Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([S-:44])[CH3:43].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C=O)C.CCOC(C)=O>[CH2:42]([S:44][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1)[CH3:43]
Reactant: CC[S-]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Na+]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
(R)-1-(3-Bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Intermediate 14B; 59 mg, 0.098 mmol), sodium ethanethiolate (20.59 mg, 0.245 mmol), and aluminum oxide (100 mg, 0.979 mmol) were dissolved in DMF (2 mL) and heated in a microwave reactor to 100° C. for 2 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (7-60% EtOAc/hexane) to give (R)-1-(3-(ethylthio)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C36H33N5OS [M+1]+ 584. found 584.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[CH:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:14]=1.CN(C=O)C>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[C:20]([C:6]#[N:5])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH:14]=1
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1-c1c(C#N)c2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Chlorosulfonyl isocyanate [1189-71-5] (0.453 mmol) was added to a mixture of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.302 mmol) in CH3CN (2 mL) at 0° C. After stirring at rt for 2.5 h, additional chlorosulfonyl isocyanate (0.226 mmol) was added. After another 4 h, the reaction mixture was cooled to 0° C., treated with DMF (0.4 mL), stirred for 15 min and then warmed to 50° C. After 30 min, the reaction mixture was cooled to rt, poured onto ice-H2O and extracted with EtOAc. The organic layer was successively washed with a 1N aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as an off-white solid. tR: 5.59 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.12 (1:3 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.79/7.83 (s, 1H), 7.58 (m, 1H), 7.35-7.46 (m, 3H), 7.31 (m, 2H), 7.25 (m, 1H), 7.21 (m, 1H), 7.09-7.17 (m, 2H), 6.61 (s, 1H), 3.97/4.01 (m, 1H), 3.77/3.83 (s, 3H), 1.93 (s, 3H), 1.26/1.35 (m, 3H), 0.42/0.58 (m, 3H).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.Cl.CNC.[CH2:12]([CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[O:32])=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(O)(=O)C>[CH2:12]([CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][N:3]([CH3:4])[CH3:1])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[O:32])=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCN(CC)CC
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C=O)cc3)cc2)cc1)C(=O)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CNC
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(CN(C)C)cc3)cc2)cc1)C(=O)O
Reaction time: 18 h

Procedure:
To triethylamine (0.56 ml), dimethylamine hydrochloride (167 mg) and titanium tetraisopropoxide (0.59 ml) was added a suspension of 2-butyl-3-[4-[2-(4′-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid (474 mg) in ethanol (20 ml) at ambient temperature to afford a clear solution. Sodium borohydride (60 mg) was added to the solution and the mixture was stirred under nitrogen atmosphere for 18 hours. At the end of this time 50% acetic acid was added to the reaction mixture. This mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Diisopropyl ether was added to the residue to give the title compound (135 mg) as colorless crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P(Cl)(Cl)([Cl:18])=O.O.[OH-].[NH4+]>C(Cl)Cl>[Cl:18][C:6]1[C:5]2=[CH:1][CH:2]=[CH:3][N:4]2[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccccc2Cn2cccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: ClC1=Nc2ccccc2Cn2cccc21
Temperature: 25 °C

Procedure:
A slurry of 881 g of 10,11-dihydro-5-H-pyrrolo-[2,1-c][1,4]benzodiazepin-11-one is stirred in 12 L of methylene chloride, and 819 g of 99% phosphorus oxychloride is added all at once. The mixture is stirred and refluxed for 19 hours. The reaction mixture is cooled to room temperature. A mixture of 5 L of crushed ice, 7.5 L of cold water and 1.81 kg of 28% ammonium hydroxide solution is stirred and 1.25 L portions of the reaction mixture are added over a period of 15 minutes. The reaction temperature is kept below 25° during the addition. After stirring for 15 minutes, the layers are separated, the methylene chloride layer is washed by stirring with 1 L of cold water then dried by stirring with magnesium sulfate for 1 hour. Charcoal (90 g) is added and the mixture is filtered through filter-cel. The methylene chloride solution is concentrated to dryness in vacuo to give 11-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, m.p. 102°-104°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)=[O:4].[F:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>>[F:13][C:2]([F:1])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][C:18]3[CH:28]=[CH:29][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:21][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: O=C(N1CCCC(O)C1)C(F)(F)F
Product: O=C(N1CCCC(OCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Yield: 54.6 %

