Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[NH2:26])=[CH:20][C:19]=3[CH3:28])=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:29]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[NH2:26])=[CH:20][C:19]=3[CH3:28])=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([NH2:29])=[CH:4][N:3]=1
Reactant: Cc1cc(NC(N)=O)ccc1-c1ccccc1-c1c(C)sc2c([N+](=O)[O-])cnc(N)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(NC(N)=O)ccc1-c1ccccc1-c1c(C)sc2c(N)cnc(N)c12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A suspension of Example 66E (0.44 g, 1.01 mmol), NH4Cl (0.054 g, 1.01 mmol), and iron powder (0.45 g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80° C. for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), flitered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 0.15 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 4.48 (s, 2H), 4.59 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.29 (m, 3H), 7.30 (s, 1H), 7.31 (s, 1H), 7.60 (d, J=8.81 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)=[O:16].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[O:16])=[CH:9][N:8]=2)[N:7]=1
Reactant: O=C(CBr)c1ccc2ncccc2c1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12

Procedure:
A mixture of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (Stage 1.6, 2 g, 10.8 mmol), 2-bromo-1-quinolin-6-yl-ethanone (Stage 1.3, 3.36 g, 10.8 mmol) and triethylamine (1.1 g, 10.8 mmol) was stirred under reflux for 90 min. The reaction was allowed to cool and water (100 mL) was then added. The resulting red precipitate was filtered off to afford the title compound as a red solid (tR 1.2 min(conditions 1), MH+=309).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:28][CH:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)[CH2:27][CH2:26]2)[C@H:6]([C:13]#[N:14])[CH2:7][CH2:8]1)#[C:11][CH3:12]
Reactant: NC1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.030 g, 0.15 mmol, Example 88D) in acetonitrile (1 mL) at room temperature was added 4-(4-trifluoromethyl-phenoxy)-cyclohexylamine (79 mg, 0.31 mmol, Example 55A). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 434 (M+H)+; 1H NMR (DMSO) δ ppm 7.63 (d, 2H), 7.15 (d, 2H), 4.86 (m, 1H), 4.20-4.41 (m, 2H), 3.94 (m, 1H), 2.09-2.43 (m, 8H), 1.88 (d, 3H), 1.41-1.65 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]=2[NH2:15].[NH2:21][CH2:22][CH2:23][OH:24]>C(#N)C>[NH2:15][C:9]1[N:8]=[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[N:4]2[CH2:3][CH2:2][NH:21][CH2:22][CH2:23][OH:24]
Reactant: NCCO
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCBr)c2n1
Solvent: CC#N
Product: CCCCOc1nc(N)c2nc(OC)n(CCNCCO)c2n1
Temperature: 70 °C

Procedure:
To the compound obtained by Example 2-39 step (i) (300 mg) in acetonitrile (5 ml) was added 2-aminoethanol (265 mg) and heated at 70° C. for 24 hours. The reaction mixture was purified by column chromatography (ethyl acetate: 7N ammonia-methanol 95:5) to give the titled compound. Yield: 295 mg (100%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:27][CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.O>C1COCC1>[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][O:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1CBr
Reactant: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: BrCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of NaH (909 mg/22.7 mmol) in THF (50 ml) was added 3-(tritylamino)-1-propanol, and the solution was stirred at reflux temperature for 2 hours. To the solution was added α,α′-dibromo-o-xylene, and the solution was stirred at reflux temperature for 16 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=100:0-20:1) to afford a yellow oil (4.84 g/51%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:2].[H][H]>CO.[Pd]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCN(CC)C(=O)Cc1ccc(N)cc1
Reaction time: 0.25 h

Procedure:
N-Ethyl-N-heptyl-4-nitrophenylacetamide (Preparation 18) (7.5 g) is hydrogenated on the Parr hydrogenator in two portions; i.e., 3.75 g in 150 ml methanol plus 0.4 g of 10% Pd/C catalyst at an initial hydrogen pressure of 50 psi. The hydrogen uptake ceases after 15 min; after 15 min more, the mixture is filtered through Celite. The filtrates of both runs are pooled and concentrated in vacuo. The residue is dissolved in 20 ml of EtOH, 200 ml of Et2O is added and the mixture treated with 12.0 ml of ca. 2.8M ethereal HCl with a resulting precipitate. This precipitate is collected and washed with ether to give the title compound; m.p. 172°-174° C.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:68])(=[O:67])[NH:37][C:38](=[O:66])[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([C@H:51]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]4[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=4)[OH:52])[CH2:47][CH2:46]3)=[CH:41][CH:40]=2)=[CH:32][C:31]=1[S:69]([C:72]([F:75])([F:74])[F:73])(=[O:71])=[O:70])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:17])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl.CO>[ClH:65].[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:68])(=[O:67])[NH:37][C:38](=[O:66])[C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([C@H:51]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]4[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=4)[OH:52])[CH2:47][CH2:46]3)=[CH:43][CH:44]=2)=[CH:32][C:31]=1[S:69]([C:72]([F:73])([F:75])[F:74])(=[O:70])=[O:71])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:17])=[O:2]
Reactant: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(CCOP(=O)(O)O)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 173.8 %

