Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:13][CH:12]=1)(=O)=O.[C-:35]#[N:36].[K+]>>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:35]#[N:36])=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Reactant: [C-]#N
Agent: [K+]
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCC#N)cc1

Procedure:
According to the method described for Reference Example 38, 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate was allowed to react with potassium cyanide to give 6-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]hexanenitrile. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.116°-117° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[N+:5]([C:8]1[CH:25]=[CH:24][C:11]2[O:12][C:13]([CH2:19][C:20]([F:23])([F:22])[F:21])([C:15]([F:18])([F:17])[F:16])[O:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>S(=O)(=O)(O)O>[N+:1]([C:25]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]2[O:14][C:13]([CH2:19][C:20]([F:23])([F:21])[F:22])([C:15]([F:17])([F:16])[F:18])[O:12][C:11]=2[CH:24]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid was added dropwise to an initial charge of 317 g of the product from Example 15a. The mixture was stirred at 55° C. for 2 hours. The mixture was then cooled and poured into ice-water. The product was extracted with methylene chloride, washed until neutral with sodium hydrogen carbonate solution, dried, and freed on a rotary evaporator from readily volatile constituents. The yield was 339 g (=94% of theory) and the melting point was 101° to 103° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C#N)cn1CCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (220 mg, 0.82 mmol) was dissolved in 4.0 ml of dimethyl sulfoxide and treated with a solution of potassium carbonate (136 mg, 0.980 mmol) in water (1.60 mL, 88.8 mmol). After cooling at 0° C., hydrogen peroxide (0.751 mL, 9.80 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of water and extracted with ethyl acetate (3×20 ml). The oprganic extracts were washed with 5% sodium thiosufate, sat. NaHCO3, brine, dried over sodium sulfate and concentrated to give 180 mg (77%) of crude methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. MS (ESI+): 288.0.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1.[Li]CCCC.[B:21](OC(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>C1COCC1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH3:10])[C:2]=1[B:21]([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1cccc(C2OCCO2)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C2OCCO2)c1B(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To the solution of 2-(2-bromo-3-ethoxyphenyl)-1,3-dioxolane (132 g, 0.48 mol) in anhydrous THF (500 mL) was dropwise added n-BuLi (2.5 M in THF, 386 mL, 0.97 mol) at −78° C. under nitrogen protection. The mixture was stirred at −78° C. for 2 h and then triisopropyl borate (227 mL, 0.97 mol) was dropwise added. The resulting mixture was stirred at this temperature for 4 h. After the reaction was quenched by adding saturated aqueous NH4Cl solution (200 mL), the resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give the target compound (136 g, yield 87%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:40]([O:41]CC2C=CC=CC=2)[C@H:39]([O:49][C@H:50]2[O:79][C@H:78]([CH3:80])[C@@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]([O:61]CC3C=CC=CC=3)[C@H:51]2[O:52]CC2C=CC=CC=2)[C@@H:38]([CH2:81][O:82]CC2C=CC=CC=2)[O:37][C@@H:10]1[O:11][C@H:12]1[C@H:16]([F:17])[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:28][O:29]CC1C=CC=CC=1)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@H:50]1([O:49][C@@H:39]2[C@@H:38]([CH2:81][OH:82])[O:37][C@H:10]([O:11][C@H:12]3[C@H:16]([F:17])[CH2:15][NH:14][C@@H:13]3[CH2:28][OH:29])[C@H:9]([OH:8])[C@H:40]2[OH:41])[O:79][C@H:78]([CH3:80])[C@@H:69]([OH:70])[C@H:60]([OH:61])[C@H:51]1[OH:52]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@H]3[C@H](F)CN(C(=O)OCc4ccccc4)[C@@H]3COCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](F)CN[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 65 %

Procedure:
The compound (109 mg, 90.2 μmol) synthesized in Example 9 (9d) was dissolved in 1% hydrochloric acid methanol solution (5 mL) and 20% palladium hydroxide-carbon (55 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 1 hour. After the catalyst was removed by celite filtration, 28% ammonia water (0.2 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and it was passed through ion exchange resin (Dowex 50w×8) column with water (30 mL), 1% ammonia water (30 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (26 mg, 65%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[S:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([C:20]1[S:19][CH:23]=[N:22][N:21]=1)([CH3:25])[C:26]#[C:27][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)c1nncs1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)c1nncs1
Yield: 2 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,3,4-thiadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (1.7 mg, 2%).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([CH3:23])(O[Si](C)(C)C)[C:14]([F:17])([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:12][O:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:13]([CH3:23])([C:14]([F:15])([F:16])[F:17])[O:24][C:3](=[O:2])[CH2:4]2
Reactant: COC(=O)Cc1cc(OC)ccc1C(C)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC(=O)OC2(C)C(F)(F)F
Reaction time: 1 h
Yield: 54 %

