Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C.[H][H]>[Pd].CCCCCC>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10%palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20%ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[C:25]([CH2:27][NH2:28])[CH:24]=[CH:23][C:22]=2[Cl:29])=[CH:15][C:14]=1[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[C:25]([CH2:27][NH:28][C:4]([C:3]([CH3:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[O:5])[CH:24]=[CH:23][C:22]=2[Cl:29])=[CH:15][C:14]=1[C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:32]
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C(F)(F)F)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To 1.0 mL of a 0.13 M solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid (0.13 mmol) in DMF was added 1.0 mL of a 0.1 M solution of N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol) in DMF and triethylamine (70 μL, 0.50 mmol). Then 1.0 mL of a 0.115 M solution of TBTU (0.115 mmol) in DMF was added and the mixture was stirred overnight. The reaction mixture was directly purified via prep. HPLC to furnish the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.O>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([B:24]([OH:29])[OH:25])=[CH:8][C:9]=1[C:20]([F:23])([F:22])[F:21]
Reactant: COCCOCOc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexane, 91.2 ml) was added dropwise to a solution of 4-bromo-1-(2-methoxy-ethoxymethoxy)-2-trifluoromethyl-benzene (30 g) in dry THF (335 ml) at −78° C. under nitrogen atmosphere. The mixture was then stirred at −78° C. for another 30 minutes. Triisopropyl borate (101 ml) was then added slowly at −78° C. under nitrogen, the mixture was then allowed to slowly warm up to room temperature and stirred at this temperature overnight. After adding water (300 ml), the mixture was extracted with ethyl acetate (300 ml×3). The combined organic layers were dried over sodium sulphate. After removal of solvent under reduced pressure, the residue was columned on silica gel using DCM-MeOH as eluant to give 4-(2-methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl-boronic acid (14.4 g).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[C:63]([F:66])([F:65])[F:64])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:68])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[C:63]([F:66])([F:64])[F:65])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:68])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc3)cc2C1=O
Yield: 81 %

Procedure:
The compound of example 200 was prepared analogous to compound of example 98 by hydrolysis of compound of example 199.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AlBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH3:18].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH3:18])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCBr
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, ethyl bromide and sodium ethylate in ethanol. EI-MS m/e (%):256 (M+, 29), 255 ([M—H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:12]
Reactant: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN2CCC(Cc3ccccc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (1.0 g, 3.77 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice /acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (4.25 mL, 1 M in THF, 4.52 mmol). After 30 minutes, add a solution of benzyl bromide (0.77 g, 4.52 mmol) in tetrahydrofuran (1 mL). After the addition of benzyl bromide is complete, warm slowly to ambient temperature. After 15 minutes, add water and extract three times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound: Rf=0.69 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH:23]4[CH2:25][CH2:24]4)[CH:22]=2)[O:19][C:18]([CH3:27])([CH3:26])[CH2:17][C:16]3([CH3:29])[CH3:28])=[CH:7][CH:6]=1)C.CO.[OH-].[Na+].O>C(#N)C>[CH:23]1([C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:26])([CH3:27])[CH2:17][C:16]3([CH3:29])[CH3:28])[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using 4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid ethyl ester (Compound 33, 0.135 g, 0.34 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.093 g, 73%).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([CH:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:56])[CH3:55])[CH2:50][CH2:49]2)=[O:47])=[CH:44][N:43]=[N:42]1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([OH:47])([C:45]3[N:41]([CH3:40])[N:42]=[N:43][CH:44]=3)[CH:48]3[CH2:53][CH2:52][N:51]([C:54](=[O:56])[CH3:55])[CH2:50][CH2:49]3)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N1CCC(C(=O)c2cnnn2C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
