Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:36]([Si:40]([CH3:43])([CH3:42])Cl)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:23][Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:43])[CH3:42])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccccc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6.35 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoic acid in 90 ml of DMF is treated, while being stirred, with 8 g of imidazole and 10 g of t-butyldimethylchlorosilane. After having been stirred at RT for 18 h, the yellow, clear solution is poured onto ice-water, and this mixture is extracted three times with 250 ml of ethyl acetate on each occasion. The combined extracts are washed, in succession, three times with 10% citric acid, once with water, three times with aqueous, saturated sodium bicarbonate solution, once with water and, finally, with saline. After drying over sodium sulfate, the solvent is evaporated and the resulting tert-butyl dimethylsilyl ether (13.5 g) is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After having been stirred at RT for 3 h, the mixture is poured onto water, and this mixture is extracted three times with ether. The collected ether extracts are washed twice with water and once with saline and dried over sodium sulfate. After concentrating, the crude product is purified by column chromatography (SiO2, hexane/ethyl acetate: 3.5/1.5), and the title compound is obtained. TLC Rf (D)=0.37; FAB-MS (M+H)+ =528.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[NH:8][C:9](=[O:19])[C:10]([OH:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOCC>[CH2:26]([O:18][C:10]1[C:9](=[O:19])[N:8]2[C:7]([CH2:6][S:5][CH2:4][CH2:3][CH2:2]2)=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1nc(CSCCCCl)[nH]c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 2-((3-chloropropylthio)methyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (5 g, 16 mmol) and K2CO3 (4.5 g, 32.5 mmol) in DMF (150 mL) was placed in preheated oil bath and stirred for 1.5 h. After this, benzylbromide (2.4 mL, 20 mmol) was added and continued stirring for additional 3 h. Then, the reaction mixture was cooled, diluted with ether (250 mL0, washed with water (3×50 mL). The combine aq. layers extracted with ether (4×100 mL) and combined with previous organic phase, and washed with brine (50 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give viscous paste. Crystalization of this paste from CH2Cl2/hexanes provided the product as a white solid (4.4 g, 75%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.36-4.31 (4H, m), 3.89 (2H, s), 2.94 (2H, t, J=5.6 Hz), 2.16-2.12 (2H, m), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C18H21N2O4S: 361.1222; found: 361.1221.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH:24]=[C:25]([CH3:34])[CH2:26][CH:27]([OH:33])[CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:34][C:25]1[CH2:26][CH:27]([CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])[O:33][CH2:22][CH2:23][CH:24]=1
Reactant: C=C(C)C=CC(O)CC(C)=CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=C(C)C=CC1CC(C)=CCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To an ice-cool solution of the diol prepared according to g) (2.0 g, 10.2 mmole) in pyridine (22 ml) was added p-toluenesulfonyl chloride (2.13 g, 11.2 mmole) in small portions and over 30 min. The mixture was stirred at 0° for 30 min and then stored overnight at 3°. The usual extraction with ether and treatment of the organic phase gave 2.85 g of a crude product which, on thin layer chromatographic analysis, showed two components. The further purification of this product by MPLC [LOBAR® column (origin: Merck), mixture of hexane-ethyl acetate as elution agent] gave 2.20 g (yield: 61.6%) of the desired product, i.e. 6-hydroxy-4,9-dimethyl-3,7,9-decatrienyl p-toluenesulfonate, and 220 mg of an unidentified by-product. A suspension of sodium hydride (ca. 80%, 630 mg, ca. 21 mmole; previously washed with anhydrous pentane) in monoglyme (30 ml, freshly distilled from LiAlH4) was prepared under argon and cooled to 0°. 900 μl (7.48 mmole) of DMPU (N,N'-dimethyl-N,N'-propylen urea) were added to the suspension and, afterwards, dropwise, a solution of the abovementioned p-toluenesulfonate (2.20 g, 6.28 mmole) in monoglyme (30 ml). The mixture was allowed to warm to room temperature and was stirred overnight. It was then extracted with ether and the organic phase was washed to neutrality, dried and concentrated as usual. 1.14 g of the crude oxepin were thus obtained. This product was further purified by MPLC [LOBAR® column (origin: Merck), 95:5 mixture of hexane-ether as elution agent] and then by bulb-to-bulb distillation. 450 mg of pure (E)-2,3,6,7-tetrahydro-4-methyl-2-(3-methyl-1,3-butadienyl) oxepin were obtained.
Reaction SMILES: [F:1][C@@:2]1([CH2:15][OH:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([Cl:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>CN(C=O)C.C(Cl)Cl>[Cl:30][C:28]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([O:16][CH2:15][C@:2]2([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)[N:29]=1
Reactant: Clc1cc2ncccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COc2nc(Cl)cc3ncccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To an ice cooled solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (1.406 g, 6.03 mmol) in DMF (20 ml) was added sodium hydride (0.313 g, 7.84 mmol) (60% dispersion in mineral oil). This was stirred for 15 min before adding 5,7-dichloro-1,6-naphthyridine (1.2 g, 6.03 mmol). This was warmed to room temp and stirred for 4 h. The reaction had gone to completion and so was cautiously quenched with aqueous ammonium chloride before partitioning between aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and concentrated in vacuo to give the crude product. This was dissolved in DCM and purified through silica (50 g), eluting with a gradient of 0-50% ethyl acetate in DCM. Appropriate fractions were concentrated in vacuo to yield the title compound as a cream foamy gum (1.91 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: CN(C)CCN
Reactant: O=C1Nc2cc(F)ccc2Nc2ccccc21
Product: CN(C)CCNC1=Nc2cc(F)ccc2Nc2ccccc21
Yield: 36.9 %

