Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>C1(C)C=CC=CC=1>[CH:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:8]=1)[CH:14]=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1ccc(O)cc1
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCCCC=Cc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
NMR (200 MHz, DMSO-d6) (mixture of cis and trans isomers): δ9.33 (s, 1H), 7.14 (m, 2H), 6.70 (m, 2H), 6.26 (m, 1H), 6.1-5.35 (multiplets, together 1H), 2.35-2.08 (m, 2H), 1.36 (m, 4H), 0.89 (m, 3H). 4-(1-Hexenyl)phenol in toluene (8 ml) was added to Mg(OMe)2 (7.3 ml, 8% wt/wt solution in methanol, 5.5 mMol) and the resultant red solution heated at reflux for 1 hour. The mixture was then distilled until the reaction temperature rose to 95° C. A suspension of paraformaldehyde (0.78 g, 26 mmol) in toluene (5 ml) was then added and the reaction heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and to stir overnight. The reaction mixture was then diluted with toluene and washed with 2M aqueous H2SO4 (10 ml). The organic layer was washed with water (3×), dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl ether/hexane) to give 5-(1-hexenyl)-2-hydroxybenzaldehyde as a yellow/green oil (0.65 g, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO>O.C(COC)OC.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>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)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: O
Solvent: OCCCO
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 3-nitrophenylboronic acid (50 g, 0.3 mol), 3-bromopyridine (48 ml, 0.5 mol), potassium carbonate (207 g, 1.5 mol), 1,3-propanediol (107 ml, 1.5 mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixture of water (200 ml) and dimethoxyethane (400 ml) was stirred in a nitrogen atmosphere at 80° C. for 3 hours. After cooling the dimethoxyethane was removed under reduced pressure and the residue was stirred with additionally 200 ml water overnight. The precipitate was filtered off and extracted with aqueous hydrochloric acid (4M, 300 ml). The extract was rendered alkaline by addition of aqueous sodium hydroxide (12M). The product was filtered off, washed with water and dried with suction to yield 3-(3-nitrophenyl)pyridine (50.6 g, 84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:5]3[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[OH:26])[CH2:19][C:6]=3[N:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH2:34]>>[C:25]([OH:34])(=[O:26])[CH3:27].[Cl:2][C:3]1[C:4]2[C:5]3[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][CH:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[OH:26])[CH2:19][C:6]=3[N:7]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O
Agent: Cl
Agent: OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3cccc(Cl)c23)C1)c1ccc(F)cc1
Product: CC(=O)O

Procedure:
Five grams of 8-chloro-4-(p-fluorphenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrochloride in 75 ml. of water is treated with 3 ml. of water containing 1.0 g. of sodium hydroxide, and the liberated free base extracted into 150 ml. of diethyl ether. The ether layer is separated, dried over magnesium sulfate and treated with 1 ml. of glacial acetic acid. The organic solvent and excess acetic acid are removed under reduced pressure and the residue triturated with hexane and filtered.
Reaction SMILES: CN(C=O)C.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C>[Si:22]([O:6][CH2:7][C@@H:8]([OH:9])[C@@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([OH:15])[CH:16]=[O:17])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
DMF (10 mL) was placed in a 50 mL flask and cooled to 0° C. in an ice bath. 5 g of D-glucose was added, followed by 0.9 molar equiv. (6.5 mL) of tert-butylchlorodiphenylsilane. The reaction was left for 21 h at 0° C., after which it was poured into 5 mL of ethyl acetate and washed with saturated NaHCO3, brine, dried, isolated by flash column chromatography and evaporated to a yellow solid of 11 (30%). 1NMR [(300 MHz, CDCl3) 5 (ppm): 7.64 (m, 4 H), 7.32 (m, 6 H), 5.13-2.94 (m, 11 H), 1.0 (s, 9 H)], 13C NMR [(300 MHz, CDCl3) 8 (ppm): 135.5 (s, TBDPS-O), 135.45 (s, TBDPS-O), 133.3 (s, TBDPS-O), 133.2 (s, TBDPS-O), 133.0 (s, TBDPS-O), 132.9 (s, TBDPS-O), 129.6 (s, TBDPS-O), 129.5 (d, TBDPS-O), 127.6 (s, TBDPS-O), 127.55 (s, TBDPS-O), 96.6 (s, C1,β), 92.6 (s, C1,α), 77.8 to 60.7 (C2-C6), 26.7 (s, TBDPS-O, 4° C.), 19.1 (s, TBDPS-O), 19.0 (s, TBDPS-O)].
