Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14].[CH3:15][S:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17].C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:23]\[C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:26][CH:25]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC1=C(CCO)c2cc(F)ccc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=C(CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reaction time: 6 h

Procedure:
5-Fluoro-2-methyl-1H-3-indenyl-(2-hydroxy) ethane (15 g, 0.072 mol), p-methylsulfonylbenzaldehyde (14.0 g, 0.091 mol) and sodium methoxide (13.0 g, 0.24 mol) are heated in methanol (200 ml) at 60° C. under nitrogen with stirring for 6 hours. The reaction mixture is poured onto ice-water (750 g), and is acidified with 2.5N hydrochloric acid. The collected solid is triturated with a little ether to produce (Z)-5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-1H-3-indenyl-(2-hydroxy) ethane. Recrystallization of the crude reaction product results in the separation of the mixture of geometrical isomers (Z/E) and gives the title compound (R1 =5-fluror, R2 =CH3, R3 =H, R4 =CH2OH, n=1, R5 =CH3SO2).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:30])([F:29])[O:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([O:17][C:16]([F:15])([F:29])[F:30])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC(F)(F)F)c3)nc2n(CC)c1=O
Yield: 60 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.00 g (5.05 mmol) of 5,6-diamino-1,3-diethyluracil and 1.2 9 g (5.56 mmol ) of 3-trifluoromethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.19 g (yield 60%) of Compound 142 as white needles.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH2:5].[C:8]([OH:12])(=[O:11])C=C>[Ru].C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH:5][C:8]([OH:12])=[O:11]
Reactant: C=CC(=O)O
Reactant: C=CCC(C)(C)C
Agent: [Ru]
Solvent: ClCCl
Product: CC(C)(C)CC=CC(=O)O
Yield: 98.7 %

Procedure:
5,5-Dimethyl-hex-2-enoic acid was prepared using a modified procedure from Chatterjee, A. K. et al. J. Am. Chem. Soc. 2003, 125(37), 11360-11370. 4,4-Dimethyl-1-pentene (5.0 mL, 34.77 mmol, 1.5 eq.) and acrylic acid (1.54 mL, 22.51 mmol, 1.0 eq.) were added to a solution of ruthenium catalyst ([1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro [[2-(1-methylethoxy-)phenyl]methylene-]ruthenium, 282 mg, 0.45 mmol, 2 mol %) in CH2Cl2 and heated to reflux for 12 hours under nitrogen atmosphere. The resulting brown solution was diluted with CH2Cl2 and washed with 1M NaOH (3×15 mL). The organic phase was acidified with 4 M HCl (20 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over MgSO4, filtered and evaporated to provide intermediate 5,5-Dimethyl-hex-2-enoic acid as a light brown oil (3.16 g, 22.21 mmol, 99%): 1H NMR (CDCl3, 400 MHz) δ 0.94 (s, 9H), 2.11 (d, 2H, J=8.0 Hz), 5.82 (d, 1H, J=16.0 Hz), 7.12 (dt, 1H, J=16.0, 8.0 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]2[C:36]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(OCC)(=O)C.[ClH:52]>>[ClH:52].[ClH:52].[CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]2[C:36]=1[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27]
Reactant: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3S,5R)-3-[(2-methylpropyl) {[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (290 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to give the object product (278 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:21]>C(O)(C)C.C(OCC)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O-:4])=[O:2])=[N:6][CH:7]=1.[Na+:21]
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C([O-])c1ccc(NCc2cccc(Cl)c2)cn1

Procedure:
To the solution of 7 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester in 30 ml of isopropanol, 15 ml of 2 N aqueous sodium hydroxide are added and the mixture is warmed on the steam bath for 1/2 hour. It is diluted with 20 ml of isopropanol and 20 ml of diethyl ether whereupon a precipitate formes on cooling. It is collected and recrystallized from the mixture of 15 ml of water and 5 ml of isopropanol, to yield the sodium 5-(m-chlorobenzylamino)-pyridine-2-carboxylate melting at 250°-255°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19](OCC)([CH3:22])[NH:20][N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(C)NN=C(C2CCN(C(=O)OCc3ccccc3)CC2)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(5-ethoxy-5-methyl-1,3,4-oxadiazolin-2-yl)piperidine (200 mg) in toluene (5 mL) containing pyridine (0.25 mL) was heated under reflux for 20 hours. The mixture was cooled to room temperature, and the solvent was evaporated. The residue was purified by chromatography, eluting with chloroform:methanol:ammoniumhydroxide (98:2:1), to give the 1,3,4-oxadiazole derivative (0.143 g) as a clear oil; NMR (CDCl3): 7.35 (m, 5), 5.13 (s, 2), 4.16 (broad d, 2, J=12.8), 3.05 (m, 1), 2.50 (s, 3), 2.04 (m, 2), 1.83 (m, 2).
Reaction SMILES: [C:1]1([P:7]2(=[O:26])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10](=O)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>C(O)C.N1CCCCC1>[C:29]([C:28]([C:27]#[N:31])=[C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[P:7](=[O:26])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9]1)#[N:30]
Reactant: N#CCC#N
Reactant: O=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a mixture of 0.25 g of 1,2,6-triphenylphospha-2,5-cyclohexadien-4-one P-oxide and 0.060 g of malononitrile in 100 ml of ethanol was added 1 drop of piperidine. The red mixture was heated on a steam bath for about one hour, then allowed to cool to room temperature overnight. The product crystallized as dark greenish brown metallic needles. It was collected and dried to give 0.247 g of 4-dicyanomethylene-1,2,6-triphenylphospha-2,5-cyclohexadiene P-oxide, whose structure was confirmed by 1HNMR and FDMS analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH3:12])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10]Cl.[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:10][CH2:9][NH:8][C:7]4[CH:6]=[N:5][N:4]([CH3:12])[C:3](=[O:13])[C:2]=4[Cl:1])[CH2:26][CH2:27]3)=[N:20][O:21][C:17]=2[CH:16]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cn1ncc(NCCCl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Reaction time: 24 h
Yield: 80.2 %

