Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1>O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
In a reaction vessel were placed p-tolylboronic acid (0.177 g, 1.3 mmol) and (GLCAphos)2PdCl2 (11 mg, 0.01 mmol), and the atmosphere was replaced with argon. To the mixture were added water (2 ml), an aqueous solution of sodium carbonate (2M solution, 1 ml, 2 mmol) and 4-methoxybromobenzene (0.125 ml, 1.0 mmol) as an aryl halide derivative at room temperature and the mixture was heated at 80° C. with stirring for 16 hours. During the reaction, a white solid was gradually precipitated. After cooling to room temperature, toluene (10 ml) was added to extract the product. The organic layer was washed with water five times and dried under a reduced pressure to give a substantially pure 4-methoxy-4′-methylbiphenyl in an yield of 95%.
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of (2.3 g, 19.46 mmol) 1H-benzimidazole in DMF (80 mL) at 0° C. was added sodium hydride (0.78 g, 19.46 mol, 60 wt. %) and the reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. Methyl 4-fluorobenzoate (3.0 g, 19.46 mmol) was then added and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with dichloromethane (4×250 mL). The combined organic layers were washed with water (2×250 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:10) provided 3.7 g (76%) of methyl 4-(1H-benzimidazol-1-yl)benzoate as a white solid. To a solution of methyl 4-(1H-benzimidazol-1-yl)benzoate (3.7 g, 14.7 mmol) dissolved in THF/MeOH (1:1, 90 mL) was added 1.0 M aqueous NaOH (0.587 g, 14.67 mmol) and the reaction mixture was allowed to stir for 12 h at room temperature and the solvent removed in vacuo. The residue was diluted with water (100 mL), cooled to 0° C., and the pH was adjusted to 6.0 with 1.0 N aqueous HCl. The resulting precipitate was filtered and dried to afford 3.4 g (96%) of 4-(1H-benzimidazol-1-yl)benzoic acid as a white solid. MS [239.0 m/e (M+H)].
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[CH:16](=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2)(=[O:18])[CH3:17]
Reactant: CC=O
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Solvent: c1ccccc1
Product: CC(=O)c1c2sc3ccccc3nc-2ccc1=O

Procedure:
A solution of 3H-phenothiazin-3-one (2 g) and acetaldehyde (32 ml) in benzene (240 ml) was irradiated with a 450 watt lamp for 2 days. The volatiles were removed under vacuum and the residue chromatographed on a silica gel column eluting with 25% EtOAc/hexane to afford the desired compound, m.p. 222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) in 1.6 mL THF was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (16.8 mg, 0.076 mmol) and the reaction stirred at rt. After 45 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. After 1.5 hours the stirring was stopped and the reaction left to stand at rt overnight. Then using a stream of nitrogen and gentle heating, the THF was evaporated to 1 mL, let mixture stand for 30 minutes, then filtered and rinsed with 50% EtOAc in hexane to give the title compound as an off-white solid (20.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.69 (br. s, 1H), 9.14 (br. s, 1H), 8.82 (br. s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.97-7.99 (m, 1H), 7.59-7.65 (m, 2H), 7.42-7.45 (m, 3H), 7.26 (d, J=8.8 Hz, 2H), 7.05-7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.52-3.59 (m, 2H), 2.94-3.01 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH:24]=[C:25]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:26][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of benzothiophene (3 g, 22.4 mmol) in anhydrous tetrahydrofuran (50 ml) at -10° C. under nitrogen was added n-butyllithium (9.83 ml of a 2.5M solution in toluene), the mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was cooled to -40° C. and 1-benzyl-4-piperidone (4.23 g, 22.4 mmol) added, allowed to warm to room temperature and stirred for 14 hr. The reaction mixture was concentrated in vacuo and trifluoroacetic acid (10 ml) added. This mixture was stirred at room temperature for 14 hr and then concentrated in vacuo. The product was extracted into dichloromethane (3×100 ml) from aqueous potassium carbonate. The organic layer was washed with water (1×50 ml), brine (1×50 ml) and dried (MgSO4). After concentration of the extracts the crude product was purified using silica gel column chromatography to yield the title compound (4.2 g, 68%) as a colourless oil; δH (CDCl3) 2.64 (2H, m, tetrahydropyridinyl CH2), 2.74 (2H, m, tetrahydropyridinyl CH2), 3.18 (2H, m, tetrahydropyridinyl CH2), 3.65 (2H, s, PhCH2N), 6.18 (1H, m, CH=CR), 7.11 (1H, s, 3'-H), and 7.24-7.73 (9H, m, Ar--H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:7]=1[C:8]([OH:10])=O.O.