Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.C[O:5][C:6](=[O:23])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]=1[Cl:22]>O.CO>[ClH:13].[Cl:22][C:8]1[C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([OH:23])=[O:5]
Reactant: COC(=O)c1c(Cl)ccc(OCCN2CCCC2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(Cl)ccc(OCCN2CCCC2)c1Cl
Temperature: 90 °C
Yield: 169.9 %

Procedure:
To a solution of NaOH (2.73 g, 68.25 mmol) in 80 ml of water and 40 ml of methanol was added in one portion 8 g (22.56 mmol) of 2,6-dichloro-3-(2-pyrrolidinoethoxy)benzoic acid methyl ester hydrochloride and the mixture was heated at 90° C. for 15 hours. The mixture was concentrated in vacuo to remove methanol, the aqueous layer was acidified with 20 ml of conc. HCl solution, and the white solid was filtered. The white solid was dissolved in hot water, filtered, and the filtrate was treated with 15 ml of conc. HCl solution. The solid product was recrystallized from methanol/ether to afford 6.53 g (85%) of 2,6-dichloro-3-(2-pyrrolidinoethoxy)benzoic acid hydrochloride (Formula III: Ar=2,6-Cl2 -3- (OCH2CH2 -1-pyrrolidinyl)phenyl) as a white crystalline solid, m.p. 257°-259° C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccc(N2CCN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine (0.43 g, 2.0 mmol), phenylisocyanate (0.29 ml, 2.5 mmol) and methanol (60 ml) was stirred at room temperature for 40 hours. The mixture was evaporated and diethylether (30 ml) was added, the precipitate was filtered. The product was isolated. Yield 0.23 g (34%). Mp. 145° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NS(=O)(=O)c3ccccc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with benzene sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 467.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.90 (s, 1H), 8.77 (s, 1H), 8.42 (d, 1H, J=5 Hz), 8.23 (s, 1H), 8.10 (d, 1H, J=5.5 Hz), 7.68 (d, 2H, J=7.5 Hz), 7.56 (t, 1H, J=7.5 Hz), 7.45 (t, 2H, J=7.5 Hz), 4.47 (m, 2H), 3.35 (s, 3H), 1.87 (m, 1H), 1.75 (m, 1H), 1.39 (d, 6H, J=6.5 Hz), 0.77 (t, 3H, J=7.5 Hz).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([SH:26])=[N:22][N:21]=1.Cl>O.CC(C)=O.C([O-])(O)=O.[Na+]>[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([S:26][CH2:5][C:6]2[CH2:15][S:14][C@@H:9]3[CH:10]([NH2:13])[C:11](=[O:12])[N:8]3[C:7]=2[C:16]([OH:18])=[O:17])=[N:22][N:21]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1C
Yield: 60 %

Procedure:
To a solution of NaHCO3 (4.2 g., 0.05 mol.) in water (50 ml.) was added 7-ACA (6.8 g., 0.025 mol.), water (50 ml.) and acetone (25 ml.). The resulting solution was warmed to 45° and then a solution of 3,4-dimethyl-5-mercapto-1,2,4-triazole (5.0 g., 0.038 mol.) in acetone (50 ml.) and 5% NaHCO3 (10 ml.) was added. The reaction was refluxed until the reaction was completed as determined by the disappearance of the acetoxy carbonyl band in the infrared absorption spectrum. During this time the pH was maintained at ca. 7.6. The solution was cooled to 10° and adjusted to pH 3.5 with 3N HCl. The precipitated product was collected, washed with acetone, and dried to give a 60% yield of 3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-7-amino-3-cephem-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[CH2:6]2.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:5]1[CH2:6][C:7]2[C:3]([CH:4]=1)=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([CH3:11])=[CH:9][CH:8]=2
Reactant: Br[Mg]c1ccccc1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(ccc(C)c2-c2ccccc2)C1

Procedure:
4-Bromo-2,5-dimethylindene (9.0 g, 40 mmol), prepared as described under I.(b) above, and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 300 ml of diethyl ether (Et2O). Phenylmagnesium bromide, 3.0 M in Et2O, (13.5 ml, 40 mmol) was added under vigorous stirring and the reaction stirred overnight at reflux. The resultant reaction was slowly quenched with H2O to neutralize unreacted Grignard reagent, subsequently treated with 100 ml of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The resultant organic layer was dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield is 1.3 g (15%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[C:21]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1.N>CN(C=O)C>[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH:65][C:17]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:22]=[C:21]([S:23]([F:26])([F:28])([F:27])([F:24])[F:25])[CH:20]=2)=[O:19])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 16A (320 mg, 0.74 mmol) was dissolved in 2.3 ml of DMF, HATU (309 mg, 0.81 mmol) and then 4-methylmorpholine (0.32 ml) were added, and the mixture was stirred at RT for 30 min. At −5° C., the compound of Example 7A (103 mg, 0.37 mmol) was then added and the mixture was stirred at RT for 16 h. A few milliliters of concentrated aqueous ammonia solution were then added. The mixture was stirred at RT for 15 min and then extracted with ethyl acetate. The organic phase was washed with conc. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 28). This gave 210 mg (purity 61%, 50% of theory) of the title compound which was used without further purification for the next synthesis step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19]([N:30]3[CH2:31][CH2:32][N:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:28][CH2:29]3)=[CH:18][CH:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(Br)cc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)C2
Yield: 97.9 %