Procedure:
1.9 g (8.6 millimoles) of 4-chloro-5-(2-choroethylamino)-2-methyl-2H-pyridazine-3-one, 40 ml of acetonitrile, 2.07 g (9.4 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 2.36 g of potassium carbonate and 0.17 g potassium iodide are admixed. The reaction mixture is heated to boiling for 24 hours, filtered over a magnesium sulfate containing carbon bed and the organic phase is evaporated. The crude product is dissolved in ethyl acetate, washed with water, the organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product is recrystallized from ethyl acetate. Thus 2.8 g of the desired compound are obtained, yield 80.5%. Mp.: 145–147° C.
Reaction SMILES: Br[CH:2]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].CN(CCN(C)C)C>C(#N)C>[C:13]([O:16][CH:2]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(Br)c1noc2ccccc12
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC(C)c1noc2ccccc12

Procedure:
A mixture of 5.6 g of 3-(1-bromoethyl)-1,2-benzisoxazole, 2.4 g of potassium acetate, 2.1 g of N,N,N,N-tetramethylethylenediamine and 50 ml of acetonitrile are refluxed for 14 h. After cooling and filtering the mixture, the filtrate is concentrated under vacuum and diluted with diethyl ether. The ether phase is washed once with water, then twice with a 10% solution of hydrochloric acid and finally washed once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3) to give 3-(1-acetoxyethyl)-1,2-benzisoxazole having a refractive index nD20 of 1.5229.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]1[CH:14]=[C:15]([C:22](Cl)=[O:23])[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12.Cl.O>N1C=CC=CC=1>[F:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([C:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:13][CH:14]=1)=[O:23]
Reactant: O=C(Cl)c1cnc2ccccn12
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C

Procedure:
A solution of methyl 3-amino-4-fluorobenzoate (5 g, 29.6 mmol) in pyridine (200 ml) was treated with imidazo[1,2-a]pyridine-3-carbonyl chloride.HCl (step 1) (6.43 g, 29.6 mmol) and the mixture was stirred at RT for 2 days. The mixture was poured into water (30 ml) and a small exotherm was observed. After cooling to RT, the resulting precipitate was filtered and dried in a vacuum oven to afford the title compound;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C=O)C.[Cu]>[O:7]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 157 %

Procedure:
A mixture of potassium carbonate (5.53 g, 0.04 mol) and 3-phenoxyphenol (15 g, 0.08 mol) in DMF (60 ml) was heated at 80° C. with stirring for 30 minutes. 2-Chloro-3-cyanopyridine (11.08 g, 0.08 mol) and copper bronze (0.8 g) were added and the resulting mixture heated at reflux for 90 minutes. GC analysis indicated the formation of a single product (96%). The reaction mixture was cooled and filtered, and then poured into water (300 ml) and allowed to sand over the weekend. The yellow-brown oily precipitate was extracted into dichloromethane and dried. The dichloromethane solution was then filtered and evaporated to yield crude 2-(3-phenoxyphenoxy)-3-cyano-pyridine (36.2 g, contaminated with DMF) which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:28])C.Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:28]
Reactant: Cc1ccc(-c2ccccc2)cc1C#N
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, 126 g (650 mmol) of 2-methyl-5-phenylbenzonitrile was dissolved in 700 ml of anhydrous toluene, and to the resulted solution was dropped 780 ml of a toluene solution of diisobutyl aluminum hydride (1.0 M solution; 780 mmol) at −10 to 0° C., and the mixture was stirred at room temperature overnight. To the reaction solution was dropped 25 ml of ethyl acetate, and this was poured into a mixture of 2.5 L of ice water and 270 ml of concentrated hydrochloric acid. After stirring at 70 to 75° C. for 1 hour, the mixture was cooled to room temperature, and separated. The organic layer was washed with water, saturated sodium bicarbonate solution, then, water, and concentrated to obtain 123 g of 2-methyl-5-phenylbenzaldehyde.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:27])[C:16](=[O:26])[CH2:17][O:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:29][NH:30][CH3:31]>>[ClH:25].[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:27])[C:16](=[O:26])[CH2:17][O:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([N:30]([CH3:31])[CH3:29])[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC
Reactant: CN(C(=O)COc1cncc(Cl)n1)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CN(C)c1cncc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)n1

