Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23](B(O)O)[CH:24]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Product: Cc1ccc(Cl)cc1[Pb+3]
Temperature: 40 °C
Yield: 99.8 %

Procedure:
To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 5-chloro-2-methylphenylboronic acid (0.76 g, 4.46 mmol) is added in one portion, and the suspension is heated at this temperature for 5 hours. After cooling to room temperature the mixture is concentrated to a small volume then triturated with hexanes and filtered to yield crude 5-chloro-2-methylphenyllead triacetate (2.27 g).
Reaction SMILES: [C:1](=O)([O:34]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH2:12][CH2:13][CH2:14][N:15]3[C:20](=[O:33])[CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])=[CH:6][CH:5]=1.Cl.[NH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49]>C(Cl)Cl>[CH3:32][C:26]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][CH2:21][C:20]([N:15]1[C:16]2[C:11](=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:34])=[CH:9][CH:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:33]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(COC(=O)Oc5ccc([N+](=O)[O-])cc5)cc4)cccc32)c1C
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)OCc1ccc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)cc1
Yield: 62.6 %

Procedure:
A solution of 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyl 4-nitrophenyl carbonate (0.020 g, 0.034 mmol), methyl 2-aminoacetate hydrochloride (5.07 mg, 0.040 mmol) and TEA (9.38 μL, 0.067 mmol) in DCM (0.200 mL) was stirred at room temperature for 16 h. After this time, the reaction mixture was quenched with 1 N NaOH. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 30×100 mm; 10 min gradient from 75% A:25% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (11.6 mg, 63% yield) as a clear colorless oil. LCMS, [M+H]+=545.2. 1H NMR (400 MHz, MeOD) δ 7.37 (d, J=7.9 Hz, 2H), 7.25 (d, J=7.4 Hz, 2H), 7.13 (d, J=7.5 Hz, 1H), 7.09 (d, J=6.8 Hz, 2H), 6.98 (t, J=7.9 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 5.14 (s, 2H), 3.87 (s, 3H), 3.79-3.63 (m, 6H), 2.82 (t, J=6.9 Hz, 2H), 2.35 (s, 2H), 2.20-2.04 (m, 5H), 1.87-1.66 (m, 5H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](OC)=[O:11])[C:5]=12.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=12
Reactant: COC(=O)c1cccn2ccnc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1cccn2ccnc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of methyl imidazo[1,2-a]pyridine-8-carboxylate (1.76 g, 10 mmol) in toluene was added DIBAL (1M/THF, 20 ml) at −78° C. dropwise. The mixture was stirred at −78° C. for 1 h, quenched with MeOH (2 mL) and saturated NH4Cl solution (50 mL) and warmed up to rt. The mixture was continued to stir at rt for 1 h and diluted with DCM (60 mL). The aqueous layer was extracted with DCM (60 mL) twice. The combined organic layer was dried over MgSO4 and concentrate. The residue was purified on silica gel with 10% MeOH/DCM to give imidazo[1,2-a]pyridine-8-carbaldehyde (0.8 g, 55%). LRMS (M+H+) m/z 147.1.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]#[N:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Cl)nc1NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cl)nc1NCc1ccccc1
Temperature: 55 °C
Yield: 41 %

Procedure:
To a solution of 2-benzylamino-6-chloro-nicotinamide (3, 1.71 g, 6.6 mmol) in acetonitrile (anhydrous, 80 mL) were added pyridine (4.26 mL, 52.7 mmol) and POCl3 (2.41 mL, 264 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq., 30 mL) was slowly added till pH 9. EtOAc (200 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 2%-20% EtOAc/hexanes gradient, to afford 0.66 g (42% yield) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:14]([Br:15])=[CH:13][S:12][N:11]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:14]([Br:15])=[CH:13][S:12][N:11]=1)=[N:2][CH3:1])#[N:16]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1nscc1Br
Agent: [Pb]
Product: CN=C(NC#N)NCCSCc1nscc1Br

Procedure:
Reaction of N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-N"-methylguanidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(=O)(O)[O-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([CH3:33])[C:30]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:31])=[CH:27][CH:28]=1
Reactant: C[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g) in DMF (45 mL) and dichloromethane (90 mL) was added sodium bicarbonate (766 mg), (2R)-2-(4-fluorophenyl)propanoic acid (844 mg) and HATU (2.6 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica-gel chromatography gave 1.53 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][NH:25][C:24]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[C:24]=2[CH:29]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCOc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (0.1 g, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (0.065 g, 0.47 mmol), ethyl iodide (0.028 mL, 0.35 mmol) and stirred the solution at 20° C. for 2 h. Reaction mixture was quenched by the addition of water (2 mL), extracted with dichloromethane (3×5 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (20 mg).
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]>O1CCCC1>[F:6][C:5]([F:8])([F:7])[C:4]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:4](=[O:9])[C:5]([F:6])([F:7])[F:8])=[O:9]
Reactant: NCCNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCNCCNC(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
113.3 g (790 mmol) of trifluoroacetic acid ethyl ester is added in drops to a solution consisting of 41.14 g (390 mmol) of 1,4,7-triazaheptane in 350 ml of tetrahydrofuran at 80° C. and under nitrogen. It is allowed to stir overnight at room temperature, concentrated by evaporation in a vacuum. The remaining oil is crystallized from hexane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(C)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Yield: 88 %