[CH3:20]COC(C)=O>CN(C=O)C>[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:7]=1[C:8](=[O:10])[CH3:20]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To thionyl chloride, obtained from Aldrich, (125 mL) at 0° C. was slowly added 2,3-Dichloro-5-nitrobenzoic acid (246) (21.7 g, 91.9 mmol). The ice bath was taken away and the resulting solution was heated to reflux for 17 hours (note: acid completely dissolves upon heating). After cooling to ambient temperature, the excess thionyl chloride was removed under vacuum and the resulting acid chloride was allowed to stand under high vacuum for 15 h and used in the next step without further purification. To a 1M solution of NaH, 60% oil dispersion obtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0° C. was slowly added diethylmalonate, obtained form Aldrich, (14.65 mL, 96.5 mmol) dropwise and the resulting solution was allowed to stir for 30 minutes. The acid chloride was dissolved in DMF (184 mL) and slowly added via cannula to the reaction mixture. The resulting solution was then allowed to stir for 16 h as ambient temperature was reached followed by recooling to 0° C. and slowly quenching with excess 2M aqueous HCl (200 mL). To the crude reaction was added H2O (500 mL) and EtOAc (500 mL). The aqueous layer was extracted three times with EtOAc (500 mL), the organic layers were combined, washed four times with saturated aqueous brine (500 mL), dried over Na2SO4, and concentrated under vacuum to yield an oil which was used in the next step without further purification. The resulting product was dissolved in 111 mL of a 7.7/5/1 AcOH/H2O/conc. H2SO4, solution and heated to reflux for 22 hours. The AcOH was removed under vacuum followed by EtOAc addition (200 mL). The solution was neutralized using 2M aqueous NaOH, extracted 3 times with EtOAc (200 mL). The combined organic layers were washed twice with saturated aqueous brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (30% CH2Cl2 in hexane) to yield 17.6 g (82%) of ketone 248 as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH2:40])[CH3:39].CCN(C(C)C)C(C)C>CCO>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH:40][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2)[CH3:39]
Reactant: C[C@H](N)Cc1cc(F)ccc1Br
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1cc(F)ccc1Br)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 22.7 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine (48 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silica gel, DCM:MeOH 9:1) to give 2-(4-((1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (17 mg, 23%) as yellow solid. ESI-MS: m/z (MH+) 593.0. 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J=58.6 Hz, 1H), 7.53 (d, J=80.9 Hz, 1H), 7.47 (m, 1H), 7.15 (m, 2H), 6.80 (m, 1H), 6.00 (m, 1H), 4.56 (m, 2H), 4.13 (m, 1H), 3.82 (m, 2H), 3.10 (m, 2H), 2.83 (m, 2H), 2.65 (m, 4H), 1.80 (m, 4H), 1.43 (d, J=6.60 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C@@H:28]3[CH2:29][CH2:30][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@@H]1CCOC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CCOC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-tetrahydrofuran-3-amine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (t, J=4.4 Hz, 2 H), 7.83 (s, 1 H), 7.65 (t, J=3.7 Hz, 1 H), 7.47 (t, J=3.8 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.24 (d, J=2.1 Hz, 1 H), 6.56 (d, J=1.5 Hz, 1 H), 6.01 (s, 1 H), 5.08 (s, 2 H), 4.40 (brs, 2 H), 4.02 (t, J=3.6 Hz, 1 H), 3.88 (m, J=7.2 Hz, 1 H), 3.80 (m, J=5.4 Hz, 1 H), 3.64 (d, J=4.5 Hz, 3 H), 2.30 (t, J=3.7 Hz, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([OH:16])=O)[N:6]=1)=[O:4].C[N:46]1CCOCC1.ClC(OCC(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([NH2:46])=[O:16])[N:6]=1)=[O:4]
Reactant: CN1CCOCC1
Reactant: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-carboxybutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.3 g, 0.5 mmol)) and N-methylmorpholine (0.17 mL, 1.5 mmol) in CH2Cl2 (50 mL) is cooled to −10° C., and isobutyl chloroformate (0.065 mL, 0.5 mmol) is added dropwise over 10 minutes. After stirring for 15 minutes, ammnonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes. The solution is then warmed to room temperature over 30 min. CH2Cl2 is evaporated, the residue is treated with water (30 mL). The suspension is adjusted to pH=7 with 1 N HCl, and filtered. The solid is washed with water (50 mL) and dried in vacuo to yield N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-(aminocarbonyl)-butyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[F:27].[OH-].[Na+].[CH2:31]1COCC1>>[CH2:16]([C:12]1[C:11]([C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH:26][CH3:31])=[CH:24][CH:25]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([F:27])[CH:6]=2)[CH:15]=[CH:14][N:13]=1)[CH3:17]
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 850 mg (2.18 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester (A-45) using 3.3 mL (3.3 mmoL) 1N NaOH in 22 mL THF. The reaction mixture is stirred for 72 h at 65° C. The product is precipitated by addition of water and is collected by filtration. Yield after drying: 747 mg (91%).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)(=[O:14])[CH3:13].CCOCC>C(O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:12](=[O:14])/[CH:13]=[C:3](\[OH:5])/[C:2]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
