Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:15]([CH2:16][CH2:17]/[C:18]/2=[CH:19]/[CH3:20])[C@H:14]2[C@H:5]1[C@:6]1([CH3:25])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:24])[CH2:8][CH2:7]1)[CH3:3]>C(O)C.[Pd]>[CH3:1][N:2]([C@@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:15]([CH2:16][CH2:17][C@@H:18]2[CH2:19][CH3:20])[C@H:14]2[C@H:5]1[C@:6]1([CH3:25])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:24])[CH2:8][CH2:7]1)[CH3:3]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N(C)C)C[C@]12C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N(C)C)C[C@]12C
Reaction time: 1.67 h
Yield: 77.7 %

Procedure:
(Z)-11α-N,N-Dimethylamino-5α-pregn-17(20)-en-3α-ol (750 mg) in ethanol (25 ml) containing 10% Pd-C (511 mg) was stirred under hydrogen for 100 min. The catalyst was removed by filtration through Kieselguhr and the solvent evaporated in vacuo. Purification of the residue by filtration through a plug of silica in ethyl acetate-petroleum ether (2:1) and crystallisation from aqueous methanol gave the title compound (586 mg) m.p. 147°-150°, [α]D -15.0°
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)c1ccc(F)cc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 45.3 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (3.0 g), 1-[5-fluoro-2-(methylsulfonyl)phenyl]methanamine hydrochloride (3.67 g) and potassium carbonate (5.29 g) were stirred in ethanol (50 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained yellow solid was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (5 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.14 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[NH4+]>CN(C)C=O>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: OCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(COCc2ccc(Br)cc2)cc1
Yield: 64.9 %

Procedure:
To a solution of 812 mg (20.3 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (100 ml) was added 3.01 g (16.1 mmol) of 4-bromobenzyl alcohol in the atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. followed by addition of 2.85 g (13.2 mmol) of 4-nitrobenzyl bromide. The mixture was reacted at room temperature for 17 hours. To the reaction mixture at 0° C. was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:1) yielded 2.76 g (8.57 mmol) of 4-bromobenzyl 4-nitrobenzyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:19](N)=[NH:20].C(N)=O.[OH-].[Na+]>C(O)C>[C:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:19][NH:20][C:4]2=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(=O)O)c1N
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cccc2c(=O)[nH]cnc12
Temperature: 160 °C
Reaction time: 12 h

Procedure:
Procedure analogous to M. Berg et al., Chem. Med. Chem. 2009, 4, 2, 249: a mixture of 19.3 g (100 mmol) of 2-amino-3-tert-butylbenzoic acid [917874-35-2], 31.4 g (300 mmol) of formamidine acetate [3473-63-0] and 4.4 ml (110 mmol) of formamide is stirred at 160° C. for 12 h. After cooling to 60° C., a mixture of 200 ml of ethanol and 200 ml of 2 N sodium hydroxide solution is added dropwise, the mixture is filtered through a P4 frit covered with sea sand in order to remove polymeric material and then rendered neutral by addition of 2 N hydrochloric acid. After stirring for 12 h, the crystals formed are filtered off with suction and washed three times with 100 ml of water each time. Yield: 13.9 g (68 mmol), 68%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Br:8])[C@H:3]1[C:9]([OH:11])=[O:10].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Br:8])[C@H:3]1[C:9]([O:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:10]
Reactant: CC1(C)[C@H](C=C=CBr)[C@H]1C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C=C=CBr)[C@H]1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Using the procudure of Example 1, 1.2 g of the acid of Example 29 and 1 g of 3-phenoxy-benzyl alcohol were reacted to obtain after chromatography over silica gel and elution with a 9-1 hexane-ethyl acetate mixture 1.49 g of 3-phenoxybenzyl (1R,trans) 2,2-dimethyl-3-(3-bromo-1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+15.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[O:9][C:10]1[CH:36]=[CH:35][C:13]([CH2:14][N:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[C:17]([CH3:27])=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[CH2:28]([N:15]([CH2:14][C:13]1[CH:35]=[CH:36][C:10]([O:9][C:8]2[CH:7]=[C:6]([CH:39]=[CH:38][CH:37]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])=[CH:11][CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:17]=1[CH3:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 70C (0.028 g, 0.0514 mmoles) in CH2Cl2 (1 mL) was treated with acetic anhydride (0.0060 mL, 0.0617 mmoles) and stirred overnight at room temperature. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 10 H), 6.96 (d, 1 H), 6.89 (d, 2 H), 6.60 (m, 2 H), 6.44 (t, 1 H), 6.29 (s, 1 H), 5.85 (br.s, 1 H), 4.09 (s, 2 H), 4.06 (s, 2 H), 3.98 (t, 2 H), 3.44 (dd, 2 H), 2.91 (s, 3 H), 2.31 (s, 3 H), 1.98 (s, 3 H), 1.90-2.10 (m, 2 H); MS (ESI+) mn/z 588 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Oc2ccc(Br)c(C=O)c2)cc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a mixture of 6-chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (4.8 g, 16.62 mmol) and 2-bromo-5-hydroxy-benzaldehyde (4.01 g, 19.94 mmol) in DMF (30 mL) was added potassium carbonate (3.44 g, 24.93 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure and the residue was diluted with EtOAc (200 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 2-25% EtOAc/hexanes as gradient elution yielding the title compound (4.8 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 8.46 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.09 (s, 1H), 4.75-4.67 (m, 1H), 4.49-4.45 (m, 2H), 4.00-3.89 (m, 1H), 3.85-3.74 (m, 2H), 3.49-3.41 (m, 1H), 1.78-1.53 (m, 2H), 1.39-1.53 (m, 4H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].S(=O)(=O)(O)O.[CH2:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1)[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:6][C:14]1([CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCC1=CCCCC1
Reactant: C=C(C)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(CC)CCCCC1
Temperature: 30 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 43.0 g (0.5 mol) of methacrylic acid, 0.5 g (5 mmol) of sulfuric acid and 100 g of toluene. Separately 110.2 g (1.0 mol) of 1-ethylcyclohexene, prepared by the same procedures as described in Reference Example 3, was dissolved in 100 g of toluene. The obtained solution of 1-ethylcyclohexene in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 30° C. Then the content was stirred for 15 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 68.6 g (yield: 69.9%) of the object 1-ethylcyclohexyl methacrylate was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:21][N:22]=[C:23]=[S:24].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:21][NH:22][C:23](=[S:24])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: CN=C=S
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CNC(=S)C(c1ccccc1)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-Benzylpyridine (6.1 g.) dissolved in 25 ml. of dry benzene is added dropwise to 20 ml. of 2M phenyl lithium in benzene/ether with cooling. The mixture is stirred for 30 minutes, then 2.6 g. of methyl isothiocyanate, dissolved in 40 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% aqueous hydrochloric acid. The phases are separated, the organic phase is washed with water and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from isopropyl ether/ethanol to give N-methyl-2-phenyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[F-].[K+].[CH3:39][O:40][CH2:41][CH2:42][OH:43]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5]3=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[C:10]3[C:2]([O:43][CH2:42][CH2:41][O:40][CH3:39])=[N:3]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Reactant: COCCO
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1nn(Cc2ccc(OC)cc2)c2ncc([N+](=O)[O-])cc12
Yield: 23 %