Procedure:
3-(4-Bromophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.64 g, 1.7 mmol), 1-methanesulfonylpiperazine (0.43 g, 2.6 mmol), tris-(dibenzylideneacetone)dipalladium (0.069 g, 0.07 mmol), S-Phos (0.11 g, 0.28 mmol), and sodium t-butoxide (0.25 g, 2.6 mmol) are placed in 10 ml of toluene under nitrogen. The reaction medium is stirred at reflux for 1 h 30. After hydrolysis with a saturated aqueous NaHCO3 solution, and extraction with ethyl acetate, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over MgSO4. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol/ethyl acetate in dichloromethane ranging from 100/0/0 to 7/2.5/0.5 (dichloromethane/ethyl acetate/methanol). 0.75 g of expected 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-3,8-diazabicyclo[3.2.1]-octane-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)[C:31](Cl)=[O:32]>C(Cl)Cl>[OH:32][CH2:31][C:27](=[O:29])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CC(=O)CO
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of about 50 g of 2-(octadecyloxy)phenyl acetic acid in about 400 ml of methylene chloride was added about 19.6 g of oxalylchloride. After stirring about 3 hours the solvent was removed and the residue was dissolved in hexane and filtered through celite. The hexane was removed and to the residue was added about 79.5 g of tris-trimethylsilyloxyethylene. This mixture was stirred at about 90°-95° C. for 1.5 hours, then the oil was poured into a mixture of about 30 ml of concentrated (about 12N) hydrochloric acid, about 170 ml of water and about 200 ml of tetrahydrofuran and stirred at reflux for about 1/2 hour. The tetrahydrofuran was removed and the residue was extracted with ether. The ether extract was washed with dilute sodium bicarbonate, then brine and dried. The solvent was removed and the residue recrystallized from hexane, giving about 31 g of the desired title compound as a white solid, mp 59°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([OH:21])=O)[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])=[O:21])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reactant: C[C@@H](O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-2,6-naphthyridin-5-yl)amino]-4-methylbenzoic acid (Example 1, Step 5) (25 mg, 0.07 mmol) and (2R)-1-aminopropan-2-ol (8 mg, 0.1 mmol) in DMF (0.7 mL) was added BOP (91 mg, 0.21 mmol) and Hunig's base (0.4 mL, 0.21 mmol). The reaction was warmed to 60° C. and the reaction stirred for 18 hours and was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-10% MeOH/CH2Cl2) afforded the title compound.
Reaction SMILES: [CH2:1]=[O:2].C([Al](CCCCCCCCCC)[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])CCCCCCCCC>CCCCCC>[CH2:1]([OH:2])/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=O
Reactant: CCCCCCCCCCC=C[Al](CCCCCCCCCC)CCCCCCCCCC
Solvent: CCCCCC
Product: CCCCCCCCCC/C=C\CO
Yield: 21.5 %

Procedure:
Similarly to the procedure described in Example 1, a 17% slurry of 159 grams (5.29 moles) of paraformaldehyde in n-hexane was treated with 1488 grams (3.12 moles) of di-n-decyl dodecenyl aluminum (obtained from tri-n-decyl aluminum and acetylene). Distillation of the hydrolysis product was performed under 0.35 mm Hg. The product fraction was removed at 89°-99° C. There was obtained 133 grams (0.67 moles) of cis-2-tridecen-1-ol (13.3% of theoretical yield), having a purity of 92%. Identity of the compound was confirmed by ir and nmr spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Br-].[F:20][C:21]1[C:46]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].FC(O)C1C=CC=C(OCCCCCCCC)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.FC1C(OCCCCCCCC)=CC=CC=1CBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Cl>C1COCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:23][C:22]1[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:21]=1[F:20]
Reactant: CCCCCCCCOc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reactant: CCCCCCCCOc1cccc(C=O)c1F
Agent: BrBr
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCOc1cccc(C(O)F)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOc1cccc(C=Cc2cccc(OCCCCCCCC)c2F)c1F