Procedure:
Using 1-trifluoroacetyl-3-hydroxypiperidine (394 mg, 2.00 mmol) and 4-(4-fluorophenoxy)benzylchloride (473 mg, 2.00 mmol), the same procedure was followed as in Step 6a of Example 6 to give 434 mg (55%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(C1C=C(C)C(=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)(C)(C)C.Cl>C(OCC)C>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20]OC)=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=3[N:13]=2)[CH:8]=1.COC1C=CC(OC)=CC=1C=NC1C(C)=CC=CC=1O>>[CH3:20][O:19][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=2[N:13]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Agent: COc1ccc(OC)c(C=Nc2c(C)cccc2O)c1
Product: COc1ccc(OC)c(-c2nc3c(C)cccc3o2)c1

Procedure:
2-(2,5-dimethoxyphenyl)-4-methylbenzoxazole (F10) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) by using 2-[(2,5-dimethoxybenzylidene)amino]-3-methylphenol (F7) (5.43 g, 20 mmol) instead of 2-[(5-methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) in 85% (4.55 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 3H), 5.24 (s, 3H), 7.17 (d, H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:13][C:12]([CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8][NH:7]1)=[O:14]
Reactant: O=C(O)C1Cc2cc(F)ccc2CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1Cc2cc(F)ccc2CN1

Procedure:
To a suspension of 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in methanol (500 mL) was added SOCl2 (50 mL). The reaction mixture was then refluxed for 1 h until LC-MS indicated the completion of the reaction. The mixture was concentrated, and the resulting residue was dissolved in a mixture of EtOAc (1 L) and sat. sodium bicarbonate solution (500 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give 6-fluoro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester as an oil (92 g). LRMS (M+H+) m/z 210.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.C(O)(=O)C>[OH-].[Na+]>[NH:14]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2ncccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1cc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (Preparation 31, 0.34 g, 1.77 mmol) in aqueous sodium hydroxide solution (2M, 10 mL) was heated under reflux for 3 h and the resulting solution was allowed to cool to rt. The pH was adjusted to 4 by addition of glacial acetic acid. Excess acetic acid was removed in vacuo and the resulting suspension cooled to 0° C. and then left standing at rt for 16 h. The resulting beige precipitate was collected by filtration and dried to give the title compound as a beige solid. δH (d6 DMSO): 7.12 (1H, s), 7.23 (1H, dd), 7.79 (1H, d), 8.42 (1H, dd).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](=[O:17])[CH3:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:16][C:15]1[O:17][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCC(=O)NC(C(C)=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCc1nc(-c2ccccc2)c(C)o1
Reaction time: 0.67 h

Procedure:
Phosphorous oxychloride (5.58 ml) was added to a solution of 1-hexanoylamino-1-phenyl-2-propanone (4.94 g) in toluene (50 ml) and the solution was refluxed with stirring for 40 minutes. The solvent was distilled off and water was added to the residue. The mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [silice gel: 80 g; eluent: hexane-ethyl ether (4:1)] to give an oil of 5-methyl-2-pentyl-4-phenyloxazole, yield 4.25 g (92.8%).
Reaction SMILES: [Cl:1][C:2](=[N:16][OH:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CCOCC>[Cl:1][C:2](=[N:16][O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(Cl)=NO)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A 500 mL flask was charged with tert-butyl 4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (2.3 g, 8.7 mmol), methanesulfonyl chloride (0.68 mL, 8.7 mmol), and Et2O (200 mL). Triethylamine (1.2 mL, 8.7 mmol) was added slowly over ˜1 minute and the reaction was stirred at ambient temperature for 10 minutes. The resultant precipitate was filtered and the filtrate concentrated and purified on silica (100% CH2Cl2) to afford tert-butyl 4-(chloro(methylsulfonyloxyimino)methyl)piperidine-1-carboxylate (1.6 g, 53.63% yield) as a c.c. oil.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:14])=O.CN(C=O)C>>[Cl:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCOCCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCOCCCl

