Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>ClCCl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:1][CH2:2][CH:3]2[O:4][CH2:5][C:6](=[O:9])[NH:7][CH2:8]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1COC(CO)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)CO2)cc1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)morpholin-3-one (Step-2 of Intermediate-9) (4.1 g, 31.29 mmole) in dichloromethane (25 mL), triethylamine (8.31 mL, 62.59 mmole) and TsCl (tosyl chloride) (6.56 g, 34.42 mmole) were added at 0° C. The reaction mixture was allowed to RT and further stirred overnight. Reaction mixture was diluted with dichloromethane (30 mL), and washed with brine solution (2×30 mL) and DM water, separated the organic layer, dried over Na2SO4, concentrated and further purified by flash chromatography (n-hexane:ethyl acetate, 1:4) to get the title compound as a white solid (3.8 gm). m/z 286.1
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH2:27]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:34]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCNCc1ccccc1
Reactant: CC(c1ccccc1)N(CCCCCC(=O)O)C(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccccc1)N(CCCCCC(=O)N(CCCC(=O)O)Cc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-6-(1-phenylethylamino)caproic acid and ethyl 4-benzylaminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-6-(1-phenylethylamino)hexanoyl]-4-benzylaminobutyric acid.
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.[NH4+].[OH-].Cl>C1COCC1.O>[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26]([NH2:4])=[O:27])=[CH:20][CH:19]=1
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccccc2C)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(CC(N)=O)c1ccc(OCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Carbonyl diimidazole (0.46 g, 2.84 mmol) was added to a solution of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid (See Example 13) (0.73 g, 2.37 mmol) in anhydrous THF (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated NH4OH (10 mL) was then added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL) and the solution was adjusted to pH=7 with conc. HCl. The aqueous layer was then extracted with 3×25 mL ethyl acetate. The combined organic layers were washed with water, followed by brine. The organic layer was then dried (Na2SO4) and concentrated under reduced pressure to yield 0.48 g (70%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid amide (23.2) as a light yellow solid. LC/MSD m/e: 308.4 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N:4]=1)#[N:2].NC(N)=[O:40].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])[C:24]([F:25])([F:26])[F:27])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N+:4]=1[O-:40])#[N:2]
Reactant: NC(N)=O
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)ccc2c1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc(C#N)[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
2-Cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide (240 mg) was dissolved in dichloromethane, added with urea-hydrogen peroxide adduct (85 mg) and trifluoroacetic anhydride (190 mg), and stirred at room temperature for 20 hours. The reaction solution was concentrated under the reduced pressure, and the resulting residues were dissolved in ethyl acetate. The solution was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide-1-oxide (0.20 g, 81%).
Reaction SMILES: [CH2:1]([C:8]1([OH:23])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>[Cl-].[Na+].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.O>[CH2:1]([C:8]1([OH:23])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccnc1Cl)N1CCC(O)(Cc2ccccc2)CC1
Reactant: OB(O)c1ccncc1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of (4-benzyl-4-hydroxypiperidin-1-yl) (2-chloropyridin-3-yl)methanone (5.0 g), tetrakis(triphenylphosphine)palladium(0) (0.87 g), pyridine-4-boronic acid (2.2 g), sodium carbonate (4.8 g), DMF (50 mL) and water (10 ml) was stirred overnight at 100° C. under a nitrogen atmosphere. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.4 g). The compound was crystallized from ethyl acetate/heptane to give the title compound as crystals.
Reaction SMILES: C(C1SC2C(=O)N(C3C=CC=C(C4N=C(NC5C=CC(C6C(=O)NCCN6C)=CC=5)C(=O)N(C)C=4)C=3C)CC=2C=1)(C)(C)C.C([O:47][CH2:48][C:49]1[C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][CH:52]=[CH:51][C:50]=1[N:64]1[CH2:72][C:71]2[C:66](=[CH:67][CH:68]=[C:69]([N:73]([CH3:75])[CH3:74])[CH:70]=2)[C:65]1=[O:76])(=O)C.Br[C:78]1[CH:79]=[C:80]([NH:86][C:87]2[CH:92]=[CH:91][N:90]=[CH:89][N:88]=2)[C:81](=[O:85])[N:82]([CH3:84])[CH:83]=1>>[CH3:74][N:73]([CH3:75])[C:69]1[CH:70]=[C:71]2[C:66](=[CH:67][CH:68]=1)[C:65](=[O:76])[N:64]([C:50]1[CH:51]=[CH:52][CH:53]=[C:54]([C:78]3[CH:79]=[C:80]([NH:86][C:87]4[CH:92]=[CH:91][N:90]=[CH:89][N:88]=4)[C:81](=[O:85])[N:82]([CH3:84])[CH:83]=3)[C:49]=1[CH2:48][OH:47])[CH2:72]2
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Agent: Cc1c(-c2cn(C)c(=O)c(Nc3ccc(C4C(=O)NCCN4C)cc3)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Product: CN(C)c1ccc2c(c1)CN(c1cccc(-c3cc(Nc4ccncn4)c(=O)n(C)c3)c1CO)C2=O
Yield: 33.6 %