n-BuLi (2.5 M in THF, 0.60 mL, 1.5 mmol) was added dropwise over a 3 minute period to a mixture of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (0.5 g, 1.16 mmol, Intermediate 12: step d) and 1-(4-(1-methyl-1H-1,2,3-triazole-5-carbonyl)piperidin-1-yl)ethanone (0.27 g, 1.16 mmol, Intermediate 52: step b) in dry THF (8 mL) at −78° C. Stirring was continued at −78° C. for 10 minutes. The reaction mixture was then immersed in an ice bath and stirred at 0° C. for 1 hour. The reaction was then quenched with saturated aqueous NaHCO3, diluted with water and extracted with EtOAc (2×). The EtOAc extracts were dried over Na2SO4, filtered, evaporated in vacuo and purified by FCC (0-10% MeOH in DCM, gradient) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 2H), 7.80 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 6.25 (s, 1H), 4.41-4.57 (m, 0.5H), 4.34 (s, 2.5H), 4.01 (s, 3H), 3.67-3.94 (m, 0.5H), 3.63 (d, J=3.5 Hz, 3H), 3.08-3.23 (m, 0.5H), 2.82-2.96 (m, 0.5H), 2.56-2.74 (m, 1.5H), 2.27-2.44 (m, 0.5H), 1.84-2.05 (m, 4H), 1.65-1.84 (m, 0.5H), 0.76-1.38 (m, 3H); MS (ESI) 588.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)[N:11]=[N:10][C:9]=2[C:24]([OH:26])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:30]2N(O)N=[N:33][C:31]=2[CH:32]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(=O)([O-])O.[Na+].O>[CH:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=3)[N:11]=[N:10][C:9]=2[C:24]([NH:33][CH:31]2[CH2:32][CH2:30]2)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 183.6 %

Procedure:
5-(Cyclohexylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (357 mg, 1.00 mmol) obtained in Example 102b), HOBt (68.2 mg, 0.500 mmol, 0.5 eq.) and cyclopropylamine (0.093 ml, 1.30 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 4.5 ml), WSC (215 mg, 1.10 mmol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the obtained suspension was diluted with 2% aqueous sodium hydrogen carbonate solution. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (363 mg, 0.918 mmol, 91.8%).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].Cl.[C:8](=[N:16][OH:17])([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8](=[N:16][OH:17])[NH2:15])=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: NC(=NO)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccccc1C(N)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Following the known process [Ber, 18, 2467 (1875)], a solution of 13.4 ml (0.14 mol) of ethyl chlorocarbonate in 100 ml of chloroform was added dropwise to a solution of 38.2 g (0.28 mol) of benzamidoxime hydrochloride in 380 ml of chloroform. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours. The benzamidoxime thus precipitated was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl alcohol, to which 30 ml, of water were added. Most ethyl alcohol was then distilled off under reduced pressure. Crystals thus formed were collected by filtration, washed with water and then dried under reduced pressure, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH:10]([CH3:32])[CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:10]([CH3:32])[CH2:9][C:1]#[N:2])=[C:25]([F:31])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C(C)COS(C)(=O)=O)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C(C)CC#N)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
16.2 mg (0.25 mmol) of potassium cyanide were added to 70 mg (0.12 mmol) of the compound from Example 55A in 3 ml of DMSO. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 33.4 mg (69% of theory) of the title compound were obtained as a mixture of diastereomers.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.C(=CC(C1C=CC=CC=1)=O)C1C=CC=CC=1>CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCO
Agent: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCCCCCC
Temperature: 125 °C
Reaction time: 40 h
Yield: 16.1 %

Procedure:
In a typical combined dehydrogenation/decarbonylation, 1-decanol (398 μmol) was treated with RuCl2 (PPh3)3 (19 μmol), RhCl(PPh3)3 (96 pmol) and benzalacetophenone (438 pmol) in 2 ml of N-methyl-2-pyrrolidinone and heated under nitrogen at 125° C. After 40 hours, 64 μmol of nonane had formed; after 6 days the yield of nonane was 92 μmol (96% based on Rh).
Reaction SMILES: C1(C([O:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[C:17](=[O:19])[CH3:18])=O)CCCCC1.[H-].[Na+].O.[C:23]([OH:26])(=O)[CH3:24]>O1CCCC1>[CH:24]1([C:23](=[O:26])[CH2:18][C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[OH:9])=[O:19])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]1
Reactant: CC(=O)c1cccc(C)c1OC(=O)C1CCCCC1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)CC(=O)C2CCCCC2)c1O
Temperature: 25 °C

Procedure:
2-Acetyl-6-methylphenyl cyclohexanecarboxylate (5.2 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and to the solution was added 60% sodium hydride (880 mg) by portions with stirring at room temperature. After stirring under reflux for 2 hours, the mixture was poured into cold water, acidified with acetic acid and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and then concentrated under reduced pressure to obtain the title compound (5.2 g) as crystals in a quantitative yield. The crystals were recrystallized from methanol to obtain the prisms, m.p. 42°-43° C.