Procedure:
8-Fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (160FE15C) (23 mg, 0.1 mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) were reacted according to GP4 to give 11 mg of the title compound (160FE20D). MS (ESI) 299 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([OH:37])[CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[C:21]([CH3:35])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[OH:37][CH:4]([CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:9]=[CH:10][C:11]([CH:14]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)=[C:21]([CH3:35])[CH:20]=2)[CH:15]([CH3:16])[CH3:17])=[CH:12][CH:13]=1)[C:3]([OH:38])=[O:2]
Reactant: COC(=O)C(O)CNC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(c2ccc(C(=O)NCC(O)C(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(C)C)cc1
Reaction time: 4 h
Yield: 63.7 %

Procedure:
To the solution of isomer 1 of 2-Hydroxy-3-{4-[1-(4′-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic acid methyl ester (150 mg) in methanol (10 mL) is added sodium hydroxide (5 N aqueous, 1 mL) and stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (1 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (93 mg) as a white solid. MS (ES): 504.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[C:13](=O)[NH:14][N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:13]1[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]([CH3:18])[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:12]=12
Reactant: COc1ccc(Cn2c(C)cc3cn[nH]c(=O)c32)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(C)cc3cnnc(Cl)c32)cc1
Yield: 76 %

Procedure:
17.8 g (66 mmol) of 1-(4-methoxybenzyl)-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one are reacted at 100° C. for 2 h in 130 ml of phosphorus oxychloride. Purification: chromatography on silica gel (eluent: ethyl acetate). Yield: 76%. M.p.: 126°-128° C.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>CN(C)C=O>[CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([O:19][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1Cc1ccccc1

Procedure:
2.5 Grams of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 0.48 g of 50% oily NaH are mixed with 30 ml of dimethyl formamide and stirred, then 4 g of 1-chloro-3-(4-phenylpiperazinyl)propane are added thereinto and warmed to 50°-60° C. for 2.5 hours. The reaction mixture is concentrated under a reduced pressure and the residue thus obtained is extracted with chloroform. After removing the chloroform by distillation, the thus obtained residue is recrystallized from ligroin to obtain 2.1 g of 1-benzyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[C:28]([O:35]CC5C=CC=CC=5)[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:11]([F:45])[C:10]=2[F:46])=[CH:6][C:5]=1[O:49]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:10]([F:46])=[C:11]([F:45])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([OH:35])[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:49]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 168 h

Procedure:
72 g of 4,4'-Bis(4-nitro-3-benzyloxyphenoxy)octafluorobiphenyl prepared as described in Example 1 (0.09 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 7 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 7 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 96%0).
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][OH:10])[C:7](=[O:11])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:1]=[C:2]1[C:8](=[CH:9][O:10][S:34]([CH3:33])(=[O:36])=[O:35])[C:7](=[O:11])[N:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=CO)C2=O)C(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COS(C)(=O)=O)C2=O)C(C)C)cc1

Procedure:
A solution of 2-[2,4-dioxo-3-(hydroxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (−12r, 0.500 g) in CH2Cl2 (10 mL) under argon was treated with methanesulfonyl chloride (0.266 mL) and diisopropylethylamine (0.598 mL). After several minutes, the reaction was transferred to a separatory funnel and washed with aqueous 1N NaHSO4. The aqueous layer was back-extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 2:3 ethyl acetate/hexane. Fractions containing the product were combined, evaporated in vacuo and triturated with hexane. Hexane was removed in vacuo and the residual solid was dried under high vacuum to provide 2-[2,4-dioxo-3-(methanesulfonyloxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (12s, 0.502 g) as a solid. The product was contaminated with approximately 40% of 2-[2,4-dioxo-3-methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide which reacted equally well in the subsequent steps. 1H NMR (300 MHz, CDCl3) 1.10 (d, J=7 Hz, 6H), 3.15 (s, 3H), 3.89 (s, 3H), 3.96 (d, J=2 Hz, 2H), 4.92 (m, 4H), 6.03 (m, 2H), 7.00 (m, 2H), 7.18 (m, 2H), 7.40 (m, 5H).
Reaction SMILES: [Cl-].Cl[C:3]1[NH:4]S[SH+:6][C:7]=1Cl.[CH3:9][O:10][C:11](=[O:16])/[CH:12]=[C:13](\[NH2:15])/[CH3:14].N1C=CC=CC=1>ClCCl>[C:3]([C:7]1[S:6][N:15]=[C:13]([CH3:14])[C:12]=1[C:11]([O:10][CH3:9])=[O:16])#[N:4]
Reactant: COC(=O)/C=C(/C)N
Reactant: ClC1=C(Cl)[SH+]SN1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C)nsc1C#N
Yield: 15.6 %

