Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>ClCCCl>[CH3:38][C:33]1[C:32]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[CH2:10][CH2:9]3)=[C:4]([F:28])[CH:3]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1N=C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
A mixture of 2-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (1.0 mmol) in DCE (10 mL) was stirred at rt for 16 h. The precipitate that had formed was collected by filtration and dried under vacuum to give the title compound (78 mg, 50%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28; m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.95-7.75 (br s, 1H), 7.40-7.20 (m, 5H), 7.30-6.90 (br s, 1H), 6.80-6.70 (m, 2H), 3.60-3.10 (m, 7H), 2.45-2.35 (m, 2H), 2.28 (s, 3H), 2.20-2.10 (m, 4H), 2.00-1.90 (m, 1H), 1.52-1.40 (m, 1H), 1.35-1.20 (m, 2H), 1.18-1.03 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:14][CH2:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[O:15])[CH2:23][CH2:22]1
Reactant: C=CC(=O)NS(=O)(=O)c1ccc(C)cc1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)CCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 72 h
Yield: 17.4 %

Procedure:
4-Methyl-N-(1-oxo-2-propenyl)-benzenesulfonamide (0.140 g) was dissolved in THF (10 mL) and 4-(3,4-dichlorophenoxy)-piperidine (0.120 g) and NaOH (0.080 g) were added. The reaction mixture was stirred for 72 h. The solvents were evaporated. The residue was purified by HPLC (gradient Ammonium acetate/Acetonitrile 95% to 5%; Xterra column) to give the title compound (40 mg)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (3.0 g, 12.1 mmol) in CH2Cl2 under nitrogen was added Et3N (2.45 g, 24.2 mmol), followed by benzoyl chloride (1.70 g, 12.1 mmol). The mixture was stirred at room temperature overnight, washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting solids were triturated with hexanes to afford ethyl 4-(4-benzamidopiperidin-1-yl)benzoate as a yellow solid (4.2 g, 100%).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[Cl:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1sccc1Cl
Reaction time: 1 h
Yield: 59 %

Procedure:
After dissolving 1.3 ml of diisopropylamine in 20 ml of tetrahydrofuran, 3.5 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwise while stirring at below −30° C. After stirring for 30 minutes while cooling on ice, 0.86 ml of 3-chlorothiophene was added dropwise. The mixture was stirred for another 30 minutes, and then a solution of 1.68 g of 1-benzyl-4-piperidineacetaldehyde in tetrahydrofuran (5 ml) was added and stirring was continued for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.53 g, 59% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)[OH:4].[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]>>[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH:1][CH2:2][C@H:3]([OH:4])[C:5]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]5[C:6]=4[CH:7]=[CH:8][C:9](=[O:16])[NH:10]5)[CH:39]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C=O)c1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 43, using Intermediate 4 in place of Intermediate 8 and Intermediate 30 in place of Intermediate 29.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([C:17]2[C:18]([CH3:27])=[N:19][C:20](S(C)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCOCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=1[C:17]1[C:18]([CH3:27])=[N:19][C:20]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1COCCN1
Reactant: Cc1nc(S(C)(=O)=O)ncc1-c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2CCOCC2)ncc1-c1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
A solution of the product from step (vii) (0.15 g) and morpholine (0.15 ml) in dioxane (3 ml) was heated at 90° C. for 24 h, cooled and the solvent evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[C:4](F)[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[C:4]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: OCc1cc(F)nc(F)c1F
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc(CO)c(F)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.9 %

Procedure:
To a 100 ml round bottomed flask, were placed (2,3,6-trifluoro-pyridin-4-yl)-methanol (515 mg, 3.15 mmol) and p-methoxybenzyl amine (1.0 ml, 7.57 mmol). Nitrogen balloon was attached to the flask and the mixture was stirred in an oil bath (117˜130° C.) for 2.5 hr. After cooling to room temperature, the mixture was purified by silica gel column chromatography (eluent, dichloromethane: methanol (95:5)) to afford 838 mg (94%) of [2,3-difluoro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol as a pale brown solid. 1H NMR (200 MHz, CDCl3) δ 2.04 (1H, br. s), 3.79 (3H, s), 4.52 (2H, d, J=5.6 Hz), 4.70 (2H, br. s), 4.84 (1H, br. s), 6.22 (1H, m), 6.83-6.90 (2H, m), 7.24-7.31 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH:9]([CH2:14][C:15]2([CH3:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([O:12]C)=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:14][C:15]2([CH3:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([OH:12])=[O:11])=[O:7])=[CH:26][CH:27]=1
Reactant: COC(=O)C(CC1(C)C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1
Agent: Cl
Product: CC1(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)C(=O)Nc2ccccc21