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C.[CH3:14][NH:15][C:16]([NH:18][CH3:19])=[S:17]>CO>[ClH:1].[CH3:12][C:11]1[C:2]([S:17][C:16](=[N:15][CH3:14])[NH:18][CH3:19])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CNC(=S)NC
Reactant: Cc1nc2ccccc2nc1Cl
Agent: C
Solvent: CO
Product: CN=C(NC)Sc1nc2ccccc2nc1C
Product: Cl

Procedure:
2-Chloro-3-methylquinoxaline (3.572 g., 0.02 mole) was dissolved in 17 ml. of methanol, treated with Norit and filtered. The filtrate was added to 2.084 g. (0.02 mole) N,N'-dimethylthiourea dissolved in 25 ml. of methanol. The solution was stirred at reflux for 4 hours, cooled, and evaporated to a solid residue. The residue was triturated successively with ether and acetone, filtered and dried to give 3.554 g., 62.8% of product, m.p. 130°-131.5°.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)([O-:24])=[O:23].[BH3-]C#N.[Na+]>CO.CC(O)=O>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a cooled (0) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in MeOH—AcOH (16 ml, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by sat. NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give benzyl (S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate (931 mg, 42% /) as a yellow oil. 1H-NMR (CDCl3) δ 1.21 (d, J=6.4 Hz, 3 H), 3.13–3.18 (m, 1 H), 3.88–3.97 (m, 2 H), 4.06–4.20 (m, 2 H), 5.34 (s, 2 H), 6.89–6.94 (m, 2 H), 7.29–7.65 (m, 8 H), 7.94–8.03 (m, 3 H); FAB-MAS, m/z 421 (M++1).
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.P(=O)(O)(O)O.[NH2:20][C:21]([CH3:54])([CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)[CH2:22]O.O>CO.ClCCl>[P:2]([OH:13])([OH:9])([O:3][CH2:54][C:21]([NH2:20])([CH3:22])[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)=[O:1]
Reactant: CC(N)(CO)CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(N)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)COP(=O)(O)O
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of phosphorus pentoxide (150 mg, 0.528 mmol) and 85% phosphoric acid (0.15 mL, 0.017 mmol) was stirred at 100° C. under nitrogen for 1 hr before 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (Isomer 1 of Example 93, 8 mg, 0.017 mmol) was added. The clear solution was stirred at the same temperature for 3 hr before being cooled. Water (0.4 mL) was added while the mixture was cooled with ice. The mixture was stirred at room temperature for 30 min. The mixture was dissolved in methanol and a little dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate (5 mg, 8.6 μmol, 52% yield) as a white solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=564.6. 1H NMR (400 MHz, MeOD) δ ppm 7.88 (1H, d, J=7.9 Hz), 7.76 (2H, d, J=7.3 Hz), 7.57-7.69 (3H, m), 7.31 (1H, s), 7.28 (1H, d, J=7.9 Hz), 3.82-3.99 (2H, m), 3.04-3.10 (4H, m), 2.67-2.83 (2H, m), 1.89-2.10 (2H, m), 1.40 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.CCN(C(C)C)C(C)C.[N:48]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][C@H:49]1[C:58]([OH:60])=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30][C:58]([CH:49]2[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:57][N:48]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:60])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:29])[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 52 %

Procedure:
N-[(1R)-1-[(4-Chlorophenyl)methyl]-2-(4-{2-[methyl-(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]--(tert-butoxy)carboxamide (Step 2) (327 mg, 0.593 mmol) was stirred with 25 mL of HCl satd EtOAc. The resulting crude material was diluted with EtOAc and washed with a satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. This material was treated with DIEA (115 μl, 0.660 mmol), Boc-L-Tic-OH (167 mg, 0.602 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (500 mg, 1.68 mmol), and HOAT (99 mg, 0.727 mmol) according to the procedure for preparation XIX. The crude was purified by flash chromatography (SiO2, 10% EtOAc in CH2Cl2) and concentrated in vacuo to yield tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (219 mg). MS (ESI, pos. ion) m/z: 710 (M+H), (ESI, neg. ion) m/z: 708 (M−H). Calc'd for C36H44ClN5O6S: 710.28.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CO.N1CCC[CH2:16]1>O.C(O)(=O)C>[CH:6]1([C:2]2[C:1](=[CH2:16])[CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: C1=CCC=C1