Procedure:
A solution of 2.5 g of 2-fluoro-3-octyloxybenzaldehyde (prepared by reacting 2-octyloxyfluorobenzene with lithium diisopropylamide followed by reaction with N,N-dimethylformamide) in 50 ml of THF is added dropwise at 20° C. to a fully reacted mixture of 5.6 g of 2-fluoro-3-octyloxybenzyltriphenylphosphoniumbromide (prepared by the reaction sequence: reaction of 2-fluoro-3-octyloxybenzaldehyde with LiAlH4 in THF to give fluoro-3-octyloxybenzyl alcohol, reaction of the latter with triphenylphosphine/Br2 to give 2-fluoro-3-octyloxybenzyl bromide and reaction of the latter with triphenylphosphine in toluene) and 1.2 g of potassium tert-butoxide in 100 ml of THF. When the reaction is complete, the mixture is adjusted to pH 5 using HCl, 500 ml of H2O are added, and the mixture is extracted three times with 100 ml of diethyl ether in each case. Chromatography on silica gel using dichloromethane/heptane 1:1 gives 1,2-bis(2-fluoro-3-octyloxyphenyl)ethene as an E/Z-mixture. The latter is dissolved in cyclohexane, 4 mol % of iodine are added, and the mixture is exposed to UV light for 8 hours at 25° C. in a quartz apparatus. Chromatography on SiO2 using dichloromethane and recrystallization from acetonitrile give 1.2 g of 1,8-difluoro-2,7-dioctyloxyphenanthrene as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]([NH:6][NH:7][C:8]([O:10][CH3:11])=[O:9])=[S:5].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][S:5]/[C:4](=[N:6]\[NH:7][C:8]([O:10][CH3:11])=[O:9])/[CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: COC(=O)NNC(=S)CC(C)(C)C
Reactant: C=CC(=O)OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCS/C(CC(C)(C)C)=N\NC(=O)OC
Yield: 92.7 %

Procedure:
A mixture of 20.5 g of 2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methyl ester, 12.92 g of methyl acrylate, 1 ml of triethylamine and 300 ml of dry benzene was heated at reflux for 8 hours, then cooled and concentrated in vacuo. The residual oil was chromatographed through a bed of hydrous magnesium silicate, eluting with dichloromethane and evaporated, giving 27 g of (Z)-[1-[(3-methoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>C(#N)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrile (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[C:24]([O:39][CH3:40])=[CH:23][C:4]=1[CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)C(=O)OC(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]([CH2:5][CH2:6][NH:7][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:23][C:24]([O:39][CH3:40])=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[CH:26]=1
Reactant: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(CCNCc2cccc(F)c2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 10 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
A solution of HCl in 1,4-dioxane (0.5 mL) was added to a solution of tert-butyl 2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(3-fluorobenzyl)carbamate (0.22 g 0.4 mmol) in DCM (30 mL) at 0° C. and the mixture stirred at 10° C. for 2 hours. The solvents were removed under reduced pressure to leave a solid residue that was washed with methanol (2×5 mL) and dried under reduced pressure to give the title compound (100 mg, 51%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[O:16][CH2:17][C:18](O)=[O:19])=[C:9]([F:26])[CH:8]=1)[CH3:2].Cl.CN.[CH2:31]([N:33](CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:26][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:25]=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:15]([O:16][CH2:17][C:18]([NH:33][CH3:31])=[O:19])[CH:14]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)O)c2)c(F)c1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)NC)c2)c(F)c1
Yield: 97 %

Procedure:
A solution of (3-{[4-(3-ethoxy-3-oxopropyl)-2-fluorophenoxy]methyl}phenoxy)acetic acid (0.34 g, 0.90 mmol), methylamine hydrochloride (0.073 g, 1.08 mmol), triethylamine (0.22 g, 2.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.08 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.08 mmol) in DMF (7 mL) was stirred at room temperature for 18 hours. Then, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with saturated brine and water, and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=2:8) to give the title compound (0.34 g, yield 97%) as an oily matter.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.C1(C)C=CC=CC=1.CS(O[CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:44]=[CH2:45])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)(=O)=O>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:44]=[CH2:45])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Reactant: Oc1cccc(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3cccc(F)c3F)CC2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In DMF, trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate was dissolved, and 2,3-difluorophenol and tripotassium phosphate were added thereto, and then stirred for 2 hours at 80 to 100° C. Water and toluene were added thereto, and the organic layer was fractioned. The resultant product was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography, to thereby obtain 2,3-difluoro-1-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]2[N:18]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3Cl)nc12
Yield: 17.6 %

Procedure:
Reaction of 1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 2,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light brown solid (63 mg, 18%). MS (ISP) 357.1 [(M+H)+]; mp 180° C.