Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].C(O)C.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:3](=[O:2])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: CNC
Solvent: CCO
Product: CC(C)C(=O)CC(=O)N(C)C

Procedure:
0.69 mol (100 g) of 4-methyl-3-oxovaleric acid methyl ester and 309 ml 33% dimethylamine in ethanol (about 1.73 mol dimethylamine) were stirred in a pressure reactor for 2 hours at 110° C. After cooling, the solvents were distilled on a rotary evaporator. After drying, 93 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccncc1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccncc3)c2cc1OC
Temperature: 25 °C
Yield: 26.1 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and 4-pyridineboronic acid (42 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the suspension was stirred at 80° C. for 2.5 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (13 mg, yield 26%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:14]1[C:10]2[C:11](=[O:13])[O:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Oc2ccccc2Nc2ccccc21
Yield: 52.6 %

Procedure:
A solution of 2-(2-Hydroxy-phenylamino)-benzoic acid (2.0 g, 9 mmol) and p-toluenesulfonic acid (0.5 g) in toluene (200 ml) was heated under N2 with the H2O formed being collected in a Dean-Stark receiver. Upon completion, the organic layer was washed with saturated NaHCO3, dried over anhydrous MgSO4, filtered, and evaporated by a rotatory evaporator to obtain the product (1.0 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].ClC1C=CC(C(O)=O)=CC=1S(=O)(=O)N.S(Cl)(Cl)=O.[CH2:33]([C:35]1[O:39][C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[CH:36]=1)[CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[CH2:33]([C:35]1[O:39][C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[C:36]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:34]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCc1cc2ccccc2o1
Agent: Cl
Agent: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: CCc1oc2ccccc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
10 mg of powdered 4-chloro-3-sulfamoylbenzoyl chloride (melting point, m.p. 166° C.), prepared from 4-chloro-3-sulfamoylbenzoic acid and thionyl chloride, are introduced into 70 ml of anhydrous chlorobenzene, subsequently 6.32 g of 2-ethylbenzo[b]furan are added, and the reaction mixture is cooled to 0° C. After addition of 11.4 g of anhydrous aluminum chloride, the reaction batch is maintained at a temperature of 5° to 10° C., subsequently stirred for 5 hours at 15° C., and the mixture is then poured into a suspension of 200 g of ice and 10 ml of concentrated hydrochloric acid. After extraction with ethyl acetate and washing with water, the organic phase is stirred for 6 hours with a dilute NaHCO3 solution having a pH of 8.5, dried over magnesium sulfate, and, after evaporation, a light yellow to colorless viscous oil is obtained which crystallizes from petroleum ether. Colorless crystals, m.p. 170°-172° C. (from a small amount of methanol).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:29]([CH3:30])[CH2:28][CH2:27][CH2:26][C:25]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC(C)=O.O.CN(C)C=O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:23][C:24]2[CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:27][CH2:28][C:29]=2[CH3:30])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CCOC(=O)C1=C(N)C(C)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCC(C)=C1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the product of Step F) (1.0 g, 3.11 mmol) in dichloromethane (10 mL) was added dimethylformamide (20 μL) and oxalyl chloride (299 μL, 3.42 mmol). The mixture was stirred at ambient temperature until a clear solution resulted. The solution was then concentrated under reduced pressure and placed under high vacuum (0.1 torr) for 0.5 h. The residue was redissolved in acetone (5 mL) and added to a mixture of ethyl 2-amino-3-methyl-1-cyclohexene-1-carboxylate (i.e. the product of Step B) (570 mg, 3.11 mmol) and potassium carbonate (645 mg, 4.67 mmol) in acetone (10 mL). After stirring ovenight at ambient temperature, water was added and the mixture was filtered through a column of celite and washed with dichloromethane. The eluent was concentrated and purified by silica gel column, chromatography (eluted with 60% then 80% ethyl ether in petroleum ether) to give the title compound as a white foam (0.2 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([N+:29]([O-:31])=[O:30])[S:18][CH:17]=1)=O)C.O.