Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[CH:12]=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.O.CN(C)[CH:44]=[O:45]>>[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[C:12]([CH:44]=[O:45])=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]1
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reaction time: 0.08 h

Procedure:
Phosphorus oxychloride (551 μl) was added to dimethylformamide (10 ml) at room temperature and stirred for 5 minutes. A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (502 mg) in N,N-dimethylformamide (1 ml) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (290 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>C(O)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: [NH-]c1ccc(Cl)cc1N
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1

Procedure:
A mixture of 3.0 g of (2-amino-4-chlorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid in 120 ml of glacial acetic acid is refluxed for 2.5 hours. Allow the mixture to return to room temperature and evaporate the reaction medium to dryness under vacuum. The residue is taken up with 75 ml of dichloromethane, and the organic phase is washed with twice 50 ml of a saturated solution of sodium bicarbonate, and 50 ml of a saturated solution of sodium chloride. After drying over magnesium sulphate, the organic phase is evaporated to dryness under vacuum. In this way, we obtain 3.12 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one in the form of a beige foam with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCc1ccccn1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1ccccn1

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 2-aminomethyl-pyridine (0.20 mmol, 22 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH2:27])=[O:26])[CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH2:27])=[O:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: NC(=O)C1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(C(N)=O)C3)s2)noc1C(F)(F)F
Yield: 97 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3-piperidinecarboxamide by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (120 mg, 97%). 1H NMR (DMSO-d6) 1.36-1.49 (m, 1 H), 1.55-1.75 (m, 2 H), 1.89-1.93 (m, 1 H), 2.35 (d, J=1.8, 3 H), 3.03 (br s, 2 H), 4.10 (br s, 2 H), 6.90 (s, 1 H), 7.37 (s, 1 H), 7.51 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1 H). 19F NMR −62.2. LC/MS 5.54 min, [M+1]+ 388.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@H:22]([CH3:25])[CH2:23]O)[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[I-:49].[Na+]>ClCCl.C(OCC)(=O)C.CO>[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@H:22]([CH3:25])[CH2:23][I:49])[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16]
Reactant: [I-]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CI
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Triethylamine (3.4 mL, 24 mmol) and mesyl chloride (1.5 mL, 19.2 mmol) were added to a solution of 4-[(S)-2-hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (5.1 g, 16 mmol) in dichloromethane (50 mL) under ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. After adding methanol to the reaction mixture, the mixture was blended with a mixture of ethyl acetate and a 10% citric acid solution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and then the residue was dissolved in acetone (100 mL). Sodium iodide (4.8 g, 32 mmol) was added, and the mixture was heated to reflux for 20 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The resulting residue was blended with a mixture of ethyl acetate and water. The organic layer was washed with a saturated sodium thiosulfate solution and brine, dried over magnesium sulfate, and then filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to give 6.5 g (94%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH2:15])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][C:26](=[O:27])[O:28][CH3:29])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Yield: 92.6 %

Procedure:
Treatment of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine hydrochloric salt (0.60 g, 2.3 mmol) with diisopropylethylamine (0.89 g, 6.9 mmol) and methyl chloroformate (0.44 g, 4.6 mmol) generally according to the procedure described for Intermediate 7 provided 0.6 g of (±)-methyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as white solid. mp 139-141° C.; Anal. calcd. for C14H16ClNO3: C, 59.68; H, 5.72; N, 4.97. Found: C, 58.99; H, 5.72; N, 4.86.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(C3CC3)cnc21
Temperature: 100 °C
Yield: 81.3 %

Procedure:
A mixture of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.33 g, 0.93 mmol), cyclopropyl boronic acid (0.12 g, 1.39 mmol), tricyclohexyl phosphine (0.026 g, 0.09 mmol), palladium(II) acetate (0.01 g, 0.046 mmol) and potassium phosphate tribasic (0.63 g, 2.97 mmol) in 4 mL of toluene and 0.5 mL of water was flushed with Argon for 5 min then heated at 100° C. for 18 h. The cooled mixture was filtered through a pad of Celite, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to afford 0.24 g (81%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow powder.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([CH3:28])[CH:21]=1>C1COCC1>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([C:4]2([C:7]#[N:8])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[CH:21][C:22]=1[CH3:28])#[N:25]
Reactant: N#CC1CCSCC1
Reactant: Cc1cc(F)ccc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C#N
Temperature: -78 °C
Yield: 67.1 %

