Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22](C)(C)[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:13]([CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH2:30][CH2:31]1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: Sc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCSc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([OH:22])=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Yield: 96.7 %

Procedure:
A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in 15 ml of methanol and 10 ml of water is stirred at 60° C. until a solution forms. The methanol is then evaporated in vacuo, and the remaining mixture is diluted with water. After adjusting the pH to 5–6 with 1N HCl, the solid is collected by filtration, washed with water and dried to give the title compound (450 mg) as a yellow solid, m.p. 187–90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C@H:20]([OH:24])[C:21]([CH3:23])([CH3:22])[C@@H:8]2[CH2:7][CH2:6]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH3:42][O:43][C@:44]([C:54]([F:57])([F:56])[F:55])([C:51](Cl)=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[F:55][C:54]([F:56])([F:57])[C@:44]([O:43][CH3:42])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]([O:24][C@H:20]1[CH2:19][CH2:18][C@:9]2([CH3:25])[C@@H:10]3[C@@:5]([CH3:26])([CH2:6][CH2:7][C@H:8]2[C:21]1([CH3:22])[CH3:23])[C:4]1[C:12](=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[CH2:11]3)=[O:52]
Reactant: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1C2
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](OC(=O)[C@@](OC)(c4ccccc4)C(F)(F)F)CC[C@]3(C)[C@H]1C2
Temperature: 25 °C

Procedure:
Alcohol 5b (219 mg, 0.610 mmol) was dissolved in 4 mL of methylene chloride (DCM). To this mixture was added pyridine (0.074 mL, 0.92 mmol) and dimethylaminopyridine (DMAP) (7.4 mg, 0.061 mmol), and the mixture was taken to 0° C. To this mixture was added (R)-(−)-MTPA-Cl (170 mg, 0.671 mmol), and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted 3 times with methylene chloride (3×50 mL). The organic extracts were combined and dried with MgSO4 and concentrated. A 1H NMR (400 MHz) spectrum of the crude mixture showed the absence of diastereomers, meaning that alcohol 5b was enantiomerically pure after crystallization. The product mixture was then purified using flash chromatography (hexanes:ethyl acetate 12:1) to give 10b quantitatively. 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.41 (m, 3H), 6.40 (d, J=1.8 Hz, 1H), 6.26 (d, J=1.9 Hz, 1H), 4.72 (dd, J=12, 4.9 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.54 (s, 3H), 2.62 (m, 1H), 2.51 (dd, J=14, 6.2 Hz, 1H), 2.46 (dd, J=8.4, 2.9 Hz, 1H), 1.85-1.76 (m, 1H), 1.74-1.67 (m, 3H), 1.65-1.57 (m, 3H), 1.23 (td, J=13, 4.2 Hz, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 1.04 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.5, 155.8, 144.7, 133.2, 132.3, 129.5, 128.3 (2C), 127.6 (2C), 124.9, 122.0, 101.9, 96.9, 84.5, 64.2, 56.2, 55.4, 55.3, 55.1, 46.1, 38.1, 38.0, 37.9, 36.5, 29.5, 28.1, 23.0, 20.3, 19.0, 16.2, 16.1. ESIMS [M+Na]+ calcd for C33H41O5F3Na 597.2804, found 597.2814. [α]24D=−31.76°.
