Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].C([O:50][C:51](=[O:54])[CH2:52]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C[N+](C)(C)C.COCCOCCOC>[C:1]([O:7][C@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[O:10][CH2:52][C:51]([OH:54])=[O:50])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(O)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: COCCOCCOC
Product: CC(C)(C)C(=O)OC[C@H]1OC(OCC(=O)O)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 10 °C

Procedure:
A mixture that consists of 51.66 g (100 mmol) of 2,3,4,6-tetra-O-pivaloyl-mannopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 82.93 g (600 mmol) of fine-powder potassium carbonate in 350 ml of diethylene glycol dimethyl ether is cooled to 10° C. At 10° C., 36.65 g (160 mmol) of 2-bromoacetic acid benzyl ester is added in drops within 10 minutes while being stirred vigorously. It is stirred for two hours at 10° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol, mixed with 5 g of palladium (10%) on activated carbon and hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:10]2[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(Cl)cc1S2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
38.8 G. of 3,10-dichloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin into 100 ml. of chloroform are heated with 82 g. of 1-carbethoxypiperazine for 24 hours under reflux conditions. The reaction mixture is poured on ice water and equilibrated with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. Raw 1-carbethoxy-4-(3-chloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin-10-yl)-piperazine is obtained as a yellow oil.
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH:6]=[C:5]([Cl:14])[N:4]=1.[CH3:15][OH:16]>>[Cl:14][C:5]1[N:4]=[C:3]([O:16][CH3:15])[C:12]2[C:7]([CH:6]=1)=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2
Reactant: Fc1ccc2c(Cl)nc(Cl)cc2c1
Reactant: CO
Agent: [Na]
Product: COc1nc(Cl)cc2cc(F)ccc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 125 mg (3.00 mmol) sodium in 40 mL MeOH was added 668 mg (3.00 mmol) 1,3-dichloro-6-fluoro-isoquinoline. The reaction mixture was stirred at 70° C. for 30 min. The solvent was removed by distillation and the residue diluted with ice water. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(F)ccc1C#Cc1ccnc(NC(N)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(F)ccc1CCc1ccnc(NC(N)=O)c1
Yield: 70.8 %

Procedure:
[4-(4-Fluoro-2-methyl-phenylethynyl)-pyridin-2-yl]-urea (25 mg, 0.093 mmol) is dissolved in methanol (1.0 mL) and DCM (1.0 mL). Then 5% palladium on carbon (20 mg, 0.0090 mmol) is added. The reaction is stirred for 16 hrs under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Methanol (1 mL) is added into the crude and a white solid is formed. The solid is filtered, rinsed with more methanol and dried to give 18 mg of the titled product.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1(O)C=CC=CC=1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:7]
Reactant: COC(=O)CBr
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Solvent: Oc1ccccc1
Product: COC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methoxy-5-nitrobenzaldehyde as the phenol and methyl 2-bromoacetate as the alkylating agent in the general procedure for alkylation of substituted 2-nitrophenols gives the title compound as a dark orange oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.66 (s, 3H) 3.97 (s, 3 H) 4.98 (s, 2H) 7.83 (d, J=1.77 Hz, 1H) 8.05 (d, J=1.77 Hz, 1H) 9.97 (s, 1H). ESI-MS: m/z 270.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3I)[CH3:2].Cl.N1C=C[CH:26]=[CH:25][CH:24]=1>>[CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]#[C:25][CH3:26])[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(I)cccc21
Reactant: c1ccncc1
Agent: Cl
Product: CC#Cc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3

Procedure:
A mixture of 1-ethyl-8-iodo-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (5.93 g, 14.86 mmol), copper (I) methyl acetylide (3.05 g, 29.72 mmol), and 75 mL of dry pyridine was refluxed, under a flow of nitrogen, for 6 hours. The mixture was then poured into 100 mL of 1N HCl and the aqueous solution was extracted with ether. The combined extracts were washed with 1N HCl and saturated NaCl, dried over magnesium sulfate, filtered and concentrated to give the crude product. The material was purified by flash chromatography (15% ethyl acetate/hexane, silica gel) to give the pure title compound (2.16 g).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[Na].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C=C(CBr)C(=O)O
Reactant: CCCCOc1ccc(S(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(CS(=O)(=O)c1ccc(OCCCC)cc1)C(=O)O

Procedure:
A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), 4-butoxybenzenesulfinic acid, sodium salt (3.1 g, 13 mmol), sodium carbonate (1.9 g, 18 mmol) and dimethylformamide ( 20 mL) is refluxed overnight. The reaction mixture is then partitioned between ethyl acetate and aqueous 10% hydrochloric acid and the organic phase is concentrated in vacuo. The concentrate is chromatographed over silica gel 60 (230-400 mesh) with chloroform/methyl alcohol/acetic acid (94/5/1) and the eluate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]([Cl:17])=[N:10][C:11]2[C:12](=[CH:14][S:15][CH:16]=2)[N:13]=1>CCO>[Cl:17][C:9]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:13][C:12]2[C:11](=[CH:16][S:15][CH:14]=2)[N:10]=1
Reactant: C1CNCCN1
Reactant: Clc1nc2cscc2nc1Cl
Solvent: CCO
Product: Clc1nc2cscc2nc1N1CCNCC1
Yield: 29.1 %