Procedure:
A solution of tetrahydro-2H-thiopyran-4-carbonitrile (197 mg, 1.55 mmol) and THF (2.0 mL) is slowly added via syringe to a mixture of KHMDS (324 mg, 1.63 mmol) in THF (3.0 mL), stirring at −78° C. under nitrogen. The temperature is maintained at −78° C. for 30 min. before a mixture of 4-fluoro-2-methylbenzonitrile (222 mg, 1.64 mmol) in THF (1.0 mL) is slowly added to the vessel. The mixture is allowed to warm to room temperature and is stirred for 3 hours before being quenched with saturated aqueous NH4Cl. The solvent is removed by rotary evaporator and EtOAc (10.0 mL) and water (10.0 mL) are added. The phases are partitioned and the organic is washed with brine, dried with Na2SO4 and concentrated to yield the product (252 mg, 1.04 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.84-1.95 (m, 2H), 2.03-2.14 (m, 2H), 2.51 (s, 3H), 2.57-2.72 (m, 4H), 7.23-7.31 (m, 1H), 7.41 (dd, J=9.96, 1.76 Hz, 1H), 7.89 (dd, J=8.59, 5.86 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>[Li]CCCC>[C:9]([C:8]1[NH:7][C:2]2[C:1]([CH:14]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CC(C)(C)c1cc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol) in dry THE (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15° C. After addition, the mixture was stirred overnight at 15° C. The mixture was cooled in an ice-water bath and treated with saturated NH4Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give 2-tert-butyl-1H-indole (24 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.99 (br. s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.06-7.13 (m, 2H), 6.26 (s, 1H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([O:24]CC)=[O:23])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.[CH3:28]I.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:28])[N:17]=[CH:16]2
Reactant: CCOC(=O)c1cn(Cc2ccc3[nH]ncc3c2)c2cccc(F)c2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Cn3cc(C(=O)O)c(=O)c4c(F)cccc43)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 5-fluoro-1-(1H-indazol-5-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.092 g, 0.25 mmol) in anhydrous N,N-dimethylformamide (0.8 mL) was added methyl iodide (0.10 mL, 1.60 mmol). The solution was cooled to 0° C. and sodium hydride (0.011 g, 0.28 mmol) was added. After stirring for 10 minutes at that temperature the reaction was quenched with water and 2 ml of a saturated aqueous lithium hydroxide solution was added. After stirring for 30 min, the solution was acidified with 4 N HCl and the product was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC to provide the 5-fluoro-1-[(1-methyl-1H-indazol-5-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The 5-fluoro-1-[(2-methyl-2H-indazol-5-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was isolated as the minor product. 5-Fluoro-1-[(1-methyl-1H-indazol-5-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 352 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.96 (s, 1H), 7.66-7.60 (m, 1H), 7.54 (s, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.22-7.15 (m, 2H), 5.59 (s, 2H), 4.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N.C([O-])=O.[NH4+]>C(#N)C.[Pd]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]\[C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][C:17]=1[NH2:23]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Agent: O=C[O-]
Solvent: CC#N
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N

Procedure:
A solution was prepared by dissolving (Z)-3,4,4′,5-tetramethoxy-3′-nitrostilbene (raw material 5) represented by the above formula (5) (5.0 g, 14.5 mmol in total including 14% of the trans-isomer) in acetonitrile (58 mL) followed by addition of 10% palladium on carbon (water-content: 51.3%, 633 mg, 0.29 mmol as palladium), aqueous ammonia (29%, 0.85 g, 14.5 mmol) and ammonium formate (95%, 2.88 g, 43.4 mmol, 300 mole % to the total of the above nitrostilbene derivative (raw material 5) and the trans-isomer thereof) to be subjected to a reaction at 30° C. for 28 hours. At the conclusion of the reaction, the catalyst and the insoluble matter were separated by filtration followed by analysis of the filtrate by HPLC. The resultant peak areas shown at a detection wavelength of 242 nm were 72%, 13%, 1.3%, 0.6%, 11% and 1.6%, respectively, for the (Z)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]aniline as the objective substance (objective substance 6; represented by the above formula (6)), by-products (E)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]aniline (by-product 7; represented by the above formula (7)), 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]aniline (by-product 8; represented by the above formula (8)) and 2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)ethane (by-product 9; represented by the above formula (9)), the nitrostilbene derivative as the starting material (raw material 5), and the trans-isomer of the raw material 5. In consideration that the starting material contained 14% of the trans-isomer, it was understood that isomerization from the cis-isomer to the trans-isomer was trifling during the reaction.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: N[C@H]1CCc2ccccc21
Product: O=S(=O)(N[C@H]1CCc2ccccc21)c1cccc(Br)c1
Yield: 52 %