Reaction SMILES: [O:1]1[C:12]2[CH:4]([CH2:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.[C:13]([O:16][C:17](=O)C)(=[O:15])[CH3:14].C=O.S(=O)(=O)(O)O>CCCCCC.C(O)(=O)C.O>[C:13]([O:16][CH2:17][C:10]1[CH:11]=[C:12]2[O:1][CH2:2][O:3][C:4]2=[CH:5][C:6]=1[CH2:7][CH2:8][CH3:9])(=[O:15])[CH3:14]
Reactant: C=CCC1=CC=C2OCOC2C1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCc1cc2c(cc1COC(C)=O)OCO2
Temperature: 20 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Dihydrosafrole (20 g), acetic acid (100 g) and water (10 g) were added to a mixture of acetic acid (250 ml), hexane (200 ml), acetic anhydride (40 g) and paraformaldehyde (40 g) to which 1.7 g of 40% sulphuric acid had been added. The reaction mixture was held at 60° C. for 5 hours and was then cooled to 20° C. and excess paraformaldehyde removed by filtration. Saturated brine (200 ml) was then added followed by ether (100 ml). The mixture was ether extracted (3 times) and combined extracts washed with brine (3 times). Following removal of solvent under reduced pressure the material was distilled under vacuum to give 4,5-methylenedioxy-2-propylbenzyl acetate (8) as a colourless oil (b.pt 154°-165° C. at 2.0 mm Hg) . . . Yield 59%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:12](=[O:33])[CH:11]([CH2:34][C:35]2[CH:83]=[CH:82][C:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][O:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH:56]5[O:60][C:59](=[O:61])[N:58](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[C:57]5=[O:81])=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[O:10]1>C(OCC)(=O)C>[O:8]=[C:9]1[NH:13][C:12](=[O:33])[CH:11]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([CH2:47][O:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH:56]5[O:60][C:59](=[O:61])[NH:58][C:57]5=[O:81])=[CH:51][CH:50]=4)=[CH:45][CH:46]=3)=[CH:82][CH:83]=2)[O:10]1
Reactant: O=C1OC(Cc2ccc(OCc3ccc(COc4ccc(CC5OC(=O)N(C(c6ccccc6)(c6ccccc6)c6ccccc6)C5=O)cc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(COc4ccc(CC5OC(=O)NC5=O)cc4)cc3)cc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 10 ml portion of trifluoroacetic acid was added to 220 mg of the product of Example 23, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography (toluene-ethyl acetate, 1:1) to obtain 1,4-bis[[4-[(2,4-dioxo-5-oxazolidinyl)methyl]phenoxy]methyl]benzene.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][N:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C(=O)C.O>[CH2:20]([NH:23][C:11]([C:10]1[C:5]2[C:6]([C:2](=[O:1])[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=2)=[CH:7][NH:8][CH:9]=1)=[O:13])[CH2:21][CH3:22]
Reactant: CCCN
Reactant: O=C(O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCNC(=O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 3,5-dihydro-3-oxo-2-phenyl-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (50 mg, 0.196 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was added propylamine (17.8 ml, 0.216 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (55 mg, 0.216 mmol), then, dropwise, anhydrous triethylamine (60 ml, 0.430 mmol). The mixture was stirred under nitrogen at room temperature for 2 h. Water (5 ml) was then added and the mixture was stirred before collecting the solid by filtration. The solid was washed with water, then hexane, and dried under vacuum at 70° C. The solid was then purified by recrystallisation (CH2Cl2-MeOH-EtOAc) to afford 39.1 mg (67%) of the title compound as an orange solid; 1H NMR (360 MHz, DMSO-d6) δ0.99 (3H, t, J 7.3 Hz), 1.62 (2H, sextet, J 7.2 Hz), 3.41 (2H, q, J 6.8 Hz), 7.21 (1H, t, J 7.4 Hz), 7.47 (2H, t, J 7.5 Hz), 8.16 (1H, s), 8.18 (2H, d, J 7.6 Hz), 8.68 (1H, s), 8.70 (1H, t), 12.69 (1H, br s); MS (ES+) m/z 297 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([F:8])[CH:7]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(F)cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (4.10 g) and titanium tetrachloride (4.4 mL), dichloromethyl methyl ether (3.5 mL) was added under ice cooling, and then the reaction mixture was stirred at 0° C. for 2.5 hours. To the reaction mixture was added chloroform, and the reaction mixture was poured into ice water, and then stirred at room temperature for 1 hour. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was added hexane and the produced solid was filtered to give the titled compound (1.61 g) as a white solid.