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C=C1C=CC=C1C1CCCCC1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
8.2 ml (100 mmol) of cyclopentadiene and 4.2 ml (40 mmol) of cyclohexanone were added to 40 ml of dehydrated methanol, and 5.0 ml (60 mmol) of pyrrolidine were then added dropwise at 0° C. Then, reaction was carried out at room temperature for 3 hours. Next, 3.8 ml of acetic acid were slowly added at 0° C., and 20 ml of water were further added, followed by extraction with diethyl ether. The resultant organic phase, after washed with water, was dried over magnesium sulfate, and the used solvent was then distilled off to obtain 5.95 g of a yellow liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:35]([NH:29][CH:17]1[CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=2)[CH2:20][N:15]([C:13]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:14])[CH2:16]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N=C=O
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NC(C)(C)C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 26 mg (0.26 mmol, 1.2 eq.) of tert-butyl isocyanate were reacted according to General Method 4. Yield: 69 mg (78% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1)[C:6]([O:8][CH3:9])=[O:7]>C(O)C.C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:18]=2[CH:19]=1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of (K) (0.77 g.) in anhydrous ethanol (23 ml.) was treated with stannous chloride dihydrate (2.6 g.). The mixture was stirred for 18 hours at 80° C. and then diluted with ethyl acetate. This mixture was washed successively with saturated sodium bicarbonate solution, water, and brine, then dried (MgSO4) and evaporated to give methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g., 90%): partial NMR: 3.4 (br s, 2 H, NH2), 5.2 (s,2 H, NCH2).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][NH:6][CH2:7][CH:8]=[CH2:9])([CH3:4])[CH3:3].[CH2:10]=O.CO.[C:14]([O-:17])([O-])=O.[K+].[K+]>COC(C)(C)C.O>[CH3:10][O:17][CH2:14][N:6]([CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:7][CH:8]=[CH2:9]
Reactant: C=O
Reactant: C=CCNC[Si](C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: C=CCN(COC)C[Si](C)(C)C
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To N-((trimethylsilyl)methyl)prop-2-en-1-amine (21 g, 146.5 mmol) was slowly added aqueous formaldehyde (20 g; 37% w/w) while stirring at room temperature. After 5 minutes additional stirring methanol (8 g) was added followed by the addition of K2CO3 (24 g). The reaction mixture was stirred overnight at room temperature. Water (100 ml) was added, followed by addition of tert-butyl methyl ether (75 ml). The organic layer was separated. The aqueous layer was extracted with tert-butyl methyl ether (75 ml). The combined organic extracts were dried with Na2SO4. Concentration under vacuum gave N-(methoxymethyl)-N-((trimethylsilyl)methyl)prop-2-en-1-amine as a clear oil (24 g, 128.1 mmol) in 87% c.y.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].Cl.[O:13]1CCOC[CH2:14]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[C:14]=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C1COCCO1
Reactant: COc1ccc(N)cc1OC
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COc1ccc(N=C=O)cc1OC
Temperature: 60 °C
Yield: 97 %

Procedure:
A 3 L, three-necked, round-bottomed flask was equipped with a heating/cooling bath, magnetic stirrer and stir bar, condenser, 500 mL addition funnel, thermocouple, nitrogen inlet, heating bath, vacuum distillation apparatus. To a stirred solution of 3,4-dimethoxyaniline (81.9 g, 535 mmol) in xylenes (1400 mL) was added via the addition funnel, a 4 N solution of hydrogen chloride in 1,4-dioxane (295 mL, 1180 mmol) at ambient temperature. This mixture was stirred at ˜25° C. for 30 minutes, before it was heated to reflux under a slow N2 stream. Neat triphosgene (200.0 g, 674 mmol) was added to the refluxing stirred mixture in portions via the addition funnel over 45 minutes. Upon completion of the addition, the batch was refluxed for another hour. After cooling to ˜60° C., the batch