cc([N+](=O)[O-])ccc3n12
Temperature: 0 °C

Procedure:
In the next place, a mixture of 0.8 g of 2-(2-acetylhydrazino)-4-phenyl-6-nitroquinazoline thus obtained and 16 g of polyphosphoric acid was heated at 150° to 160° C for 2 hours. The mixture was then poured into ice-water and made alkaline with concentrated ammonia water. The precipitated crystals were filtered, washed with ethanol and then recrystallized from chloroform to obtain 1-methyl-5-phenyl-7-nitro-s-triazolo[4,3-a]quinazoline as pale brown crystals, m.p. 350° - 352° C.
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[CH:4]([C:5]([OH:7])=O)[CH:3]([C:8]([OH:10])=O)[CH:2]1[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH:1]12[C:14](=[O:15])[O:16][C:5](=[O:7])[CH:4]1[CH:3]1[C:8](=[O:10])[O:12][C:11](=[O:13])[CH:2]12
Reactant: O=C(O)C1C(C(=O)O)C(C(=O)O)C1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2C1C1C(=O)OC(=O)C21
Temperature: 25 °C
Yield: 135.6 %

Procedure:
The cyclobutane-1,2,3,4-tetracarboxylic acid (501 g, 2.16 mol) and acetic anhydride (3000 ml) were added to a 5-liter flask and reacted at a controlled temperature of 150° C. for 24 hours. The reaction was cooled to room temperature; concentrated; and dried to obtain 1,2,3,4-cyclobutanetetracarboxylic dianhydride (573 g, 2.93 mol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)c1ccccn1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccccn4)nc3cc21

Procedure:
Pyridine-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and picolinic acid (109 mg, 0.89 mmol). The title compound was obtained as orange powder (121 mg, 36%).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([C:9]([CH3:14])=[CH:10][N+:11]([O-:13])=[O:12])[CH:6]=[CH:5][C:4]=1O.[O:16]=CC1C=CC(O)=C(OC)C=1.[N+](CC)([O-])=O>>[CH3:14][C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:8]=1[OH:16])=[CH:10][N+:11]([O-:13])=[O:12]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1cc(C(C)=C[N+](=O)[O-])ccc1O
Solvent: CC[N+](=O)[O-]
Product: CC(=C[N+](=O)[O-])c1ccccc1O
Yield: 80 %

Procedure:
2-methoxy-4-(α-methyl-β-nitroethenyl)-phenol was also prepared by a variation of the above procedure in which vanillin was treated with nitroethane instead of nitromethane. The conditions employed for the reaction, however, were essentially the same as those described above for nitromethylation. The α-methyl-β-nitroethenyl phenol product was obtained in 80% yield with m.p. 110°-112° and had λ max (ethanol) of 368 and λ max (TRIS 8.8) of 475 with ε of 13,100.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)=[CH2:18])[CH3:14]>CC#N>[CH2:13]([O:15][C:16](=[O:34])[CH:17]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:24][CH:25]=1)[CH2:18][P:10]([OH:11])([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[CH3:14]
Reactant: O=[PH](O)CCCc1ccccc1
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)CCCc1ccccc1
Reaction time: 72 h
Yield: 45.9 %

Procedure:
A solution of (3-Phenyl-propyl)-phosphinic acid (0.579 g, 3.143 mmol) and 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.327 g, 1.067 mmol) in MeCN (7.5 mL) was degassed using the freeze-thaw technique. BSA (2.55 g 12.57 mmol) was added and the mixture was stirred for 3 days and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (CH2Cl2/MeOH, 8:2) gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid ethyl ester (0.240 g, 16%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.[Cu](I)I.N1CCCCC1>[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:2]2[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCCOc1ccc(C#Cc2ccc(S(F)(F)(F)(F)F)cc2)cc1