Reaction SMILES: [CH2:1]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:24]1[CH2:29][CH2:28][CH2:27][C:26]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)([CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)[CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[OH2:23].[ClH:44].[C:16]([N:24]1[CH2:29][CH2:28][CH2:27][C:26]([CH2:30][CH2:31][CH2:32][N:11]2[CH2:10][CH2:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]#[N:15])[CH2:13][CH2:12]2)([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:25]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: N#CC1(Cc2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Product: O
Yield: 83.8 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 4, starting from 2.5 g of 4-benzyl-4-cyanopiperidine, 5 g of the compound obtained in step B of EXAMPLE 1, 3.7 g of K2CO3 and 50 ml of DMF. The product obtained is chromatographed on silica H using DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum to give 2.8 g of the expected product after crystallization from iso ether.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)(C)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>O>[Cl:11][C:10]1[C:3]2[C:2]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: Clc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
The product from Method I (57 mg, 0.3 mmol) was suspended in 3:0 mL of tert-butanol and to this solution was added piperidine (90 μL, 0.9 mmol) and the resulting system heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and water was added (4.0 mL). The solution was adjusted to pH 1 with 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. The solution was then extracted 2×15 mL with dichloromethane and the combined organics washed with water then brine and dried over MgSO4. Evaporation of solvent afforded 45 mg of a yellow solid that was purified by silica-gel chromatography (3:1 ethyl acetate/hexanes) to yield 23 mg (32%) of the title compound as a light yellow solid. Mp 170-172° C. 1H NMR (400 MHz, CDCl3)δ: 1.67-1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1H), 8.31 (s, 1H), LRMS: 237 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=[O:18])[N:6]([CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].O=P(Cl)(Cl)Cl.[CH3:26]N(C=O)C>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3[NH:1][N:2]=[CH:26][C:4]=3[C:5](=[O:20])[N:6]([CH3:19])[C:7]2=[O:18])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn[nH]c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (4.0 g, 14.5 mmol) in anhydrous DMF (200 mL) is added POCl3 (16 mL) dropwise with IPA-dry ice bath cooling. After the completion of the addition, the mixture is allowed to warm up to room temperature and stirred at r.t. overnight. DMF is removed under reduced pressure, and the residue is treated with cold water very carefully. The generated precipitate is filtered, washed with water to give pure product as white solids (3.74 g, yield: 90%). MS (ESI) m/z 287.1 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.[CH3:25]CN(CC)CC>C1COCC1>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:12]1[CH3:25]
Reactant: ClCc1nc2ccccc2o1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixture of N—BOC-piperazine (2.22 g, 11.93 mmol) and 2-chloromethylbenzoxazole (2 g, 11.93 mmol) in anhydrous THF (20 ml) was added Et3N (2.5 ml, 17.9 mmol) and the resulting mixture stirred at RT overnight. Partitioned between water and EtOAc, organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100% Hexanes (190 ml), gradient rising from 100% Hexanes to 50% EtOAc in Hexanes (900 ml), then 50% EtOAc in Hexanes (500 ml) to give 2.63 g (69%) of the title compound as a light pink solid. 1H NMR (CDCl3): 1.45 (s, 9H), 2.58 (m, 4H), 3.49 (m, 4H), 3.89 (s, 2H), 7.33 (m, 2H), 7.53 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+].Cl>O.CO>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a mixture of 4-[(2-phenyl-4-thiazolyl)methoxy]benzaldehyde (6.35 g), tetrahydrofuran (30 ml) and methanol (20 mL) was added sodium borohydride (0.45 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Dilute hydrochloric acid and water were added to acidify the reaction mixture. The precipitated solid was collected by filtration, and dried with air to give crystals (5.76 g, 90%) of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 145-146° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][C:3]=1[CH3:15].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:18]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][C:3]=1[CH3:15])[CH:17]=[CH2:16]