was concentrated under reduced pressure to remove most of the solvent. The oily residue was distilled under high vacuum (b.p. 84-88° C. @ 0.92 mmHg) to afford the title compound as an oil (93.0 g, 97%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC(O)(c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl (1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxylate (130.0 mg, 0.0003775 mol) in anhydrous tetrahydrofuran (4.0 mL, 0.049 mol) at −78° C. was added 1.00 M of phenylmagnesium bromide in tetrahydrofuran (0.755 mL). The reaction mixture was stirred at −78° C. for 1 h, then slowly warmed to −35° C. over 3 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 30-80% EtOAc/Hex to give the product as a colorless solid. (123 mg, 62% in yield). MS (ESI): (M+H)+=423.1.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)[CH3:3].C(OC(N(C)C)N(C)C)(C)(C)C.C1N2C3CC4C=CC=CC=4C=3NC(=O)C2=NC=1.O>CN(C)C=O.CO>[CH3:3][N:2](/[CH:4]=[C:5]1\[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[NH:13][C:14](=[O:21])[C:15]3[N:16]([CH:18]=[CH:19][N:20]=3)[C:17]\1=2)[CH3:1]
Reactant: CN(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: CN(C)C(OC(C)(C)C)N(C)C
Agent: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=c1\c2ccccc2c2[nH]c(=O)c3nccn3c12
Reaction time: 0.5 h

Procedure:
10-Dimethylaminomethylene-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one may be prepared in the following way: 6.3 g of t-butoxybis(dimethylamino)-methane are added dropwise over 5 minutes, at a temperature in the region of 25° C., to a suspension of 5.5 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 100 ml of dimethylformamide. After stirring for 30 minutes at the same temperature, the mixture is poured into 500 ml of distilled water and extracted 5 times with 1.5 liters in total of chloroform. The organic extracts are combined, washed with 250 ml of distilled water, dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained (4.5 g) is suspended in 25 ml of methanol, filtered off, washed twice with 20 ml in total of methanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (4.5 g) is dissolved in 45 ml of boiling dimethyl2formamide and, after cooling, the solution is stored for 4 hours at a temperature in the region of 5° C. The crystals are isolated by filtration, washed successively with 10 ml of dimethylformamide and 10 ml of acetone, and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 4 g of 10-(E-dimethylaminomethylene-5H,10H-imidazo[1,2-a)indeno-[1,2-e]pyrazin-4-one are thus obtained, melting at 293° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 3.35 [S 6H: --N(CH3)2 1; 7.18 and 7.28 (2t, J=7.5 Hz, 2H: --H7 and --H8); 7.48 and 7.92 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.63 and 8.50 (2 broad s, 1H each: --H of the imidazole); 8.09 (s, 1H: =CH--N); 12.30 (mult., 1H: --NH--)].
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])#[N:12].CCN(C(C)C)C(C)C.Cl>C1COCC1>[C:11]([CH:13]([CH2:1][C:2](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A solution (1 M) of phenacyl bromide in THF was added dropwise to a solution (5.5 M) of methyl cyanoacetate (1.1 eq.) and DIEA (2.4 eq.) in THF at RT. The resulting solution was stirred at RT for 20 h then the mixture was filtered and the filtrate was concentrated in vacuo to obtain an oil that was treated with little portions of aqueous HCl (1 N). The organic phase was washed with brine, dried and concentrated affording the title compound (97%) as an oil that solidified when stored in the fridge.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:14])[CH2:12][CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-nitro-pyridine(18.0 g, 114 mmol) in EtOH(300 ml) is added n-propylamine(46.9 ml, 568 mmol) slowly at 0° C. and the resulting yellow mixture is warmed to room temp. After stirring for 2 h, the reaction is concentrated in vacuo. The residue is purified by flash chromatography (eluent 50% Hex/EtOAc) to give (3-nitro-pyridin-4-yl)-propyl-amine as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.25(d, J=6 Hz, 1H), 8.15(br s, 1H), 6.68(d, J=6 Hz, 1H), 3.29(q, J=6.8 Hz, 2H), 1.74(sextet, J=7.2 Hz, 2H), 1.02(t, J=7.6 Hz, 3H). LRMS calcd 181.19, found 182.5 (MH+).