Procedure:
A solution of di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(methyl)amino)ethyl phosphate (INTERMEDIATE 56, 140 mg, 0.13 mmol) in DCM (3 ml) was treated with a solution of HCl (4M in dioxane, 0.6 ml). When the addition was completed, a white precipitate was observed. The mixture was diluted with MeOH after an hour and the volatiles were evaporated under reduced pressure to give a gummy residue. The material was dissolved in MeOH, and diluted with ˜20 ml DCM, resulting in a white precipitate. The mixture was concentrated under reduced pressure to provide a white solid. The material was triturated in 10-15 ml CH2Cl2, and dried under high vacuum to provide the title compound (120 mg, yield: 95%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2/[CH:11]=C\C(OCC)=O)[CH:4]=[CH:3][CH:2]=1.[O:18]=[O+][O-]>ClCCl.CO>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[CH:11]=[O:18])[CH:4]=[CH:3][CH:2]=1
Reactant: O=[O+][O-]
Reactant: CCOC(=O)/C=C\c1cncc2cccnc12
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cncc2cccnc12
Temperature: 25 °C

Procedure:
A solution of ethyl (2Z)-3-(1,6-naphthyridin-8-yl)prop-2-enoate (30 g) in dichloromethane (500 mL) and methanol (125 mL) was cooled to −78° C. and reacted with ozone until the color of the reaction mixture became light blue (˜3 h). The reaction was purged with nitrogen to remove the residual ozone. Methyl sulfide (60 mL) was then added, and the reaction was allowed to warm to room temperature and then concentrated. The resulting residue was dissolved in dichloromethane (300 mL), washed with water (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and dried over sodium sulfate. The solvent was removed and product was slurried in heptane/ethyl acetate mixture (5:1). The solid was then filtered and dried under reduced pressure to provide the title compound: LCMS m/z 158.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.39 (s, 1 H), 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[S:24])[NH2:15])[CH:12]=2)[NH:7][CH:6]=1
Reactant: S
Reactant: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCc1c[nH]c2ccc(C(N)=S)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-[2-(dimethylamino)ethyl]-1H-indole-5-carbonitrile (13.0 g) and triethylamine (50 ml) in dimethylformamide (300 ml) was stirred for 2 h whilst gaseous hydrogen sulphide was bubbled through it. More triethylamine (10 ml) was added and the solution was stirred at room temperature for 2 days, then evaporated in vacuo to give an oil (15 g) which was partitioned between ethyl acetate (500 ml) and water (3×250 ml). The organic layer was dried (MgSO4) pre-absorbed onto silica and purified by flash chromatography (A). The appropriate fractions were combined, concentrated in vacuo and triturated with ether (250 ml) to give the title compound (12.0 g) as a solid, m.p. 155°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Brc1cc(Br)c2c(c1)CCO2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc2c1OCC2
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A sample of 19 (6.0 g, 26.5 mmol) in freshly distilled dry THF was degassed at −78° C. and n-butyllithium (25 mL of 1.05 M, 26 mmol) was added dropwise by syringe. Then N,N-dimethylformamide (2.9 mL, 26 mmol) was added dropwise via syringe. The reaction mixture was allowed to come to room temperature overnight. Saturated ammonium chloride (10 mL) was added to and the mixture was stirred for 30 minutes. The solvent was removed and the residue was taken up in dichloromethane (50 mL), and washed with water (3×50 mL) then dried with anhydrous sodium sulfate. Solvent removal yielded yellow crystals (1.6 g) which were washed with ether and recrystallized from a minimum of hot methanol to give white crystals of 20 (1.32 g, 22%) mp=99–100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(F)ccc1F

Procedure:
Following General Procedure I above, and using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>COCCO>[NH:10]([C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)[NH2:11]
Reactant: NN
Reactant: Oc1ccnc(O)c1
Solvent: O
Solvent: COCCO
Product: NNc1cc[nH]c(=O)c1
Reaction time: 24 h
Yield: 88.3 %