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl>[CH2:22]([S:21][C:20]1[C:16]([CH2:14][OH:13])=[CH:17][S:18][C:19]=1[N+:29]([O-:31])=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Diisobutylaluminum hydride (154 mL of a 1.0 M solution in dichloromethane, 154 mmol) was added via cannula over 25 min to a solution of 4-benzylsulfanyl-5-nitro-thiophene-3-carboxylic acid ethyl ester (22.63 g, 70.0 mmol) at −50° C. The reaction mixture was stirred at −50° C. for 2 h, then was warmed to 0° C. and was maintained at that temperature for 35 min. Water (200 mL) was added via addition funnel over 15 min and the resulting suspension was warmed to 25° C. whereupon additional water (200 mL) and D/L-tartaric acid (20 g) were added. After stirring vigorously at 25° C. for 30 min, the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (300 mL) and dichloromethane (2×400 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm; 10-50% ethyl acetate in hexanes) afforded the desired product, (4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol (10.52 g, 37.4 mmol, 53%), as a dark brown oil. 1H NMR (400 MHz, CDCl3) δ: 4.21 (2H, s), 4.40 (2H, s), 7.09-7.12 (1H, m), 7.21-7.24 (4H, m), 7.39 (1H, s).
Reaction SMILES: [CH2:1]([CH:21]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([C:21]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(=O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of diarachidonyl methanol (IV, 0.41 g, 0.71 mmol) and anhydrous potassium carbonate (0.05 g) in 10 mL of CH2Cl2 was added pyridinium chlorochromate (PCC, 0.50 g, 2.3 mmol). The resulting suspension was stirred at room temperature for 90 mins. Ether (50 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of floresil (30 mL). The pad was further washed with ether (3×30 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 0.40 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 10 mL) eluted with 0-3% ether in hexanes. This afforded 0.30 g (75%) of diarachidonyl ketone (V). 1H NMR (400 MHz, CDCl3) δ: 5.3-5.5 (16H, m, 8×CH═CH), 2.82 (12H, t, 6×C═C—CH2—C═C), 2.40 (4H, t, 2×CO—CH2), 2.08 (8H, m, 4× allylic CH2), 1.25-1.65 (20H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: COC(=O)c1cc(F)ccc1CN
Product: COC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 38, methyl 2-(aminomethyl)-5-fluorobenzoate. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.61 (6H, s, gem-Me), 3.88 (3H, s, OMe), 3.97 (2H, t, J=5.5 Hz, CH2), 4.02 (2H, t, J=5.5 Hz, CH2), 4.73 (2H, d, J=6.7 Hz, NCH2), 5.25 (2H, s, OCH2), 7.19 (1H, dt, J=3, 8.5 Hz, Ar—H), 7.27–7.31 (3H, m, Ar—Hs), 7.48–7.50 (2H, m, Ar—Hs), 7.61 (1H, dd, J=5.5, 8.5 Hz, Ar—H), 7.66 (1H, dd, J=3, 9.5 Hz, Ar—H). LC/MS m/z 496 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6][CH3:7])=[O:5].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8](=[O:10])[CH:3]([O:2][CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[C:14]([F:19])[CH:13]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)C(OC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a stirred mixture of 2.78 grams (0.02 mole) of monomethyl methoxymalonate prepared in Example LVI (Compound 214) and 3.56 grams (0.02 mole) of 4-bromo-2-fluoroaniline in approximately 100 milliliters of dry tetrahydrofuran was fed dropwise a solution of 3.87 grams (0.02 mole) of 1,3-dicyclohexylcarbodiimide in about 30 milliliters of dry tetrahydrofuran, while cooling the reaction mixture in an ice-water bath. The reaction mixture was allowed to warm slowly to room temperature and stirring continued for an approximate 65-hour period. The precipitated 1,3-dicyclohexylurea by-product (3.15 grams) was removed by filtration and the filtrate vacuum evaporated and the residue dissolved in methylene chloride. The latter solution was extracted with dilute HCl and then water, then dried (MgSO4) and solvent vacuum evaporated to give a colorless liquid. Flash column chromatography of the latter on silica, eluting with hexane-ethyl acetate (7:3) gave, after workup, a liquid which crystallized on standing. Recrystallization from hexane containing a small amount of ethyl acetate gave 2.3 grams (0.01 mole) of methyl 3-[(4-bromo-2-fluorophenyl)amino]-2-methoxy-3-oxopropanaote having a melting point of 51° C.-53° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][CH2:14][CH2:15][CH:16]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCC(CCCCl)OC1CCCCO1
Solvent: CN(C)C=O
Product: CCCCCC(CCCN1C(=O)c2ccccc2C1=O)OC1CCCCO1
Temperature: 95 °C
Yield: 45 %