Procedure:
Piperazine (92 mg, 1.07 mmol) was added to a stirred suspension of 2,3-dichlorothieno[3,4-b]pyrazine (110 mg, 0.54 mmol) in EtOH (5 mL) at room temperature. The mixture was stirred at reflux for 16 h and filtered. The solid was purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give 40 mg (29%) of the product as an orange solid. The material was used without further purification in the next step.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@H:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CS(C)=O>[OH:13][C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][C:1]#[N:2]
Reactant: CCCCCC[C@@H](O)CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCC[C@@H](O)CC#N
Yield: 86.5 %

Procedure:
Under nitrogen atmosphere, 6.2 g (126 mM) of sodium cyanide and 50 ml of dimethyl sulfoxide (DMSO) were placed in two-necked round-bottomed flask and dissolved by heating, followed by stirring. The solution was left standing and a solution of 10.4 g of (R)-1-chloro2-octanol in 20 ml of DMSO was added dropwise to the solution at 50° C., followed by stirring for 20 hours at 50° C. After the reaction, distilled water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with distilled water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain 8.48 g (54.7 mM) of (R)-3-hydroxynonanenitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[S:5][CH:6]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]=[C:9]1[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:29]#[N:30])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1N(Cc2cc(Br)cs2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1csc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1
Reaction time: 0.12 h
Yield: 62 %

Procedure:
To a suspended mixture of 1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.456 g, 1.0 mmol) and zinc cyanide (0.117 g, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (0.04 g, 0.03 mmol). The reaction mixture was put into a microwave reactor set at 100 W at 133° C. for 7 min. The solid was filtered and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]thiophene-3-carbonitrile (0.25 g, 62%) as a colorless solid: mp 207-209° C. (dichloromethane/hexane); 1H NMR (300 MHz, DMSO-d6) δ8.48 (d, J=1.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.33 (dd, J=7.8, 1.1 Hz, 1H), 7.23-7.19 (m, 2H), 7.06 (d, J=7.4, 0.8 Hz, 1H), 6.71 (s, 1H), 6.15 (s, 1H), 5.93 (d, J=1.5 Hz, 2H), 5.14 (d, J=4.6 Hz, 2H), 4.81 (d, J=9.4 Hz, 1H), 4.69 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ176.5, 155.4, 148.3, 141.7, 141.5, 141.3, 137.8, 131.5, 128.8, 127.9, 123.7, 123.3, 119.4, 115.1, 109.3, 108.7, 102.8, 101.4, 93.3, 79.7, 57.3, 37.9; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: C([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:17][C:14]1([F:16])[CH2:15][CH:9]2[NH:8][CH:13]1[CH2:12][C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:18])[CH2:10]2
Reactant: [H][H]
Reactant: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2
Yield: 90 %

Procedure:
Step VIIII: A mixture of compound 116i (340 mg, 1 mmol, 1.0 eq) and Pd(OH)2/C (100 mg, 30%) in MeOH (20 mL) was stirred at room temperature for 16 h under 1 atmosphere of hydrogen. The mixture was filtered, and the filtrate was concentrated to give ethyl 2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a as a colorless oil, 224 mg, yield: 90%. MS: calc'd (MH+) 250, measured (MH+) 250.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12](C(=O)C)[CH:11]=[CH:10]2>Cl>[ClH:6].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[C:10]2[CH2:2][C:1]([OH:5])=[O:4]
Reactant: CC(=O)N1C=Cc2cc(Cl)ccc2C1
Reactant: O=CC(=O)O
Agent: Cl
Product: O=C(O)Cc1cncc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Glyoxylic acid (1.37 g, 9.28 mmol) is added to mixture of 1-(6-chloro-1H-isoquinolin-2yl)-ethanone [J. Org. Chem., 1980, 45, 1950] (1.44 g, 5.90 mmol) in 6N HCl (24 ml). The reaction is heated at 100° C. for 3 hours, cooled to RT, washed with ether and evaporated to 10 ml volume. After overnight refrigeration, the solid is collected by filtration and dried to afford (6-chloro-isoquinolin-4-yl)-acetic acid hydrochloride. 1H NMR (400 MHz, DMSO) δ: 4.45 (s 2H), 8.18 (d J 9 1H), 8.52 (s 1H), 8.70 (d J 8 1H), 8.83 (s1H), 9.96 (s 1H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[CH2:32][CH2:33][CH3:34])=[CH:8][C:5]=1[C:6]#[N:7].B(F)(F)F.CCOCC.C([BH3-])#N.[Na+].O>O1CCCC1>[OH:1][CH2:3][CH2:2][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[CH2:32][CH2:33][CH3:34])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C2CO2)c(C#N)c1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(CCO)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of 2-oxiranyl-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (5.0 mg, 0.0102 mmol) in tetrahydrofuran (200 μL) was sequentially added with boron trifluoride diethyl ether (2.5 μL, 0.0204 mmol) and sodium cyanoborohydride (2.6 mg, 0.0409 mmol) under ice-cold conditions, and stirred at room temperature for 2 hours. Subsequently, the resultant mixture was further sequentially added with boron trifluoride diethyl ether (2.5 μL, 0.0204 mmol) and sodium cyanoborohydride (2.6 mg, 0.0409 mmol) under ice-cold conditions, and stirred at room temperature overnight. After completion of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 2-(2-hydroxy-ethyl)-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (2.2 mg, yield 44%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]([Br:14])=[CH:3][C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[CH2:6][CH2:5]1.Br>C(O)(=O)C>[Br:1][C:2]([Br:14])=[CH:3][C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@@H](C=C(Br)Br)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@H]1CC[C@@H](C=C(Br)Br)CC1

