Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C([Mg]Br)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[CH2:16]Br>C1COCC1.CCOCC>[CH3:22][O:21][C:19]1[CH:18]=[C:15]([CH2:16][C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:14]=[C:13]([O:12][CH3:11])[CH:20]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(CBr)cc(OC)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a stirred solution of ethynyl trimethylsilane (39.1 mL, 277 mmol, 4 equiv) in THF (120 mL) at 0° C. was added ethylmagnesium bromide (3.16 M in Et2O; 87.6 mL, 277 mmol, 4 equiv). The reaction was allowed to warm to room temperature and stirred for 30 min. After 30 min at room temperature, CuBr (9.93 g, 69.2 mmol, 1 equiv) was added and the reaction was allowed to stir at room temperature for an additional 15 min prior to addition of 3,5-dimethoxybenzylbromide (16.0 g, 69.2 mmol, 1 equiv). The resulting mixture was heated to reflux overnight (20 h). The reaction was diluted with Et2O, cautiously quenched with brine, and extracted with Et2O (×2). The combined organic layers were washed with a saturated aqueous solution of NH4Cl, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by chromatography on SiO2 (EtOAc/hexanes, 1:10) to give 17.2 g (100% yield) of 7 as a pale yellow oil: Rf 0.41 (EtOAc/hexanes, 1:20); IR (neat) 2956, 2898, 2175, 1754, 1596, 1459, 1428, 1204, 1156, 1122, 1101, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.53 (d, 2H, J=2.4 Hz), 6.34 (t, 1 H, J=2.4 Hz), 3.79 (s, 6 H), 3.60 (s, 2H), 0.19 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 160.8, 138.7, 105.9, 104.0, 98.7, 87.1, 55.3, 26.3, 0.1; HRMS (ESI+) m/z calcd for C14H21O2Si 249.1311, found 249.1287.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][NH:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8].Cl[CH2:17][C:18]([N:20]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH2:3][CH2:4][N:5]([CH2:17][C:18]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:19])[CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8]
Reactant: O=C(CCl)N(Cc1ccccc1F)C1Cc2ccccc2C1
Reactant: CC1=C(C)C(c2ccccc2C)NCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)C(c2ccccc2C)N(CC(=O)N(Cc2ccccc2F)C2Cc3ccccc3C2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4,5-dimethyl-6-o-tolyl-1,2,3,6-tetrahydro-pyridine (170 mg; 0.85 mmol), 2-chloro-N-(2-fluoro-benzyl)-N-indan-2-yl-acetamide (403 mg; 1.27 mmol) and K2CO3 (587 mg; 4.25 mmol), and acetonitrile (20 ml) is stirred at 80° C. for 20 hours. The reaction mixture is filtered, the insolubles are washed with ethyl acetate, and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography over silica gel (elution with hexanes/ethyl acetate 3:1) to give the product (Compound 13) as an oil. LC-MS [MH+] 483.25, RT=2.69 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CN(C)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)(Cl)Cl>[C:14]([O:1][CH2:2][C:3]([CH2:8][O:9][C:2](=[O:1])[CH:3]=[CH2:4])([CH3:7])[C:4]([OH:6])=[O:5])(=[O:17])[CH:15]=[CH2:16]
Reactant: CC(CO)(CO)C(=O)O
Reactant: C=CC(=O)Cl
Agent: CN(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCC(C)(COC(=O)C=C)C(=O)O
Reaction time: 2 h

Procedure:
Into a reactor equipped with a stirrer, a thermometer a gas introducing tube and a dropping funnel, 201 g (1.5 mol) of 2,2-bis(hydroxymethyl)propionic acid, 304 g (3.0 mol) of trimethylamine and 600 ml of chloroform were charged. Under ice cooling, 406 g (4.5 mol) of acryloylchloride were dissolved in 400 ml of chloroform, and the resulting solution was added dropwise to the reaction liquid from the dropping funnel while the temperature of the reaction liquid was kept below 5° C. After the completion of dropping, the reaction liquid was kept under ice cooling and stirred for two hours. Chloroform was then removed from the reaction liquid under reduced pressure. Resulting yellow crystals were purified by column chromatography using as a developing solvent ethyl acetate/n-hexane mixed solvent (1:4 by volume). The solvent was then removed under reduced pressure to obtain 2,2-bis(acryloyloxymethyl)propionic acid as white crystals. ##STR17##
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[CH:24]=[CH:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(n2ccnc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 2-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21].O>O1CCCC1>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 59.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.050 g, 4.066 mmol) in tetrahydrofuran (16 ml), lithium hydroxide monohydrate (0.161 g, 3.84 mmol) was added and the mixture was stirred at room temperature for approximately 1.2 hours. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in tetrahydrofuran (3 ml), and water (0.57 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, approximately half of the solvent was evaporated from the solution under reduced pressure. Ethyl acetate and water were added to the solution and the solution was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 27 g, ethyl acetate:hexane =1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.719 g; 1.35 mmol; yield: 59.8%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[I-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O>[N:26]([C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)C)ccc1C1(Cl)C(=O)c2ccccc2C1=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)ccc1C1(N=[N+]=[N-])C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 99396.7 %