Procedure:
2,4-dihydroxypyridine (20.3 g, 183.0 mmol) was added to the mixture of 2-methoxyethanol (400 ml) and 55% solution of hydrazine hydrate (80 ml) at room temperature. The reaction mixture was refluxed under stirring for 24 hours and then concentrated under reduced pressure. The resulting residue was recrystallized with ethanol to give the titled compound as a white solid. (Yield: 88.3%)
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12](Br)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+]>COCCO>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(N)c(Cl)c1Cl
Reactant: CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CCCCNc1ccc(OC)c(Cl)c1Cl
Reaction time: 48 h

Procedure:
A mixture of 2,3-dichloro-4-methoxyaniline (19.2 g), n-butylbromide (22.0 g), sodium hydrogen carbonate (40 g) and methylcellosolve (350 ml) is stirred at 95°-100° C. for about 48 hours. The cooled mixture is filtered, and the filtrate is evaporated in vacuo. The remaining material is washed with water and is thereafter recrystallized from ethanol to give the title compound with a melting point of 47°-49° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.N1C=CC=CC=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1>[Br:19][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2ccccc2o1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Benzofuran-2yl methanol (1.0 g, 6.7 mmol) was dissolved in toluene (50 mL) and pyridine (653 μL, 8.1 mmol) was added. The solution was cooled to 0° C. PBr3 (760 μL, 8.1 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo and product was purified by flash chromatography, eluting with hexane:EtOAc (4:1) to give 10 (780 mg, 55%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.57 (1H, d, J=7.75 Hz, H-4), 7.52 (1H, d, J=8.40, H-7), 7.35 (1H, t, J=8.90, H-4), 7.27 (1H, t, J=8.9 Hz, H-5), 6.79 (1H, s, H-3), 4.64 (2H, s, 2-CH2). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 155.34 (C-2), 152.65 (C7a), 129.08 (C3a), 125.20 (C-6), 123.16 (C-5), 121.34 (C—C-4), 111.46 (C-7), 106.30 (C-3), 23.61 (CH2—Br).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCOCC1>[CH2:20]([O:19][C:17]([CH2:16][N:10]1[CH2:11][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C1C[C@H](c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Temperature: 90 °C
Yield: 63.9 %

Procedure:
The solution of 4(R)-phenyl-2-pyrrolidinone (1) (345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80÷90° C. during 30 min and then cooled to room temperature. Ethyl bromoacetate (393 mg, 2.37 mM) was added and the reaction mixture was refluxed at 110÷120° C. for 6 hours. Obtained mixture was concentrated under reduced pressure. Residue was purified by column chromatography on silicagel with ethylacetate-hexane mixture 1:1, giving N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (338 mg, 64%). [α]D20=+4.6° (c=3; MeOH). 1H NMR (CDCl3), δ: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, quintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q, CH2CH3); 7.20-7.39 (5H, m, C6H5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Yield: 132.5 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.62 g, 2.0 mmol), methyliodide (0.25 mL, 4 mmol) and potassium carbonate (0.21 g, 1.5 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by crystallization from dichloromethane to obtain a white solid of 2-(2,4-dichloro-5-methyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.65 g, yield:100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:40][Si:41]([CH3:55])([CH3:54])[CH2:42][CH2:43][O:44][CH2:45][N:46]1[C:50](B(O)O)=[CH:49][CH:48]=[N:47]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:2]([C:50]4[N:46]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:55])([CH3:54])[CH3:40])[N:47]=[CH:48][CH:49]=4)[CH:3]=3)[C:7]([CH2:27][C:28]3([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:8][C:9]=2[CH:14]=1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccnn3COCC[Si](C)(C)C)c2)CCCC1
Temperature: 25 °C

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentane carboxylate (59 mg, 0.1 mmol), Pd(Ph3)4 (10 mg, 0.008 mmol), (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)boronic acid (65 mg, 0.26 mmol), Na2CO3 (0.15 mL, 2 M) and 1,4-dioxane (1.5 mL). The vial was flushed with N2 then capped and placed in a heating block at 100° C. After 16 h the mixture was cooled to RT, transferred to a round-bottomed flask and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C41H47N5O4Si, 701.94; m/z found 702.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([F:11])[CH:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>S(=O)(=O)(O)O.O1CCOCC1>[Cl:2][C:3]1[CH:4]=[C:5]([F:11])[C:6]2[NH:9][C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][C:15]=3[C:7]=2[CH:8]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(Cl)cc1F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(F)cc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-2-fluorophenyl hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxan. N-Methylpiperidine-4-one (0.76-1.4 equiv.) is added and the contents are stirred at RT for 10 min. The reaction mixture is then stirred at 100° C. for 6 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated and then slowly quenched with aq. NaHCO3 solution, followed by extraction with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography to afford 8-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.