In a dry flask, under argon atmosphere, sodium (317 mg, 13.8 mmol, Eq: 1.00) was added portionwise to ethanol (9.0 ml). (The temperature increased to 60° C.). The reaction mixture was cooled at 0° C. Then Diethyl oxalate (2.01 g, 1.87 ml, 13.8 mmol, Eq: 1.00) was added dropwise followed by 4-acetylbenzonitrile (2 g, 13.8 mmol, Eq: 1.00) in Ethanol (3.00 ml). A white solid appeared. The reaction was stirred with mechanical stirrer overnight and monitored by TLC. Then the reaction mixture was concentrated in vacuo. The residue was cooled at 0° C. and water was added to the flask. 1M HCl was added to this solution (pH=3), then the solution was extracted two times with EtOAc. The organic layer was washed three times with 20 mL Brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. This off-white solid was mixed with Ether at 0° C. The suspension was filtered to give a white solid (2.082 g, 61.6%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C@H:6]1[CH2:21][N+:22]([O-])=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[NH2:22][CH2:21][C@H:6]1[C@H:5]([CH2:3][OH:2])[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: COC(=O)[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1CO

Procedure:
A solution of trans-8-Chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester (8) (5.0 g, 13.23 mmol) in dry THF (25 ml) is added at −15° C. to a mixture of THF (25 ml) and 3.5 M LAH suspension in THF/Toluene (16.4 ml, 57.5 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN(SSc1ccccc1)C(=O)F
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SSc1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 6.24 g (0.0287 m) of N-methyl-N-(phenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 100 ml of dioxane. 2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 7.0 g of a white solid. m.p. 73°-74° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]OC(C1(CC)CCN(C(OC(C)(C)C)=O)CC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH2:14][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Product: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the method of 4-(3-aminopropyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester, the title compound is synthesized from 4-ethylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester and isolated as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CS(C)=O>[N:31]([CH2:24][C:22]1[N:23]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:26])[C:11]2[N:27]([CH3:30])[C:28](=[O:29])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)[S:20][CH:21]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CCl)cs4)ccc3n(C)c21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN=[N+]=[N-])cs4)ccc3n(C)c21
Temperature: 45 °C

Procedure:
400 mg (0.8 mmol) of compound A, 3-(4-bromophenyl)-6-(4-chloromethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 10 ml of DMSO. 160 mg (2.4 mmol) of NaN3 are added. The mixture is heated at 45° C. overnight. The mixture is allowed to return to ambient temperature. The reaction medium is poured into water, and the precipitate is filtered off and washed with water. The product is taken up in ethanol and evaporated to dryness.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Trimethylaluminium (2M in toluene) (4.97 mL, 9.94 mmol) was added carefully to 5-methylpyridin-2-amine (1.075 g, 9.94 mmol) in toluene (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2 g, 4.97 mmol) in toluene (4 mL) was added. The reaction was heated to 120° C. for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was concentrated. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.800 g, 76%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 2.29 (3H, s), 3.65 (2H, t), 3.76-3.90 (5H, m), 4.31-4.37 (1H, m), 7.34-7.45 (6H, m), 7.48-7.54 (1H, m), 7.64-7.71 (4H, m), 8.07-8.13 (2H, m), 9.13 (1H, s); m/z (ES+) (M+H)+=479.60; HPLC tR=3.16 min.
Reaction SMILES: [Na].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](=O)[CH3:24])[CH:13]=[CH:14][CH:15]=1)[CH3:8]>C(O)C>[C:21]1([C:22]2[C:3]([C:4]#[N:5])=[C:2]([NH2:6])[N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:7][CH3:8])[CH:11]=3)[CH:17]=2)[CH:20]=[CH:19][CH:18]=[CH:23][CH:24]=1
Reactant: CCOc1cccc(Nc2ccccc2C(C)=O)c1
Reactant: N#CCC#N
Agent: [Na]
Solvent: CCO
Product: CCOc1cccc(-n2cc(-c3ccccc3)c(C#N)c2N)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.4 g of sodium is dissolved in 70 ml of ethanol and subsequently first 1.24 g of malononitrile and then 4.0 g of 2'-(3-ethoxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated, 4-phenyl-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole being obtained. The oily product is employed in the next stage without further purification.