Procedure:
To the crude reaction mixture described in example 8 containing a solution of [5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-acetic acid methyl ester was added tetrabutylammonium fluoride (9.00 mL of a 1.0M solution in tetrahydrofuran, 9.00 mmol). The reaction mixture was stirred for 1 hour after which it was poured into water (50 mL) and extracted with methyl tert-butyl ether (50 mL). The organic layer was washed with water (50 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one as an oil (1.26 g, 54%). 1H NMR (400 MHz, CDCl3) δ1.89 (s, 3), 3.71 (d, 1, J=20.6), 3.79 (s, 3), 3.89 (d, 20.8), 6.65 (d, 1, J=1.5), 6.85-6.89 (m, 1), 7.29 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ21.45, 34.32, 55.33, 83.01 (q, J=30.3), 112.21, 113.88, 120.57, 124.68 (q, J=285.7), 127.73, 132.18, 160.75, 167.45. IR 1765, 1614, 1509, 1322, 1301, 1274, 1259, 1183, 1101, 997, 813 cm−1. Analysis calculated for C12H11F3O3: C, 55.39; H, 4.26. Found: C, 55.03; H, 4.54.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1.[CH3:24][S:25][CH3:26].ClN1C(=O)CCC1=O.C[O-].[Na+]>CO.O>[CH3:24][S:25](=[N:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1)[CH3:26]
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Reactant: CSC
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)n1nc(-c2ncc(N=S(C)C)nc2-c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
To a suspension of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.01 g) was added dimethyl sulfide (0.263 ml) and N-chlorosuccinimide (435 mg) under −5° C. The mixture was stirred at −5° C. for 30 minutes and at 20-25° C. for 20 hours. A solution of 28% sodium methoxide in MeOH (1.13 ml) was added to the mixture and the solution was stirred at the same temperature for an hour. After addition of water (10 ml), the organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (1:99 v/v) to give 6-{5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone as a solid (0.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O.CN(C)C=O>ClCCCl>[Cl:19][C:10]([CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:11]
Reactant: COC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)C(Cc1cccc(Cl)c1)C(=O)Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
A total of 8.0 g of the residue containing 3-(3-chlorophenyl)-2-methoxycarbonylpropionic acid prepared in Step B of Example 1 was dissolved in 32.8 g of 1,2-dichloroethane under nitrogen atmosphere, and 11.8 g of thionyl chloride and 0.05 g of dimethylformamide were added thereto, followed by stirring at 40° C. for 7 hours. The resulting mixture was concentrated under reduced pressure to remove 1,2-dichloroethane and unreacted thionyl chloride to thereby yield 7.98 g of methyl 2-chloroformyl-3-(3-chlorophenyl)-propionate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[CH3:13])[CH:8]=[CH:7][N:6]=1)=[O:4]>[OH-].[Li+].C1COCC1.CO>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:12]([CH3:13])[C:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1)([OH:26])[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)c1cc(C(O)(C(C)c2ccc(F)cc2Cl)C(F)(F)F)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(F)cc1Cl)C(O)(c1ccnc(C(=O)O)c1)C(F)(F)F
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
4-[2-(2-Chloro-4-fluoro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridine-2-carboxylic acid methyl ester (24 mg) was dissolved in an aqueous lithium hydroxide solution (1N, 5 ml), THF (5 ml), and methanol (2.5 ml). The mixture was stirred for 10 min. LCMS indicated complete hydrolysis. Volatile solvents were evaporated. The residue was diluted with water (10 ml) and washed with diethyl ether. The aqueous layer was acidified to about pH 4 with HCl (aq., 1N) and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (22 mg) as a white solid. MS (m/e)=378.2 [M+H+].
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH2:21][CH2:22][CH3:23])[N:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH2:21][CH2:22][CH3:23])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCc1nc(Cl)c(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (8.10 mL) was added to a mixture of dimethyl 2-hydroxy-6-propylpyridine-3,5-dicarboxylate (11 g) and acetonitrile (50 mL), and the resultant mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and then, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (11.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1ccc(N)c(C(=O)O)c1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NS(=O)(=O)c2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 1C (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M chlorotrimethylsilane in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of benzenesulfonyl chloride (0.042 g, 0.24 mmol) in dichloromethane (1 mL), and shaken for 16 hours at ambient temperature. The mixture was concentrated, the residue was acidified to pH 1.0 with 5% aqueous HCl, and the solution was extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.5 mM ammonium acetate to provide the desired product. MS (ESI(+)) m/e 306 (M+H)+, 323 (M+NH4)+, 328 (M+Na)+; (ESI(−)) m/e 304 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.96 (br s, 1H), 7.78 (d, 2H), 7.73 (d, 1H), 7.64 (m, 1H), 7.55 (m, 2H), 7.42 (m, 2H), 2.54 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][Cl:19])=[CH:13][CH:12]=1.[C:20](Cl)(=O)[CH2:21][CH3:22]>>[Cl:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[C:20]2[CH2:21][CH3:22])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(N)c(Nc2ccc(CCCl)cc2)c1
Reactant: CCC(=O)Cl
Product: CCc1nc2ccc(C#N)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 Example 1 from 4-amino-3-[4-(2-chloroethyl)anilino]benzonitrile (step 3) and propionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23]C(S)=[CH:21][CH:20]=1)=[O:17]>C(O)(C)(C)C>[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:12]([S:9][C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[N:5]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccc(S)cc1)c1c(F)cccc1F
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A 250 ml round bottom flask equipped with a condenser was charged with 4,6-dichloro-2-methanesulfonyl pyrimidine (4.2 g, 18.8 mmol), 2,6-difluoro-N-(4-mercapto-phenyl)-benzamide (4.98 g, 18.8 mmol) and tert-butanol (75 ml) under nitrogen. The reaction mixture was degassed thoroughly and then heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated until the product began to precipitate. The mixture was then cooled and aged for 12 hrs. The product was collected by filtration, washed with cold ethyl acetate and dried. This gave the title compound as an off-white solid (2.7 g, 35%). 1H NMR (DMSO) 7.32 (2H, m), 7.61 (3H, m), 7.79 (1H, s), 7.82 (2H, d), 10.9 (1H, s). MS (ES+): 412.19
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Yield: 82.5 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole), 2.17 g (0.01 mole) of 3,4,5-trimethoxybenzyl chloride, 0.51 g (0.005 mole) of triethylamine, and 1.4 g (0.01 mole) of potassium carbonate were mixed with 20 ml of toluene, and the resulting mixture was heated at the refluxing temperature for 2 hours. The reaction liquid was left to cool, washed by shaking with water, and then the organic liquid layer was concentrated under reduced pressure to obtain 3.8 g (82.5% yield) of oily 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (745 mg, 2.3 mmol), benzoic acid (337 mg, 2.76 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.31 g, 3.45 mmol) in dichloromethane (10 mL) and triethyl-amine (0.8 mL, 5.75 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([OH:8])[CH3:7])[CH3:2].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([O:8][C:13](=[O:14])[CH2:12][C:10]#[N:11])[CH3:7])[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CCOC(=O)CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(C)OC(=O)CC#N
Reaction time: 8 h