Procedure:
Sodium hydride (53%) (1.5 g. excess) is washed with benzene three times by decantation, then dimethyl formamide (100 ml.) is added. To this stirred suspension is added a solution of phthalimide (4.3 g., 0.03 mole) in dimethyl formamide (50 ml.) at such a rate as to keep the temperature below 35° C. A clear solution is obtained and to it is added 1-chloro-4-(2-tetrahydropyranyloxy)nonane (7.8 g. 0.03 mole) and the resulting solution is stirred and heated at 95° C. for 20 hours. The reaction is then concentrated to one-half its volume in vacuo, poured into ice water (200 ml.) and extracted with ether (2 × 150 ml.). The ether is washed with 5% sodium hydroxide (2 × 50 ml.), saturated sodium chloride solution (2 × 50 ml.), then dried over sodium sulfate. Evaporation of the ether affords 4.5 g. (45% yield) of N-[4-(2-tetrahydropyranyloxy)nonyl]phthalimide melting 59°- 61° C. After crystallization from cyclohexane the product melts at 62°-63° C. Anal. Calcd. for C22H31NO4 : C, 70.75; H, 8.36; N, 3.75 Found: C, 71.03; H, 8.28; N, 3.81
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:35][C:30]1([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32][B:28]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:29]1
Reactant: CC(C)c1cccc2nc(Nc3ccc(Br)cc3)oc12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.412 g, 1.24 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.346 g, 74%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.Cl.CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
6 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene is suspended in a mixture of 30 ml. concentrated hydrochloric acid and 30 ml. methanol, and the mixture stirred at room temperature for 24 hours. The water is added and the product isolated by filtration, yielding 1-amino-2-nitro-4-thiocyanatobenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccnc(C(F)(F)F)c2)C1=O
Temperature: 120 °C
Yield: 73.3 %

Procedure:
Using the same reaction conditions as in Example 15, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 4-bromo-2-trifluoromethyl-pyridine (229 mg, 1.017 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (29.09 mg, 0.254 mmol) and potassium phosphate (44.89 mg, 2.117 mmol). The resulting mixture was heated to 120° C. for 6 hours. The reaction workup afforded 200 mg of the product (73.52% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:28][CH:29]([O:35][CH2:36][CH3:37])[C:30]([O:32]CC)=[O:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:28][CH:29]([O:35][CH2:36][CH3:37])[C:30]([OH:32])=[O:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)C(=O)O
Yield: 70 %

Procedure:
Ethyl 3-[3-benzyl-4-({4-[(methylsulfonyl)oxy]phenethyl}oxy)phenyl]-2-ethoxypropanoate—Example 5 (0.23 g; 0.42 mmole) was dissolved in THF and water (2:1), lithium hydroxide (0.014 g; 0.59 mmole) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.15 g (70% yield) of the product.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl-:5].[CH3:6][P+:7]1([CH2:12][CH2:13]O)[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl.C>C(Cl)(Cl)Cl.CN(C)C=O>[Cl-:3].[CH3:6][P+:7]1([CH2:12][CH2:13][Cl:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[P+]1(CCO)CCCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[P+]1(CCCl)CCCC1

Procedure:
27.3 g (0.23 mole) of thionyl chloride were added dropwise, whilst stirring, to a solution of 36.5 g (0.2 mole) of 1-methyl-1(2-hydroxyethyl)-phospholanium chloride in 200 ml of chloroform and a small amount of dimethylformamide at 65° C. When the evolution of hydrogen chloride had subsided, the reaction mixture was concentrated under reduced pressure and the residue which remained was taken up in water. The solution thereby produced was treated with active charcoal and then filtered. Concentration of the filtrate under reduced pressure gave 1-methyl-1-(2-chloroethyl)-phospholanium chloride in the form of a crystal hydrate from which water was eliminated on warming at 70° C. The substance which remained melted above 250° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (321 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (239 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(O)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound I)75.0 mg (0.143 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.01 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.4 Hz), 7.45 (2H, s), 7.20-7.17 (3H, m), 6.92-6.89 (2H, m), 5.97 (1H, t, J=4.7 Hz), 2.35 (2H, d, J=4.7 Hz), 1.34 (6H, s).