Procedure:
2.9 Grams of methyl 2-(4-chlorobenzoylamino)-3-(3-methyloxindol-3-yl)propionate prepared in Example 48 was added to 10 ml of 10%-hydrochloric acid and the mixture was refluxed for 3 hours. After cooling, the reaction mixture was extracted with chloroform, the extract was washed with water and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, the residue was dissolved in a saturated sodium bicarbonate aqueous solution, then the resulting solution was filtered with Celite (trademark for diatomaceous earth product manufactured by Johns-Manville Products Corp.) as a filter aid. The filtrate was acidified with 10%-hydrochloric acid, the crystals formed were collected by filtration to obtain 230 mg of 2-(4-chlorobenzoylamino)-3-(3-methyloxindol-3-yl)propionic acid in the form of white powdery substance.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH:19](O)=O.C=O.N>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Agent: C=O
Agent: N
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C1CCc2c(cccc2NC(C)=O)C1

Procedure:
2.46 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline (Example 4.1.1) are heated with 2.34 g (0.050 mol) of formic acid and 2.2 ml of 30% formalin solution (0.022 mol of formaldehyde) for 30 minutes over a boiling water bath. The reaction mixture is shaken with 50 ml of water, 50 ml of methylene chloride and 2 ml of conc. ammonia. The aqueous phase separated off is extracted twice more with 15 ml of methylene chloride. The combined methylene chloride extract are washed with 20 ml of water, dried with sodium sulphate and concentrated by evaporation, after removal of the drying agent, in a rotary evaporator, finally at 80° C. under a total water jet vacuum. The residue is crystallised from 5 ml of acetone and 20 ml of petroleum ether. The title compound is obtained in a yield of 1.80 g (69.2% of theory) and with a melting point of 78° C.
Reaction SMILES: N(C(=O)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5])N.ClC([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O>N1C=CC=CC=1>[CH2:29]([O:28][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:5])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 43 (3.31 g, 13.40 mmol) in dry pyridine (18 mL) under an inert atmosphere at 0° C. was added benzyl chloroformate (2.30 mL, 16.08 mmol) then allowed to warm to ambient temperature and stirred for 18 hours. After concentrating in vacuo the residue was partitioned between Et2O (150 mL) and 1M aqueous HCl (20 mL). The organic phase was dried (MgSO4), filtered and evaporated to a yellow solid. Purification by chromatography through silica gave the title compound (3.50 g, 68%) as an off white solid; 1H NMR (CDCl3) δ1.03-1.12 (2H, m), 1.35-1.46 (2H, m), 1.74-1.82 (5H, m), 2.17-2.18 (2H, m), 2.33-2.39 (1H, m), 3.61 (3H, s), 5.12 (2H, s), 6.50 (1H, s), 7.06 (2H, d), 7.19-7.34 (7H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Yield: 76.1 %