Procedure:
A mixture of 194.0 g of ethyl-3-hydroxybutyrate, 149.83 g of cyanoacetic acid, and 10.76 g of 4-dimethylaminopyridine (DMAP) was stirred in 1500 ml of CH2Cl2 in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 75 ml of N-N′-dimethylformamide (DMF) was added to the above mixture to make a clear solution. The above solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (363.45 g in 600 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57])=[C:49](O)[CH:48]=1>>[C:56]([NH:55][CH2:54][CH2:53][C:50]1[CH:49]=[CH:48][C:47]([F:46])=[CH:52][C:51]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:42]=[CH:43][CH:44]=[CH:45][C:2]=3[Cl:1])=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)(=[O:58])[CH3:57]
Reactant: CC(=O)NCCc1ccc(F)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3Cl)cc2)cc1
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method G, 0.28 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.17 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide (Example 112b) are reacted. The title compound is obtained as a yellow oil. Rf=0.58 (EtOAc); Rt=5.74.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:2]#[CH:3].[CH2:18](Br)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]>>[CH2:1]([O:4][C:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([O:12][CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CC(C)=CCC/C(C)=C/CBr
Product: C#CCOC(=O)c1cc(OC)c(OCC=C(C)CCC=C(C)C)c(OC)c1

Procedure:
By utilizing the procedure of Example 1 by reacting syringic acid propargyl ester with geranyl bromide, there is obtained 4-[(3,7-dimethyl-2,6-octadienyl)oxy]-3,5-dimethoxy benzoic acid propargyl ester; nD21 = 1.5320