Procedure:
To a solution of 2-chloro-2-(4-isopropyl-2-methoxyphenyl)-1H-inden-1,3(2H)-dione (0.10 g, 0.3 mmol) in acetone (5 ml) were added with sodium iodide (54 mg, 0.36 mmol) and sodium azide (50 mg, 0.76 mmol) and distilled water (1 ml), followed by stirring at 80° C. for 6 hrs. The reaction mixture was added water, and extracted diethyl ether, and washed with water and brine in that order. The washed organic layer was concentrated to afford the title compound (100 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[Si]([O:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1)(C(C)(C)C)(C)C.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[C:26]2[CH:37]=[CH:38][C:23]([OH:22])=[CH:24][CH:25]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (952 mg), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (2.90 g) and 1N-aqueous sodium hydroxide solution (4.6 ml) in methanol (20 ml) was stirred at room temperature for 4 hours. This reaction mixture was concentrated and extracted with chloroform and the extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=19:1). The resulting 2-[4-(4-t-butyldimethylsilyloxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone was dissolved in tetrahydrofuran (15 ml). To this solution was added 1M tetrabutylammonium fluoride/tetrahydrofuran (3.8 ml), and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and the resulting precipitate was collected by filtration, rinsed with water, and dried to provide the title compound as colorless solid (1.332 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1c(Cl)cccc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(Cl)cccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-chloro-N1-phenylbenzene-1,2-diamine (1.72 g, 7.87 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.64 g, 8.65 mmol), HOAt (1.18 g, 8.65 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.66 g, 8.65 mmol) in DCM (40 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (3.3 mL, 0.0236 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) affording [(S)-1-(2-Chloro-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an off-white solid (1.60 g, 52% over three steps). LCMS: RT 3.75 min [M+H]+ 390.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([OH:28])=O)[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([NH:32][CH2:30][CH3:31])=[O:28])[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCN
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C(=O)O)n1
Agent: Cl
Product: CCNC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C)n1

Procedure:
The title compound is prepared from 4-((1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamoyl)-6-methylpicolinic acid (15 mg, 0.04 mmol, Step-2, single enantiomer) and ethanamine hydrochloride by the similar manner in Example-2.
Reaction SMILES: [OH-].[K+].[C:3]1(C)C=CC=CC=1.[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(OC)(OC)(=O)=O>CCOCC.O>[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:3])=[O:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1
Reactant: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
85% Potassium hydroxide (0.79 g, 12.0 mmol) and toluene (20 ml) were added to (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (2.70 g, 10.0 mmol) and dissolved by heating to 50° C. After 10 minutes, the solution was concentrated under reduced pressure. Toluene (20 ml) was added to the residue, and dimethyl sulfate (1.32 ml, 14.0 mmol) was added dropwise under ice-cooling and reacted at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extrcted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyimino-N-methylacetamide (2.33 g, Yield: 82.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(S(C)(=O)=O)CC2)C1

Procedure:
Compound 764 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and methanesulfonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%–20%–30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0140 g, 12% yield). HRMS (M+H) calcd for C20H27N4Cl2O5S: 505.10793. found: 505.1095.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)[CH:20]=1)[CH2:16][CH3:17])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]3[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:17]
Reactant: CCN(CCC1CCCN1C(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(O)c1
Product: CCN(CC[C@@H]1CCCN1)Cc1cccc(-c2ccnc(NCCc3cccc(O)c3)n2)c1