Reactant: Cc1cc(C2OCCCO2)cc(C)c1Br
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1c(C)cc(C2OCCCO2)cc1C
Temperature: 40 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The corresponding Grignard-reagent is prepared form 2-(4-bromo-3,5-dimethyl-phenyl)-[1,3]dioxane (2.5 g, 9.22 mmol) and Mg (258 mg, 10.6 mmol) in THF (50 mL). To this reagent allylbromide (1.23 g, 10.14 mmol) is added dropwise at rt. The reaction mixture becomes warm (40° C.) and it is stirred for 16 h. The reaction is quenched by adding water. The mixture is extracted with EA. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 10:1 to give 2-(4-allyl-3,5-dimethyl-phenyl)-[1,3]dioxane (1.8 g) as a colourless oil; LC-MS: tR=1.02 min, [M+1]+=233.22, 1H NMR (CDCl3): δ 7.12 (s, 2H), 5.94-5.80 (m, 1H), 5.44 s, 1H), 4.95 (dd, J=1.8, 10.0 Hz, 1H), 4.80 (dd, J=1.8, 17.0 Hz, 1H), 4.30-4.21 (m, 2H), 4.04-3.92 (m, 2H), 3.40-3.34 (m, 2H), 2.32-2.26 (m, 8H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1cccs1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccs1
Yield: 55 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (113 mg) with 2-thiophenecarbonyl chloride (50 uL) provided 74 mg (55%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure. Rf=0.46 (EtOAc). LSIMS=456; (mass calculated for C26H37N3O2S=455.60).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH:11]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22](OCC)=[O:23])[CH2:10]3)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[C:4]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:13]3[C:12]4[NH:37][C:22](=[O:23])[C:18]5[N:17]([CH:21]=[CH:20][N:19]=5)[C:11]=4[CH2:10][C:9]=3[CH:8]=2)[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: CCOC(=O)c1nccn1C1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Yield: 66.1 %

Procedure:
8-Phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: a mixture of 17 g of ethyl 1-(5-phthalimidomethyl-1oxoindan-2yl)imidazole-2-carboxylate and 153 g of ammonium acetate in 355 ml of glacial acetic acid is heated at reflux for 16 hours. The reaction mixture is cooled to a temperature in the region of 20° C. The precipitate is filtered on sintered glass, rinsed with distilled water to neutral pH and then washed with acetone. After drying under vacuum (1 mbar) at 80° C., 10 g of 8-phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a brown solid (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm: 4.00 (2H, s, CH2), 4.83 (2H, s, NCH2), 7.47 (1H, d, J=7 Hz, arom. CH), 7.55 (2H, d, J=7 Hz, arom. CH), 7.80 (1H, d,J=7 Hz, arom. CH), between 7.85 and 8.00 (4H, m, phthal. H), 12.30 (1H, broad s, NH)).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22]([Br:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[Br:31][CH2:22][C:23]1[CH:3]=[CH:2][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/c3ccccc3)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with cinnamyl bromide in the presence of potassium carbonate in acetone there was obtained tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(3-phenyl-allyloxy)-phenyl]-piperidine-1-carboxylate, alkylation of which analogously to Example 1 (g) with 2-bromomethyl-naphthalene yielded tert-butyl (E)-(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-phenyl-allyloxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 550 (M+H)+.
Reaction SMILES: O=C1N(C)C(=O)N(C)[CH:4]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[OH:21])N1C.[OH-:23].[Na+]>O>[OH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH:4]=[O:23]
Reactant: [OH-]
Reactant: CN1C(=O)N(C)C(c2c(O)ccc3ccccc23)N(C)C1=O
Agent: [Na+]
Solvent: O
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
29.7 g (0.1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-(2-hydroxy-naphthyl)-s-triazine and 20 g (0.5 mol) of sodium hydroxide in 50 ml of water are stirred for 8 hours at 95° C. The solution is then acidified and 2-hydroxy-naphthaldehyde of melting point 82° C is obtained.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)(=[O:17])=[O:16].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1.[F-].[K+]>C(#N)C>[Cl:23][C:24]1[N:29]=[C:28]([N:20]2[CH2:21][CH2:22][C@H:18]([S:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])(=[O:16])=[O:17])[CH2:19]2)[CH:27]=[CH:26][N:25]=1
Reactant: O=S(=O)(c1ccccc1Cl)[C@H]1CCNC1