Procedure:
2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspended in 5 ml (68.5 mmol) thionyl chloride and 20 μl (0.27 mmol) DMF are added. The reaction mixture is refluxed for 4 hours and then evaporated down i. vac. The product is further reacted without any more purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([CH3:20])[S:19][C:7]1=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[O:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:37])[CH3:36]>CN(C)C=O>[CH2:34]([N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:26])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]4[S:19][CH:18]([CH3:20])[N:8]43)=[CH:3][C:2]=2[F:1])[CH2:13][CH2:14]1)[C:35]([CH3:36])=[O:37]
Reactant: CC(=O)CBr
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(CC(C)=O)CC4)c(F)cc3c1=O)C(C)S2
Temperature: 0 °C
Yield: 84.8 %

Procedure:
Ethyl 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (3.8 g) was suspended in 50 ml of N,N-dimethylformamide, 1.66 g of potassium carbonate was added thereto, 1.65 g of bromoacetone was dropped in with ice cooling and stirring, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured over into ice water and the crystals separated out were collected by filtration, washed with water, dried and recrystallized from ethanol to give 3.7 g of desired compound in colorless powdery crystals, m.p. 196°-200° C. (decompn.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.5 mL TFA was added to a solution of 0.750 g (2.000 mmol) tert-butyl (4′-chloro-biphenyl-4-yloxy)-acetate in 20 mL dichloromethane and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated down i. vac. and diluted with 1 M aqueous NaOH and EtOAc. The precipitate was filtered off and dried at 80° C. i. vac.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C.CS(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1ccc(O)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(OCc2ccccc2)cn1
Reaction time: 0.5 h
Yield: 452.8 %

Procedure:
5-Hydroxy-2-n-propylpyridine (13.72 g, 100 mmol) was dissolved in 200 ml of dry tetrahydrofuran under a nitrogen atmosphere, and at 0° C., 60% sodium hydride (7.0 g, 175 mmol) was added in small portions. The reaction mixture was stirred for 1/2 hour when a precipitate became visible. This precipitate was redissolved by adding 30 ml of dimethyl sulfoxide. Benzylbromide (13.1 ml, 18.84 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 3 hours. Water (200 mol) and 20 ml of triethylamine was added and The pH was adjusted to 12 with a saturated sodium hydrogen carbonate solution. The organic material was extracted into ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by destillation and gave 19.39 g (85%) of 5-benzyloxy-2-n-propylpyridine as an orange coloured oil. B.p. 160-170° C. 0.3 mbar. MS(SP): m/z 227 (m+). 1H-NMR (CDCl3, 200 MHz) δ: 0.95 (t, 3H); 1.72 (sext, 2H); 2.70 (t, 2H); 5.05 (s, 2H); 7.02 (d, 1H); 7.18 (dd, 1H); 7.24-7.46 (m, 5H); 8.30 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[C:9][N:10]([CH3:22])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>N1C=CC=CC=1>[C:1]1([CH2:7]/[CH:8]=[CH:9]\[N:10]([CH3:22])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C#CCC1=CCCCC1)Cc1cccc2ccccc12
Reactant: [H][H]
Solvent: c1ccncc1
Product: CN(/C=C\CC1=CCCCC1)Cc1cccc2ccccc12

Procedure:
5 g of N-(3cyclohex-1-en-1-yl-propynyl)-N-methyl-N-(1-naphthylmethyl)amine are hydrogenated in absolute pyridine using 750 mg Pd/BaSO4 as catalyst at room temperature and normal pressure, until the calculated amount of hydrogen is taken up. The reaction mixture is filtered and the pyridine removed in a vacuum. The residue is chromatographed on silica-gel using benzene/ethylacetate (9:1) to yield the title compound in free base form as an oil after evaoporating the appropriate fractions,
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([O:28]C(C)(C)C)=O)[C@H:21]3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9]1.[OH-].[Na+].[C:35]([NH:43][C@@H:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1C(O)=O)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([C@H:45]4[CH2:46][CH2:47][CH2:48][C@H:44]4[NH:43][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:28])[C@H:21]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14]2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21
Reactant: O=C(N[C@@H]1CCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 44.1 %

Procedure:
TFA (1 ml) was added to tert-butyl (3aR*,4R*,9bR*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (178 mg, 0.5 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, the mixture was basified with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml), and (1S,2R)-2-(benzoylamino)cyclopentanecarboxylic acid (117 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) were added. DEPC (82 mg, 0.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (5:1-2:1, v/v) to give the title compound (104 mg, 44%) as a colorless powder.