Procedure:
Using the same general procedure as described for the preparation of 104, reaction of 123e (400 mg, 0.890 mmol) with 107a (207 mg, 0.740 mmol) followed by a hydrolysis gave a 28% yield (120 mg) of 124 as a white solid: mp 206-208° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.73 (d, 1H, J=2.0 Hz), 8.65 (s, 1H), 8.30 (d, 1H, J=6.0 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=2.5 Hz), 7.49 (t, 1H, J=2.5 Hz), 7.43 (dd, 1H, J=8.0, 1.5 Hz), 7.37 (dd, 1H, J=8.0, 1.5 Hz), 7.31 (dd, 1H, J=6.0, 1.5 Hz), 6.88-6.85 (m, 2H), 4.94 (t, 1H, J=4.5 Hz), 4.86 (s, 2H), 4.32 (d, 2H, J=4.5 Hz), 3.61 (s, 3H), 3.04 (s, 6H); MS (ESI+) m/z 483.2 (M+H).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20]>C(O)C.O>[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][S:1][C:2]2[N:3]([CH3:12])[C:4](=[O:11])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:27][CH:28]=1)=[O:20]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and 1N-sodium hydroxide/water (5.5 ml) in ethanol (20 ml) was added 4-(2,4-dichlorobenzoyl)benzyl bromide (1.91 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (1.69 g).
Reaction SMILES: CCOCC.C([Zn:8][CH2:9][CH3:10])C.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC>[CH2:9]([Zn:8][O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: Oc1ccccc1
Reactant: CC[Zn]CC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC[Zn]Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
In the drybox, a 100-mL Schlenk flask was charged with Et2O (30 mL) and cooled to −78° C. Diethylzinc (9.0 mL of a 1.0 M hexane solution, 9.0 mmol) was added via syringe. A solution of phenol (0.847 g of phenol in 10 mL of Et2O) was added to the Schlenk flask, and the colorless reaction mixture was stirred at −78° C. for 1 h. The mixture was evaporated to give a white solid (1.593 g, 94%). 1H NMR (300 MHz, DMSO-d6): δ 7.1, 6.6 (m, 5H), 1.2 (t, 3H), 0.1 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[I:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc(I)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
To a flask containing methyl 3-amino-5-iodobenzoate (500 mg, 1.81 mmol) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (379 mg, 2.08 mmol) in dioxane (5.6 mL). Methanesulfonic acid (199 mg, 2.08 mmol) was added and the reaction was heated at 100° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield methyl 3-iodo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoate (538 mg, 1.27 mmol, 71% yield). MS ESI: [M+H]+ m/z 424.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:19]#[N:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([NH:29][NH2:30])=O>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:15][C:16]3[O:18][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[N:29][N:30]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: NNC(=O)c1ccccn1
Reactant: N#Cc1ccc2c(nc(C(F)(F)F)n2CC(=O)O)c1Cl
Product: N#Cc1ccc2c(nc(C(F)(F)F)n2Cc2nnc(-c3ccccn3)o2)c1Cl

Procedure:
Synthesized as described Example 200C from [4-chloro-5-cyano-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetic acid and 2-pyridinecarbohydrazide: MS (ESI) m/z 405 (M+1).
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:18]([CH2:21]C)[CH2:19]C)C>COC(OC)N(C)C>[CH3:16][N:18]([CH:21]=[C:2]1[CH2:3][CH2:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:1]1=[O:15])[CH3:19]
Reactant: CCN(CC)CC
Reactant: O=C1CCCc2nc3ccccc3cc21
Agent: COC(OC)N(C)C
Product: CN(C)C=C1CCc2nc3ccccc3cc2C1=O