Procedure:
3-Bromo-5-(pentafluorosulfanyl)benzoic acid (1.35 g) was dissolved in thionyl chloride (10 ml) while stirring, and kept under reflux with exclusion of moisture for 5 h. Then the thionyl chloride was drawn off, the residue was taken up in DCM (40 ml) and the solution was admixed with N,O-dimethylhydroxylamine hydrochloride (381 mg). Subsequently Hünig's base (0.7 ml) was added and then the mixture was stirred for 2 h. Thereafter, the mixture was dried, the residue was taken up with EA and the solution was washed five times with water. The EA phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (60 g cartridge, 4:1 n-heptane/EA). 1.1 g of the title compound were obtained.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:10][C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:42][C@H:43]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1)[C:44]([N:46]1[CH2:49][C:48]([O:57][CH2:58][CH2:59][CH2:60][CH3:61])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:47]1)=[O:45].[OH-].[Na+]>CN(C)C=O>[CH2:58]([O:57][C:48]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:49][N:46]([C:44](=[O:45])[C@H:43]([NH:42][C:11](=[O:13])[CH2:10][CH:9]([OH:8])[C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:47]1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CC(O)c1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CC(O)c2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
0.5 ml (3 mmol) of triethylamine are added to a solution containing 0.5 g (3 mmol) of 3-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and 1.0 g (3 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 1.5 g (3 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one hydrochloride (prepared as described in Example 6.2) are added. The reaction medium is stirred for 24 h at ambient temperature, treated with a 1N aqueous solution of sodium hydroxide and extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by silica gel chromatography, elution being carried out with a 97/3 dichloromethane/methanol mixture. 72 mg of N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a beige powder with a yield of 5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:40][CH3:41])=[C:11](\[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C1CCCCO1)[N:16]=[CH:15]2>C(O)C.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:40][CH3:41])=[C:11](\[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
A solution of HCl (5.0 mL, 2.0 M in diethyl ether) was added to a solution of (E)-ethyl 3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (3.0 g, 5.2 mmol) in ethyl alcohol (25 mL) at room temperature. The resulting mixture was heated at 70° C. for 2 h. Upon completion, the mixture was cooled down to room temperature and concentrated to give a pale yellow solid. This crude material was dissolved in DCM and washed with water (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (2.37 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 8.11 (s, 1H), 7.69 (s, 1H), 7.58-7.52 (m, 2H), 7.48 (d, 1H), 7.43 (d, 2H), 7.36-7.32 (m, 2H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.49 (d, 1H), 4.15 (q, 2H), 2.39 (q, 2H), 1.22 (t, 3H), 0.90 (t, 3H); LCMS: 491 (M+H)+.
Reaction SMILES: O[NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])#[CH:16].CCCCCC>C(O)C>[CH2:20]([O:19][C:17]([C:15]1[N:2]=[C:3]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)[NH:14][CH:16]=1)=[O:18])[CH3:21]
Reactant: N=C(NO)c1ccc(C(F)(F)F)cc1
Reactant: C#CC(=O)OCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 26 h
Yield: 44.1 %

Procedure:
To a solution of N-hydroxy-4-(trifluoromethyl)benzamidine (3.0 g) in ethanol (30 ml) was added ethyl acetylenecarboxylate (1.44 g), and stirred at 80° C. for 26 hours. After the solvent was evaporated, diphenylether (15 ml) was added thereto, and additionally stirred at 180° C. for 5.5 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, and n-hexane was added thereto. The insoluble matter was collected by filtration, washed with n-hexane, and then dried to give 2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylic acid ethyl ester (1.84 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:8]=1.C1C(=O)N([Cl:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]=1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3, 40 mg, 0.15 mmol) and NCS (24.6 mg, 0.18 mmol) in CCl4 (20 mL). The resulting mixture was stirred for 2 h at 50° C., then cooled to room temperature and quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 30 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH:16]CC3C=CC(OC)=CC=3)[C:8]=2[N:7]=[C:6]1[CH2:26][OH:27])[CH:2]([CH3:4])[CH3:3]>FC(F)(F)C(O)=O>[NH2:16][C:9]1[C:8]2[N:7]=[C:6]([CH2:26][OH:27])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]=2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=1
Reactant: COc1ccc(CNc2nc(C)c(C)c3c2nc(CO)n3CC(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c2nc(CO)n(CC(C)C)c2c1C
Temperature: 25 °C
Yield: 93.9 %

Procedure:
{1-Isobutyl-4-[(4-methoxybenzyl)amino]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl}methanol (3.08 g, 8.36 mmol) was dissolved in trifluoroacetic acid (31 mL) and stirred at room temperature over night. The solvent was removed under reduced pressure and concentrated hydrochloric acid (5 mL) was added. The suspension was stirred for 2 hours, the solid was isolated by filtration and washed with water to give 1.95 g of (4-amino-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol as a tan powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:31]1([CH:4]([O:5][C:6]2[CH:30]=[CH:29][C:9]([C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2][N:48]2[CH2:47][CH2:46][N:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[O:38][CH3:37])[CH2:50][CH2:49]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCBr)c3ccccc3)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccccc3)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Ethyl 4-{3-[4-(3-bromo-1-phenylpropoxy)benzoyl]indol-1-yl}butanoate (1.97 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (20 ml). 1-(2-Methoxyphenyl) piperazine (0.83 g) and potassium carbonate (0.75 g) were added to the resultant solution and stirred overnight at 60° C. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), obtaining 1.95 g of ethyl 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[CH:14][C:13]=1[OH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=2)=[CH:14][C:13]=1[O:32][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.00 g, 6.35 mmol) and N-(4-chloro-3-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.00 g, 6.35 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.31 g, 9.52 mmol), and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the obtained residue, and the mixture was twice extracted with ethyl acetate (50 mL)/hexane (50 mL). The combined organic layer was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (2.57 g, 93%) as a yellow oil.