Procedure:
3-bromo-N-[(1S)-2,3-dihydro-1H-indene-1-yl]benzenesulfonamide was synthesized according to the procedure described above from (S)-1-aminoindan and 3-bromobenzensulfonyl chloride. Yield 52%. 1H NMR (400 MHz, CDCl3): 7.20 (m, 1H), 7.90 (dd, 1H), 7.80 (dd, 1H), 7.50 (t, 1H), 7.20 (m, 2H), 7.15 (m, 1H), 7.02 br d, 1H), 4.80 (t, 1H), 2.90(m, 1H), 2.70 (m, 1H), 2.20 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:28])([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCCC(N1CC(O)(CCCC2C=CC=CC=2)C[C@H]1C(O)=O)=O)(=O)C>>[OH:28][C:17]1([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(CCCc2ccccc2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SCCC(=O)N1CC(O)(CCCc2ccccc2)C[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CC(O)(CCCc2ccccc2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-(phenylpropyl)-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-(phenylpropyl)-L-proline. This amino acid is reacted with 3-acetylthiopropionyl chloride according to the procedure of Example 1 (c) to yield 1-[3-(acetylthio)-1-oxopropyl]-4-hydroxy-4-(phenylpropyl)-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1

Procedure:
A 12.8 g quantity of p-chlorophenol, 13.4 g of 1-chloro-3,3-dimethyl-2-butanone, 13.8 g of anhydrous potassium carbonate and 100 ml of acetonitrile were placed into a 200-ml egg plant type flask and refluxed for 8 hours. The resulting potassium chloride was filtered off from the reaction mixture, and the filtrate was concentrated in a vacuum to obtain crude crystals, which were recrystallized from n-hexane, giving 16.0 g of the above-identified desired compound, m.p. 62°-63° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[CH:9]([OH:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1sc2c(c1-c1ccccc1)C(=O)C(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1sc2c(c1-c1ccccc1)C(O)C(C)C2
Reaction time: 8 h

Procedure:
A solution of 2,5-dimethyl-3-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-4-one (4.4 g, 18 mmol) in 50 mL of ether was slowly added to a solution of LiAlH4 (0.35 g, 9 mmol) in 50 mL of ether and stirred overnight. The resulting suspension was poured into a mixture of ice and water, the organic layer was isolated, while the water layer was extracted with ether (3×50 mL). The combined organic layers were washed with water, dried over MgSO4 and evaporated off to dryness. The 2,5-dimethyl-3-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ol so obtained was dissolved in 100 mL of benzene, added of 1 g of p-toluenesulfonic acid and was refluxed for 10 min. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness. The residue was passed through a column packed with Al2O3 by using hexane as eluent. The evaporation of the yellow fraction was given the crystallized product. Yield 1.5 g (37% based on the starting ketone).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[Cl:23][C:4]1[CH:3]=[C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(-n4cccc4)cc3Cl)c2n1
Yield: 55.7 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (1.00 g) was dissolved in acetic acid (5.0 ml) and 2,5-dimethoxytetrahydrofuran (420 mg) was added, which was followed by refluxing under heating for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with chloroform:ethyl acetate=3:1. The objective fraction was concentrated under reduced pressure and ethyl acetate (10.0 ml) was added to the residue. After heating, the mixture was allowed to cool and the precipitated crystals were collected by filtration to give methyl 3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (641 mg) as colorless crystals.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:20])(=[O:19])[CH:16]([CH3:18])[CH3:17]>>[ClH:20].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Product: CC(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 67 %

Procedure:
5.0 g (21.4 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 20 ml of isobutyryl chloride were refluxed for 20 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from ethanol/methyl tert.-butyl ether. 4.5 g (67% of theory) of 1,4-dihydro-4-isobutyrylimino-1-phenylpyridazine hydrochloride were isolated as colorless crystals of melting point 240°-242° C.