Procedure:
3,4-Dihydroacridin-1(2H)-one (19.43 g) was refluxed in N,N-dimethylformamide dimethyl acetal (48.57 ml) and triethylamine (13.76 ml) for 10 hours. The reaction was concentrated and thereafter, triturated first with diethyl ether/pentane and then with diethyl ether, to yield 22.43 g of 2-(dimethylaminomethylene)-3,4-dihydroacridin-1(2H)-one. This was combined with an additional 1.07 g of compound and refluxed in hydrazine (12.68 ml) and ethanol (372 ml) for 2.5 hours. The reaction was cooled, concentrated, and triturated with diethyl ether to yield 20.67 g of a pale orange crystalline solid. A 3.5 g portion was recrystallized from methanol and dried under high vacuum and refluxing xylenes for 30 hours to yield 1.60 g of an off-white crystalline solid, mp 248°-248.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20]O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.ClCCl.P(Br)(Br)[Br:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][Br:27])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1nc2n(c1CO)C1CC(C1)c1ccc(Br)cc1-2
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)c1nc2n(c1CBr)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate in dichloromethane (1 eq) was added phosphorus tribromide. After 20 minutes of stirring at room temperature, the reaction was extracted with a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford crude methyl 10-bromo-3-(bromomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxy late. To this intermediate in a solution of N,N-dimethylformamide (5 mL/mmol) was added 2-chlorophenol (2 eq) and cesium carbonate (1.5 eq). The reaction was stirred at 50° C. and monitored by LC-MS until complete, whereupon the reaction mixture was extracted with dichloromethane and a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford 147 mg (59%) crude methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 124 mg (91%) of 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide, 50 mg of which was directly reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 31 mg (55.4%) of 3-[(2-chlorophenoxy)methyl]-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.N1CCNCC1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])cc(CN2CCOCC2)c1N1CCN(C)CC1
Agent: [Pd]
Agent: C1CNCCN1
Agent: O=C[O-]
Solvent: CCO
Product: Cc1cc(N)cc(CN2CCOCC2)c1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
4-{[3-Methyl-2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methyl}morpholine-piperazine (113 mg, 0.34 mmol) was hydrogenated using ammonium formate (213 mg, 10 eq) and Pd/C (10% Pd, 36 mg, 0.05 eq) in 5 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a pale yellow oil (92 mg, 89% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[Li])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:22]([CH2:35][CH3:36])[C:23]([C:25]1[C:26]([O:33][CH3:34])=[N:27][CH:28]=[CH:29][C:30]=1[CH:31]=[O:32])=[O:24])[CH3:21].C1(S(N2C3C(=CC(OC)=CC=3)C=C2[Li])(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:31]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:33][CH3:34])[C:25]=2[C:23]([N:22]([CH2:20][CH3:21])[CH2:35][CH3:36])=[O:24])[OH:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Reactant: CCN(CC)C(=O)c1c(C=O)ccnc1OC
Agent: [Li]c1cc2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Product: CCN(CC)C(=O)c1c(C(O)c2cc3cnccc3n2S(=O)(=O)c2ccccc2)ccnc1OC

Procedure:
Starting from 1-benzenesulfonyl 2-lithio 5-aza indole and 3-diethylaminocarbonyl 4-formyl 2-methoxy pyridine as reagent with electorphilic character, prepared according to paragraph (b) [stabilization reagent: tris(dioxa-3,6 heptyl)amine; amine: diisopropylamine]. White solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCCCCCCCC>[Cu]>[I:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][C:14]=2[N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:20]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(=O)Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Product: CC(=O)N(c1ccccc1)c1ccccc1-c1ccc(I)cc1
Yield: 64.9 %

Procedure:
There were mixed 20.3 g (0.15 mole) of acetanilide, 73.1 g (0.18 mole) of 4,4′-diiodobiphenyl, 22.1 g (0.16 mole) of anhydrous potassium carbonate, 2.16 g (0.034 mole) of copper powder and 35 ml of n-dodecane, followed by reaction at 190 to 205° C. for 10 hours. The reaction product was extracted with 200 ml of toluene, and the insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluate: toluene/ethyl acetate=6/1) to obtain 40.2 g (yield: 64.8%) of N-(4′-iodobiphenylyl)acetanilide. The melting point was 135.0 to 136.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(I)cc1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Temperature: 65 °C
Yield: 104.5 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-iodobenzoate (690 g, 2.2 mol), copper (I) iodide (4.2 g, 22 mmol) in triethylamine (5.6 L) was degassed with nitrogen for 5-10 minutes, treated with bis(triphenylphosphine)palladium(II) chloride (16 g, 22 mmol) and (trimethylsilyl)acetylene (470 mL, 3.3 mol), degassed with nitrogen for 2 minutes, and heated at 65° C. The heat was removed and the reaction temperature increased from 65 to 85° C. by itself. The temperature was dropped to 75° C. after 30 minutes with stirring. The reaction was cooled to room temperature, filtered over a pad of celite and rinsed with ethyl acetate (3 L). The filtrate was concentrated and dried on a high vacuum pump for 72 hours to give the desired product (650 g, quantitative) as a yellow solid. HPLC 91.3% pure @ 220 nm. LCMS for C13H16ClO3Si (M+H)+: m/z=283.1; Found: 282.8; 1H NMR (400 MHz, DMSO-d6): δ 10.5 (br s, 1 H), 7.76 (s, 1 H), 7.13 (s, 1 H), 3.85 (s, 3 H), 0.24 (s, 9 H).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[C:1]1([NH:7][C:8]2[O:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
A solution of 1-phenylurea (2.0 g, 14.69 mmol) and ethyl 3-bromo-2-oxopropanoate (2.16 ml, 14.69 mmol) in DMF (58 ml) was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to rt and quenched with water (300 ml)/Na2CO3-solution (50 ml). The product was extracted with EA (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude product. Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.)) afforded the title compound. HPLC (Method U): RtU=1.91 min, MS (Method D) [M+H]+=233.1.