Procedure:
3-Iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (2.0 g, 4.88 mmol), 1,10-phenanthroline (0.879 g, 4.88 mmol), copper (I) iodide (0.929 g, 4.88 mmol), potassium fluoride (4.96 g, 34.1 mmol), and 2-methoxyethanol (11.1 g, 146 mmol) were suspended in toluene (65 mL) and stirred at reflux for 20 hours. The mixture was cooled, diluted with EtOAc, filtered through a plug of silica, and concentrated. The crude product was purified via column chromatography eluting with 6:4 EtOAc-hexanes to afford 1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-5-nitro-1H-pyrazolo[3,4-b]pyridine (400 mg, 1.12 mmol, 22.9%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:20][O:21][NH2:22]>C(O)C>[CH3:20][O:21][N:22]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]1
Reactant: CON
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1F
Solvent: CCO
Product: CCOC(=O)c1cn(OC)c2ccccc2c1=O
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Ethyl 3-ethoxy-2-(2-fluorobenzoyl)-2-propenoate (4.0 g, prepared from ethyl 3-(2-fluorophenyl)-3-oxopropanoate as in Preparation No. 59) and O-methylhydroxylamine (16 mmol, prepared by mixing 1 eq of sodium ethoxide with 1 eq of O-methylhydroxylamine hydrochloride in ethanol) are stirred in ethanol (20 mL) for 1 hour at rt. The mixture is concentrated, diluted with dioxane (75 mL) and re-concentrated to remove any remaining ethanol. The resulting enamine is diluted in dioxane (70 mL) and sodium hydride (60% dispersion, 0.64 g) is added. The mixture is heated to reflux for 2.5 hours, cooled to rt and concentrated in vacuo. The remaining residue is partially dissolved in ethanol (100 mL) and filtered. The filtrate is concentrated in vacuo and chromatographed (7% MeOH/CH2Cl2). The combined fractions are concentrated, leaving a residue which is recrystallized in a 1:1 ether/hexanes mixture to afford 0.95 g of ethyl 1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (Mp 120-121° C.) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([CH3:19])=[CH:8][CH2:9][CH2:10]/[C:11](/[CH3:18])=[CH:12]/[CH:13]=[CH:14]/[C:15]([CH3:17])=[O:16]>C(O)(=O)C>[CH3:18][C:11]1[CH2:10][CH2:9][CH2:8][C:7]([CH3:19])([CH3:6])[C:12]=1/[CH:13]=[CH:14]/[C:15]([CH3:17])=[O:16]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 0.12 h
Yield: 51 %