Procedure:
Intermediate 107 was coupled with 3-(2-Amino-ethyl)-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.62 (s, 1H), 8.36 (d, 2H), 7.94 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H), 7.05 (t, 1H), 6.78 (s, 2H), 6.59 (d, 1H), 4.53 (m, 2H), 3.90 (m, 2H), 3.58 (m, 2H), 3.32 (m, 5H), 3.00 (t, 2H), 2.22 (m, 3H), 2.02 (m, 2H), 1.71 (m, 1H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH3:1][O:2][C:3]1[C:4]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2cc[nH]c2c1OC
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccccc1)c1ccc2cc[nH]c2c1OC

Procedure:
3-(7-Methoxy-1H-indol-6-yl)-N-methyl-3-phenyl-propionamide CXL was prepared from 3-(7-methoxy-1H-indol-6-yl)-N-methyl-3-phenyl-acrylamide using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16]
Reactant: O=C1CCc2c(O)cccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCCCl)cccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-Bromo-3-chloropropane (17.3 g) is added to a stirred mixture of 4-hydroxyindanone (14.8 g), potassium carbonate (15.3 g) in DMF/water (150 ml/50 ml) and the reaction mixture stirred at RT for about 4 days. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, dried, filtered and evaporated, affording a residue which is chromatographed on a silica gel column to yield the desired product as a white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([C:22]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
7.67 g (40.0 mmol) of EDCl was added to 106 ml of THF solution of 5.31 g (20.0 mmol) of Boc-Phe-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 1.82 ml (20.0 mmol) of aniline and 3.06 g (20.0 mmol) of HO-Bt, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (toluene/ethyl acetate=9/1 to 7/1 (volume ratio)), thereby obtaining 5.93 g of the product with a yield of 87.1%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:28][OH:29]>OS(O)(=O)=O.O.CC(=O)OCC>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH2:28][OH:29])[CH:10]=1)[CH3:2]
Reactant: CO
Reactant: CCOC(=O)c1ccnc(CC(C)C)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(CO)nc(CC(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 2-isobutyl-isonicotinic acid ethyl ester (1.00 g, 4.83 mmol) in methanol (50 mL) and H2SO4 (0.3 mL) is heated to 80° C. before a solution of ammonium peroxydisulfate (2.20 g, 9.65 mmol) in water (1.5 mL) is added carefully. Stirring is continued for 1 h at 80° C. before another portion of ammonium peroxydisulfate (2.20 g, 9.65 mmol) in water (1.5 mL) is added. The mixture is refluxed over night, cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 10% of methanol to give 2-hydroxymethyl-6-isobutyl-isonicotinic acid ethyl ester (560 mg) as an oil; LC-MS: tR=0.81 min, [M+1]+=238.40.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1.P(OCC1C=CC=CC=1)(OCC1C=CC=CC=1)OCC1C=CC=CC=1>O>[CH2:13]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:20]=1)[CH3:12]
Reactant: CCOc1ccc(N)cc1
Reactant: Oc1cccc2ccccc12
Agent: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1
Solvent: O
Product: CCOc1ccc(Nc2cccc3ccccc23)cc1
Temperature: 218 °C
Yield: 91 %

Procedure:
288 parts of α-naphthol, 411 parts of p-phenetidine and 8 parts of tribenzyl phosphite are mixed and heated to 218° C. At this temperature, the elimination of water commences. The reaction temperature rises to 250° C in the course of 10 hours. At that stage, the reaction has ended and 36 parts of water have been removed. After removing excess p-phenetidine, the N-p-ethoxy-phenyl-α-naphthylamine distils at a boiling point of 233° - 235° C/5 mm Hg. 479 parts of end product of melting point 72° - 75° C are obtained. This corresponds to a yield of 91% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=3[N:12]2[CH2:11][CH2:10]1.[Cu][C:28]#[N:29]>CN1CCCC1=O.O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=4[N:12]3[CH2:11][CH2:10]2)=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: N#C[Cu]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C#N
Temperature: 150 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(2-bromo-4-chlorophenyl)-8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (30.7 mg, 0.0677 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) was added copper(I) cyanide (18.2 mg, 0.203 mmol). The reaction mixture was stirred at 150° C. for 6 hr. After cooling, the reaction mixture was diluted with water and ethyl acetate and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (18.7 mg, 0.468 mmol, 69%).