Procedure:
The title compound was synthesized from Compound 129 and dimethylamine hydrochloride in the same manner as in Example 130.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[NH:29]1[CH2:34][CH:33]=[CH:32][CH2:31][CH2:30]1>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:29]3[CH2:30][CH:31]=[CH:32][CH2:33][CH2:34]3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: C1=CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CC=CCC3)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (2.08 g) in ethanol (20 ml) was added 1,2,3,6-tetrahydropyridine (1.38 ml), and refluxed for 1.5 hours. The resulting precipitates were collected, dissolved in chloroform, washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate. After evaporated, the residue was triturated with diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1,2,3,6-tetrahydropyridin-1-yl)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.95 g).
Reaction SMILES: BrBr.[CH3:3][C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8](=[O:20])[C:7]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])=[CH:6][C:5]=1[C:35](=O)[CH2:36][CH3:37]>C1COCC1>[CH3:7][C:8]1[O:20][C:36]([CH3:37])=[C:35]([C:5]2[CH:6]=[C:7]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)=[O:22])[C:8](=[O:20])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=3)[C:4]=2[CH3:3])[N:9]=1
Reactant: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: BrBr
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)c(C)o1
Reaction time: 2 h
Yield: 213.4 %

Procedure:
Bromine (84 μl, 1.61 mmol) in THF (5 ml) was added to a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (700 mg, 1.34 mmol) in THF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, dried and evaporated under reduced pressure to give the title compound (800 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 43.4 %

Procedure:
3-Fluoro-benzenesulfonyl chloride (116 mg, 0.59 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (65 mg, 0.81 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide as off-white solid (102 mg, yield: 42.5%). MS (ESI+APCI) M+1=436.1.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].CC1C=CC(S(O[CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:36][C@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (69%) as as an off-white solid: mp 79-81° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.16-7.04 (m, 3H), 6.63-6.62 (m, 1H), 6.39-6.32 (m, 1H), 4.96-4.92 (m, 1H), 4.72-4.67 (m, 1H), 4.54 (s, 2H), 4.37-4.26 (m, 1H), 3.98-3.85 (m, 2H), 3.82-3.70 (m, 2H), 3.15 (s, 3H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.7 (2C), 163.9 (2C), 157.4, 157.3, 146.9 (2C), 143.1, 142.6, 132.2, 131.9, 129.2, 129.1, 124.4 (2C), 123.8 (2C), 123.5, 123.1, 122.8, 109.8, 109.7, 109.6, 100.1 (2C), 80.8, 80.6, 76.9, 76.2, 68.4, 68.2, 67.7, 58.1 (2C), 44.9, 44.6, 29.3, 29.1, 28.5, 28.4, 25.7 (2C); MS (ES+) m/z 429.1 (M+23), 407.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([OH:10])=[O:9]>N1C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16])[CH2:3][O:4][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C(O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(CO)CO
Solvent: c1ccncc1
Product: CC(C)(COC(=O)c1ccc(C(=O)O)cc1)COC(=O)c1ccc(C(=O)O)cc1
Yield: 80.4 %

Procedure:
A mechanically stirred mixture of 15.6 g (0.15 M) of 2,2-dimethyl-1,3-propanediol, 92.25 g (0.5 M) of 4-carboxybenzoyl chloride and 500 ml of pyridine was refluxed under a nitrogen atmosphere. The resulting mixture was concentrated to dryness under reduced pressure, dispersed in 500 ml of distilled water, and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed three times with distilled water, and dried overnight at 100° C in a vacuum oven. The product was extracted for 5 days with 2 liters of hot benzene. The extract, on cooling, yielded 48.2 g of 4,4'-[(2,2-dimethyl-1,3-propanediyl)bis(oxycarbonyl)]bis(benzoic acid) melting at 287°-288° C. The infrared spectrum was consistent with the proposed structure and the compound was found to contain 5.13 meq of CO2H/g which corresponded to a molecular weight of 390 for the diacid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[C:10]([Mg]Br)([CH3:12])=[CH2:11].[Cl-].[NH4+]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]([OH:9])[C:10]([CH3:12])=[CH2:11]
Reactant: O=CC1CC2CCC1C2
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)C1CC2CCC1C2
Temperature: 25 °C

Procedure:
Bicyclo[2.2.1]heptane-2-carbaldehyde (47 g, 378 mmol) in THF (25 ml) was added dropwise to isopropenylmagnesium bromide (0.5 molar in THF, 860 ml, 430 mmol) at −78° C. (slurry at this temperature) under nitrogen over 2 hours. The reaction was slowly warmed up to room temperature and stirred over the week-end. After cooling into an ice-water bath, a saturated aqueous ammonium chloride solution (500 ml) was added (slowly early on) to the reaction. The phases were vigorously stirred and separated. The organic phase was washed with more ammonium chloride solution (300 ml) and brine (300 ml). Each aqueous phase was re-extracted with diethyl ether (300 ml). Combined extracts were dried over sodium sulfate. The product was purified by fractional distillation through a 20-cm Widmer column.