Procedure:
The cyclizing agent [35 g of conc. sulfuric acid (95%) and 15 g of glacial acetic acid] was placed in a 250 ml three-necked flask with a mechanical stirrer, a dropping funnel, and a thermometer reaching into the reaction mixture. The flask was cooled in an ice bath and the cyclizing agent was vigorously stirred while pseudoionone (10 g ) was added dropwise during 15-20 minutes; the rate of addition was adjusted so that the temperature of the reaction mixture did not exceed 10° C. After addition, the cooling bath was removed and stirring was continued at 10°-15° C. for 5-10 minutes. The reaction mixture was poured into a mixture of ice and water (200 g) and ether (100 ml) with vigorous stirring. The water layer was again extracted with ether and the combined ether extracts were washed with water, sodium carbonate solution (1%), then to neutral with water and dried over anhydrous magnesium sulphate. After the removal of ether, the residue was distilled under reduced pressure. β-Ionone (5.1 g) was obtained as a pleasant smelling light yellow colored liquid; boiling point 73° C./0.25 mm; nD25 1.5164.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: Clc1nc(Cl)c2cscc2n1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1nc(Cl)nc2cscc12
Yield: 97.8 %

Procedure:
45 g (0.22 moles) of 2,4-dichloro-thieno[3,4-d]pyrimidine are suspended in 1800 ml of absolute ethyl alcohol. To the cooled mixture 28.5 g (0.48 moles) of isopropylamine are added drop by drop whilst agitating vigorously and maintaining the temperature at between 0° and 5°C. A clear solution is obtained which is agitated for a further hour at ambient temperature. The solution is concentrated, making sure that the temperature of the bath does not exceed 30°C. The syrupy residue is poured into iced water whilst agitating well. A yellow solid is formed which is drained off, washed with water and dried. 49 g of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine are obtained with a yield reaching 98% of theory. M.P. : 189°-191°C.
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH:8]([C:11]1[CH:16]=[C:15]([S:17][C:18]#[N:19])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[OH:23])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH:8]([C:11]1[CH:16]=[C:15]([S:17][C:18]#[N:19])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[O:23][S:3](=[O:4])(=[O:5])[NH2:2])([CH3:10])[CH3:9]
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(SC#N)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-Chlorosulfonyl isocyanate (1.02 mL, 11.7 mmol) was added to a warm solution of 2,6-diisopropyl-4-thiocyanato-phenol (2.5 g, 10.6 mmol) in 150 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight. The reaction was concentrated in vacuo and the residue was quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1.75 g of sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([OH:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40]([O:47][C:48](=[O:51])[CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([O:27][CH2:49][C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:51])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccccc2n1
Reaction time: 16 h

Procedure:
To a solution of 6.5 g of (S)-2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester 50 ml of DMF, 6.5 g of cesium carbonate and 4.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step. Yield: 8.9 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:21][CH2:20][CH2:19][C:12]3([S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[C:10]=2[CH:11]=1>>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]2[O:21][CH2:20][CH2:19][C:12]3([S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[C:10]=2[CH:11]=1
Reactant: O=C1NC(=O)C2(CCOc3ccc(F)cc32)S1
Reactant: O=[N+]([O-])O
Product: O=C1NC(=O)C2(CCOc3c([N+](=O)[O-])cc(F)cc32)S1
Temperature: 0 °C

Procedure:
Into 2.5 ml of fuming nitric acid (96%, d 1.50), which had been cooled to -20° C. while stirring, there was introduced rapidly 500 mg of (±)-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione so that the temperature did not exceed -15° C. After stirring at -20° C. for 3 minutes, there was obtained a clear solution which was then poured immediately on to 15 ml of ice-water. After stirring briefly, the resulting precipitate was filtered, washed with cold water and dried. There was obtained (±)-6-fluoro-8-nitro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione in the form of yellow crystals which melted at 192°-194° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21

Procedure:
The product is produced as described in example 1 from 2.8 g. of NaH (80% suspension in mineral oil), 25 g. of benzimidazolin-2-one, 180 cc. of DMF, 22.1 g. of 8-bromocaprylic acid methyl ester and 2.8 g. of NaJ. Eluant in chromatographic purification: chloroform/methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].Cl.[CH:14]1[C:19]([O:20][C:21](Cl)=[O:22])=[CH:18][CH:17]=[C:16]([Cl:24])[CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:24])=[CH:15][CH:14]=2)=[O:22])[CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](C(=O)OC)CC1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 2.12 g (10.21 mmol) of trans-4-methylamino-cyclohexanecarboxylic acid methyl ester•HCl was dissolved in 30 mL of pyridine, treated at 0° C. with 1.57 mL (11.23 mmol, 1.1 eq) of 4-chlorophenylchloroformate and stirred for 22 h at RT. The solution was evaporated and partitioned between EtOAc (×3)/aqueous 1M HCl. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.41 g (90%) of trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexane-carboxylic acid methyl ester, MS: 326 (MH+, 1Cl).