Procedure:
cis-Methyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (4 g) was heated to reflux in a solution of hydrobromic acid (48%, 20 ml) and acetic acid (40 ml). After heating for 4 hours the solvent was removed under reduced pressure. Water (50 ml) was added and the mixture extracted with diethyl ether. The ether extracts were extracted with sodium bicarbonate solution. The aqueous layer was then acidified and re-extracted with ether. The ethereal layer washed with brine and dried over anhydrous magnesium sulphate. Evaporation gave cis-4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (3.6 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([NH:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]1)=[O:2]>C(O)=O>[CH:1]([NH:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1)=[O:2]
Reactant: CCOC(=O)c1cn(NC=O)c2cc3c(cc2c1=O)OCO3
Solvent: O=CO
Product: O=CNn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Yield: 43.7 %

Procedure:
A mixture of 5.8 g of ethyl 5-(formylamino)-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 3) and 100 ml of 97% formic acid was heated at reflux under a Dean-Stark separator for about eight hours. The reaction mixture was then distilled to remove 30 ml of volatiles, cooled and stirred to induce crystallization of product. The latter was collected by filtration and washed with absolute alcohol and ether to give 2.3 g of 5-(formylamino)-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid, tan crystals, m.p. 302° C. (decompn.).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:24][CH2:23][CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: O=S1(=O)N=C(NCCC(c2ccccc2)c2ccccc2)Nc2ccc(Cl)cc21

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 3,3-diphenylpropylamine (1.5 g; 7.1 mmol) with the use of same procedure as in example 21 300 mg (59%) of the title compound was prepared; 1H-NMR (DMSO-d6) ppm; 10.7 (s, 1H, NH), 7.68 (d, 1H, H-8), 7.60 (dd, 1H, H-5), 7.25 (m, 11H, ), 4.1 (t, 1H, CH), 3.11 (q, 2H, CH2), 2.35 (q, 2H, CH2); MS:EI/70eV: 425 (M+), 245, 193, 180, 165, 152, 115.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (400 mg) in dry N,N-dimethylformamide (6 ml) at room temperature and under nitrogen was added potassium carbonate (630 mg) in one go. The reaction was stirred at 60° C. for 1.5 hours and then cooled to 50° C. 2-(Bromomethyl)tetrahydro-2H-pyran (175 μl) was added in one go and the reaction heated to 50° C. overnight and then at 90° C. for 2 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was separated and concentrated in vacuo. The product was semi-purified by MDAP to afford a mixture of the title compound and an isomer. This mixture was taken on without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:18]>C(Cl)Cl>[C:1]([O:18][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Reactant: C/C=C/C(=O)Cl
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Crotonyl chloride (7 ml) was added to a solution of 2,4-dichloro-6-nitrophenol (10.3 g) in methylene chloride (20 ml) and the mixture was heated under reflux for 12 hours. The solution was diluted with further methylene chloride (200 ml) and extracted several times with a 10% sodium hydroxide solution. The organic layer was washed with water dried (Na2SO4) and the solvent removed under reduced pressure to give a pale brown oil which crystallised on standing for 24 hours 2,4-dichloro-6-nitrophenyl crotonate melted at <60°.
Reaction SMILES: C1(=O)N([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)C(=O)C=C1.[NH2:15][CH2:16][CH2:17]C[Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:12]1[C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=2[CH:17]=[CH:16][NH:15]1
Reactant: O=C1C=CC(=O)N1c1ccc(O)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 37 %

Procedure:
This compound was prepared according to the method used for the previous examples by combining 4-maleimidophenol (18.9 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The final product was a highly viscous red liquid. The yield was 37%.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.