Procedure:
8.5 g of p-bromophenyl-sulfur pentafluoride and 20 ml of piperidine are added to a mixture of 8.5 g of 4-pentoxyphenylacetylene, 20 ml of piperidine, 420 mg of triphenylphosphine-palladium(II) chloride and 30 mg of copper iodide, and the combined mixture is heated for 20 hours. Concentration and working up in the customary manner gives 4-(2-(4-pentoxyphenyl)-ethynyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[I-].[Na+]>C1COCC1>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Reactant: CCn1nnc(CCl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (5.00 g, compound B53) in anhydrous THF (100 ml) is slowly added 5-(chloromethyl)-2-ethyl-2H-tetrazole (5.62 g, compound D32), sodium bis(trimethylsilyl)amide (11.6 ml, 1.0 M solution in THF) and sodium iodide (348 mg). The reaction mixture is stirred for 48 h at 45° C. Afterwards all volatiles are removed under reduced pressure and the residue is treated with DCM (100 ml) and water (50 ml). The organic layer is separated and dried over sodium sulfate. After purification by flash column chromatography [silica gel, eluation gradient: EtOAc/cyclohexane, 1/1 (v/v)] the title compound is obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a 0° C. solution of 2-chloropyridine-3-carbaldehyde (2.0 g, 14.1 mmol) in anhydrous methanol (80 mL) was added sodium borohydride (550 mg, 14.5 mmol). The reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (20 mL) was added. The resultant mixture was extracted with dichloromethane (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (2-chloropyridin-3-yl)methanol (800 mg, 40% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.5 g) is synthesized according to the general procedure using 4-methoxybenzyl chloride (0.92 g; 5.86 mmol) and K2CO3 (2.3 g; 16.6 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (15 ml) and hydrochloric acid (6 N; 45 ml). Pure 5-amino-1-(4-methoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.71 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2-methyl-hexan-3-ol (42 mg, 3.0 eq, 0.32 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.3 mg (15%). 50% de 4R,3S: 50% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.93-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.95 Hz, —CH(CH3)2), 1.65-1.89 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.22-3.32 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.82-3.97 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.54-4.70 (m, 1H, —CH(CH3)2), 4.78-4.88 (m, 2H, —HNCH2-Pyr), 5.03-5.14 & 6.08-6.20 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.22-7.36 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.49-7.58 (m, 1H, Pyr-H), 7.71 (d, 1H, J=7.90 Hz, Pyr-H), 8.47-8.73 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (50). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20](N)=[O:21])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[OH-:29].[Na+]>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:29])=[O:21])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
26 ml of concentrated hydrochloric acid are added dropwise to a suspension of 25.2 g (0.065 mole) of dextrorotatory (+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide (prepared at point 10 above) in 70 ml of water, causing the temperature of the mixture to rise to 38° C. The mixture is then heated at 50° C. for 17 hours. The reaction mixture is then cooled in an ice bath and the pH brought to a value of between 4 and 5 by addition of a 4N aqueous solution of sodium hydroxide. The resulting solution is extracted successively with 100 ml, then twice with 50 ml of dichloromethane. The organic phases are combined and dried over magnesium sulfate. They are filtered and the solvent is evaporated. The residual oil is dissolved in 243 ml of acetone and the solution is treated with 3.5 g of Norit and filtered through Celite, which is then washed with 35 ml of acetone. The solution is heated at reflux temperature and 198 ml (0.13 mole) of concentrated hydrochloric acid are added dropwise thereto. The mixture is cooled in an ice bath and allowed to stand for one hour. The precipitate which forms is filtered off, washed with 100 ml of acetone and dried under vacuum at 50° C. 24.1 g of the levorotatory dihydroshloride of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][OH:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][O:18][CH2:22][CH:23]1[CH2:25][CH2:24]1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=CCO)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=CCOCC1CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
A reaction flask was charged with 3-(2-hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.380 g, 1.5 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.060 g, 1.5 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (0.202 g, 1.5 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give the title compound (0.115 g, 25%). 1H NMR (CDCl3) δ 5.38-5.32 (m, 1H), 4.36-3.96 (m, 2H), 3.88-3.75 (m, 2H), 3.09 (d, 2H), 2.48-1.66 (m, 6H), 1.48-1.36 (m, 2H), 1.30 (s, 9H), 0.94-0.33 (m, 1H), 0.40-0.33 (m, 2H), 0.05-0.00 (m, 2)
Reaction SMILES: [C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2].C1C=CC(OC(OC2C=CC=CC=2)=NC#N)=CC=1>C(O)(C)C.[H][H].[Pd]>[C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(NC(=NC#N)Oc3ccccc3)cc2CC1
Agent: [Pd]
Agent: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CN=C(Nc1ccc2c(c1)CC[C@@H](N)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The single enantiomer was then BOC-protected, the nitro group reduced by treatment with H2/Pd and the primary aniline treated with diphenyl cyanocarbonimidate (slight excess) in 20 mL of isopropanol with stirring at ambient temperature overnight. The solid was filtered, washed with isopropanol and ether and dried to give phenyl (7S)—N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid in high yield (from the single enantiomer via transamination).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)(C)C>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0.024 mole) of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanol was then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27](O)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH2:32])[CH3:31]>>[CH2:30]([NH:32][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:28])[CH3:31]
Reactant: CCN
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Product: CCNC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid and ethylamine in an analogous manner to example 1. MS calcd. for C25H34N3O3 [(M+H)+] 424.0, obsd. 424.0.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4].C([O-])(=O)C.[NH4+:26]>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[NH:5][C:3](=[O:4])[N:26]=1
Reactant: O=C(c1ccccc1F)c1ccsc1NC(=O)C(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Temperature: 95 °C

Procedure:
To a solution of 2.11 g of 2-trichloroacetamido-3-(o-fluorobenzoyl)thiophene in 18 ml of dimethylsulfoxide was added 0.89 g of ammonium acetate. The mixture was heated at 95° C for 2 hours and poured into ice water, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 60 g of Silica gel, using ethyl acetate as an eluent to obtain 4-(o-fluorophenyl)-1,2-dihydrothieno(2,3-d)-pyrimidin-2-one as crystals having a melting point of 272°-275° C. Recrystallization from acetone gave crystals melting at 247.5°- 249° C. The following compounds were prepared similarly:
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:6]([NH2:7])=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1)#[N:2].O.Cl>[Fe].C(O)C>[C:1]([C:3]1[C:4]([N:13]2[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[CH:5][C:6]([NH2:7])=[C:8]([NH2:10])[CH:9]=1)#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)c(N)cc1-n1ccc(=O)cc1
Yield: 63.3 %

Procedure:
First, a mixture containing 490 mg of 4-cyano-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 642 mg of iron powder, 4 ml of water, 16 ml of ethanol, and 0.2 ml of 2N hydrochloric acid was heated in an oil bath for 1 hour. The subsequent processes were conducted in the same way as in Reference Example 3 to give crude crystals. Then, 405 mg of the crude crystals were recrystallized with methanol/isopropanol to give 274 mg of crystals of 4-cyano-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.