Procedure:
The mixture of ethyl 4-methyl-2-p-tolylthiazole-5-carboxylate (0.200 g; 0.765 mmol) and sodium hydroxide (0.0643 g; 1.61 mmol) in water (4 mL) and ethanol (8 mL) was irradiated in a microwave oven at 130° C. for 5 min. The mixture was concentrated (removal of ethanol), and the pH of the solution was adjusted to 3 by addition of 6N hydrochloric acid. The acidic solution was extracted with (3×10 mL) of ethyl acetate. Combined organic layers were dried over magnesium sulfate, and evaporated to afford 0.157 g (88%) of 4-methyl-2-p-tolylthiazole-5-carboxylic acid as a white solid which was directly used in the next step.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=O)[N:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN1CCOCC1)Cc1ccccc1-3
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN1CCOCC1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 14-cyclohexyl-6-(2-morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in THF (0.15 M), 20 eq of BH3Me2S (2 M solution in THF) was added dropwise and the solution stirred at RT for 2 h. MeOH was added carefully to the mixture until effervescence ceased, then the volatiles were removed in vacuo. The crude residue was not isolated and directly used in the next step; MS (ES+) m/z 502 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded butyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [NH2:1][C:2]1([C:11]#[N:12])[CH2:7][CH2:6][N:5]([N:8]([CH3:10])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCCC1>[C:11]([C:2]1([NH:1][C:30](=[O:31])[CH2:29][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=2[CH3:28])[CH2:3][CH2:4][N:5]([N:8]([CH3:9])[CH3:10])[CH2:6][CH2:7]1)#[N:12]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CN(C)N1CCC(N)(C#N)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CC(=O)NC2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
920 mg 4-Amino-1-dimethylamino-piperidine-4-carbonitrile (from Step 1), 1.38 g triethylamine and 10 mg N,N-Dimethyl-4-aminopyridine are dissolved in 35 ml tetrahydrofuran. The mixture is cooled in an ice bath and a solution of 1.07 g (2,4,6-trimethyl-phenyl)-acetyl chloride in 15 ml tetrahydrofuran is added. The temperature is kept around 3° C. during addition. Then the mixture is allowed to warm to room temperature and stirred for 2 hours. Then saturated aqueous sodium bicarbonate is added, the mixture is extracted with t-butyl methyl ether, dried over sodium sulfate, and the solvent evaporated. Thus, 1.44 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide is obtained as an off-white solid. 1H-NMR (CDCl3): 6.90 ppm (s, 2H), 5.20 ppm (s, 1H), 3.60 ppm (s, 2H), 2.70 ppm (m, 4H), 2.36 ppm (m, 2H), 2.33 ppm (s, 6H), 2.28 ppm (s, 3H), 2.23 ppm (s, 6H), 1.72 ppm (m, 2H).
Reaction SMILES: C([CH:3]([OH:24])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:32]([O:24][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:34])[CH3:33]
Reactant: CCC(O)CCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution containing ethyl 3-(5-nitro-2-phenyl-1H-indol-1-yl) propan-1-ol (2.2 g; 7.4 mmol) and triethylamine (1.24 ml; 8.9 mmol) in CH2Cl2 (20 ml), acetyl chloride (0.6 ml; 8.9 mmol) was added dropwise; the reaction mixture was left under stirring at room temperature for 2 hours. Then water (20 ml) and NaHCO3 (saturated solution) were added to pH 7. The biphasic solution was transferred into a separating funnel extracted with CH2Cl2 (2×50 ml). The organic phases were combined, washed with brine (2×100 ml) and dried over Na2SO4. The solvent was removed by evaporation under reduced pressure to give 3-(5-nitro-2-phenyl-1H-indol-1-yl)propyl acetate (1.5 g), which was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (100 g, 444 mmol) and acetic anhydride (227 g, 2.2 mol) were heated at reflux for ˜15 minutes and then allowed to cool to room temperature overnight. The reaction mixture containing white solid was filtered. The solid was rinsed with water (2 L) and dried in a vacuum oven for several hours at ˜45° C. to yield a white crystalline solid (96 g, 81%). 1H NMR (DMSO-d6) δ 4.26 (q, 2H), 2.69 (t, 2H), 2.57 (t, 2H), 2.20 (s, 3H), 1.70 (m, 4H), 1.30 (t, 3H), LCMS RT=3.48 min, [M+H]+=268.0.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20]([CH:24]3[CH2:26][CH2:25]3)[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1nn(-c2cc(C3CC3)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 100 °C
Yield: 32 %

Procedure:
To a mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide (0.020 g, 0.053 mmol), cyclopropylboronic acid (0.014 g, 0.160 mmol), potassium phosphate (0.034 g, 0.160 mmol) and tricyclohexylphosphine (2.99 mg, 10.66 μmol) in toluene/H2O (1.5 mL/0.050 mL) under nitrogen atmosphere was added palladium (II) acetate (1.197 mg, 5.33 μmol). The reaction mixture was heated at 100° C. for 1 hour in a heavy-walled sealed tube under microwave irradiation. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid (5.7 mg). LCMS m/z=337.5 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][N:10]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[Br:35][C:6]1[CH:7]=[C:8]2[CH:13]3[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]3[N:10]3[CH2:11][CH:2]([CH3:1])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]([CH:5]=1)=[C:9]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 0.1 mmol) in DMF (10 mL) at 0° C. was added NBS (20 mg, 0.11 mmol) and stirred at 0° C. for 2 hours. The solution was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 88%) as a clear oil. MS [M+H]+ 454.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].C[O-].[Na+]>CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccco1
Reactant: CC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCc1ccco1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of 2-furaldehyde (4.15 ml, 50 mmol) and 4-fluoroacetophenone (6.16 ml, 50 mmol) in methanol (200 ml), sodium methoxide (2.85 g, 50 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was concentrated, resuspended in ethyl acetate (600 ml) and diluted with water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The crude solid (10.27 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(4-fluorophenyl)-3-(2-furanyl)propan-1-one (8.9 g, 95%) as a white solid: mp (DSC) 72° C. Anal Calc'd. for C13H10FO: C, 72.22; H, 4.20. Found: C, 72.18; H, 4.38.