Procedure:
4,5-Dichloro-[1,2,3]-dithiazol-1-ylium chloride (prepared according to Chem. Ber. (1985) 118, 1632) (8.34 g, 40 mmol) was dissolved in dichloromethane (30 ml) and methyl-3-aminocrotonate (4.6 g, 40 mmol) was added dropwise at room temperature. After stirring the solution for 1 hour at room temperature pyridine (6.47 ml, 80 mmol) was added slowly. The mixture was concentrated and purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as an orange solid (1.14 g, 15.6% yield). 1H-NMR (400 MHz, CDCl3): 2.88 (3H, s, Me), 4.0 (3H, s, Me).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].O>CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
0.70 g (0.98 mmol) of 2-butyl-4-chloro-1-{[2-[2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]quinolin-6-yl]methyl}-1H-imidazole-5-carbaldehyde obtained in Example 8 was suspended in 12 ml of methanol. 12 ml of concentrated hydrochloric acid was added thereto while in an iced water bath followed by stirring at room temperature for 24 hours. The reaction mixture was iced and alkalized with a 10N sodium hydroxide solution. After adding 10 ml of water thereto, the mixture was filter and the filtered cake was washed with 10 ml of a 1N sodium hydroxide solution. The filtrate was acidified by adding concentrated hydrochloric acid dropwise thereto and extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 0.102 g of 2-butyl-4-chloro-1-{[2-[2-(1H-tetrazol-5-yl)phenyl]-quinolin-6-yl]methyl}-1H-imidazole-5 -carbaldehyde.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15](OS(C)(=O)=O)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Si](C)(C)C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1Cl>[C:1]([N:9]1[CH2:16][C@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1ccccc1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1

Procedure:
A suspension of powdered (cis)-1-benzoyl-4-mesyloxy-L-proline (250 mg, 0.8 mmole) in 1,2-dichlorobenzene (3 ml) was stirred under argon and treated with phenyltrimethylsilane (1 ml, 5.8 mmole) followed by aluminum trichloride (383 mg, 2.87 mmole). The reaction was stirred overnight and an aliquot was removed, quenched into 1N HCl and extracted with ethyl acetate. Analysis of the organic layer by tlc showed the presence of:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH2:20].CO.Cl>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[N:20]([CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Agent: Cl
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(=O)O
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (20.0 g, 81.2 mmol) and a solution of 2M MeNH2 in methanol (162.5 mL, 325 mmol) was stirred at RT for 16 h. Volatiles were removed under reduced vacuum, and the residue was dissolved in 70 mL of de-ionized water. To the ice-cold mixture was added a 6N HCl solution (13.5 mL, 81.0 mmol) dropwise. The precipitated solid was collected via filtration, and washed with water and acetone to give the title compound as a light yellow solid (18.9 g, 90% yield). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.82 (s, 1H), 7.45-7.33 (m, 5H), 6.72 (s, 1H), 5.05 (s, 2H) and 3.84 (s, 3H); MS-ESI (m/z): 259.8 [M+1]+, 91.2.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:4]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccccc2sc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2sc1=O
Yield: 65.1 %

Procedure:
A mixture of 4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (105 mg, 0.44 mmol) and sodium glycinate (215 mg, 2.22 mmol) in 2-methoxyethanol (13 mL) was refluxed for 5 h. The reaction mixture was concentrated, and the crude residue dissolved in water (50 mL) and acidified to pH 3-4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide [(4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (80 mg). MS ESI(−) m/e: 278.10 (M−1).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCc1c(C)nc2cc(C)nn2c1O
Product: CCCCCCCCc1c(C)nc2cc(C)nn2c1Cl

Procedure:
190 g of the condensate obtained from (a), in 550 ml of phosphorus oxytrichloride, are refluxed for 1.5 hours, after which the excess phosphorus oxytrichloride is evaporated under reduced pressure and the residue is stirred with 500 ml of CH2Cl2 and 500 ml of ice water. The organic phase is separated off, washed with three times 100 ml of ice water, dried over sodium sulfate and filtered, the solvent is evaporated under reduced pressure, and 179 g of 7-chloro-2,5-dimethyl-6-n-octylpyrazolo-[1,5-a]pyrimidine are isolated as a viscous mass.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)CCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(dimethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and 2-chloro-N,N-dimethylethylamine hydrochloride following General Procedure H.