Reactant: Clc1ccnc(Cl)n1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1Cl)[C@H]1CCN(c2ccnc(Cl)n2)C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
(S)-3-(2-Chloro-benzenesulfonyl)-pyrrolidine TFA salt (250 mg) was dissolved in ACN (3.0 mL). 2,4-Dichloropyrimidine (155 mg), TEA (0.39 mL) and KF (4 mg) were added to the solution. The reaction mixture was stirred at 150° C. in the microwave oven for 2 h. The reaction mixture was evaporated to dryness and purified with preparative HPLC to yield 2-Chloro-4-[(S)-3-(2-chloro-benzenesulfonyl)-pyrrolidin-1-yl]-pyrimidine (91 mg, 36%) as a light yellow solid. MS: m/z=358.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:26]([N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:43]([OH:45])=O)[C:34]1=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(#N)C.C(N(CC)CC)C>[CH2:26]([N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:43]([N:3]([CH3:4])[CH3:2])=[O:45])[C:34]1=[O:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
Dimethylamine hydrochloride (0.57 g), WSC (1.33 g) and HOBt (0.86 g) were added to a mixed solution of 4-benzyl-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid (1.5 g) in THF (30 ml) and acetonitrile (30 ml), to which was added dropwise triethylamine (2.3 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. The precipitated insoluble substances were removed by filtration and the filtrate was concentrated. Water was added to the precipitate, which was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.47 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12]C(O)=O)[CH3:9].C([O-])(=O)C.[NH4+:21]>C(O)(C)C>[NH2:21][CH:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:16]
Reactant: O=Cc1ccoc1
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCOC(=O)CC(N)c1ccoc1
Reaction time: 5 h

Procedure:
A suspension of 3-furancarboxaldehyde (8.6 ml), malonic acid monoethyl ester (15.8 g) and ammonium acetate (9.6 g) in isopropyl alcohol (200 ml) was heated to reflux under nitrogen. After 5 hours, the excess solvent was removed under reduced pressure and the semi-solid was treated with H2O (250 ml) and acidified to pH 2 using 12N HCl. The aqueous layer was washed with CH2Cl2 (2×100 ml). The aqueous layer was neutralized to pH>9 with K2CO3. The product was extracted with CH2Cl2 (2×100 ml). The organic layer was dried over Na2SO4 and the excess solvent was removed under reduced pressure to give ethyl β-aminofuran-3-propanoate (5 g) as a golden oil. The MS and 1H-NMR were consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7]O.[Br:9]P(Br)Br>ClCCl>[BrH:9].[Br:9][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1ncsc1CO
Solvent: ClCCl
Product: Br
Product: Cc1ncsc1CBr
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (4-methyl-1,3-thiazol-5-yl)methanol (2.5 g, 19.4 mmol) in anhydrous dichloromethane (100 mL) was added dropwise tribromophosphane (2.00 mL, 21.3 mmol). The mixture was stirred at room temperature for 3.5 hours. Dichloromethane was evaporated, and the residue was then dried in vacuo, affording 5-(bromomethyl)-4-methyl-1,3-thiazole hydrobromide. The product was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=2)[N:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH:18]([O:17][CH:11]([CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][S:32]([C:30]2[S:31][C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)=[CH:28][CH:29]=2)(=[O:33])=[O:34])[CH:3]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(O)c1)OC(C)C
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1OS(=O)(=O)c1ccc(-c2csc(C)n2)s1
Reaction time: 8 h
Yield: 21.9 %

Procedure:
15 mg of Ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-isopropoxypropanoate and 25 mg of 5-(2-methyl-1,3-thiazol-4-yl)-2-thiophenesulfonyl chloride were dissolved in 0.4 ml of dichloromethane, and 50 μl of triethylamine was added, and the mixture was kept still at room temperature overnight. To the reaction mixture was added ethyl acetate and the mixture was washed with water. The solvent was concentrated, and the residue was treated with 0.4 ml of ethanol and 0.1 ml of 5N-sodium hydroxide, and the mixture was kept still at room temperature for 30 minutes. The reaction mixture was neutralized with 1N-hydrochloric acid, extracted with ethyl acetate. The solvent was distilled off, and the residue was purified by reverse-phase high performance liquid chromatography, to give 5.8 mg of the title compound.