Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[SH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([Si:16]([CH3:49])([CH3:48])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:29]2[S:33][C:32]([CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)=[C:31]([CH3:46])[CH:30]=2)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=1[CH3:47])([CH3:15])([CH3:14])[CH3:13]>CCO>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][S:5][CH2:34][C:32]1[S:33][C:29]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][Si:16]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:49])[CH3:48])=[C:19]([CH3:47])[CH:20]=2)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:30][C:31]=1[CH3:46])[CH3:11]
Reactant: CCOC(=O)CS
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(COS(=O)(=O)c2ccc(C)cc2)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1sc(C(CC)(CC)c2ccc(O[Si](C)(C)C(C)(C)C)c(C)c2)cc1C
Temperature: 25 °C
Yield: 26.8 %

Procedure:
To a solution of 2.68 M sodium ethoxide (507 μl, 1.36 mmol) in EtOH (2 ml) is added ethyl 2-mercaptoacetate (149 μl, 1.36 mmol) and stirred at RT for 30 m. The mixture is added a solution of toluene-4-sulfonic acid 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethyl ester (740 mg, 1.29 mmol) in EtOH (2 ml) is added and refluxed for 15 m. The reaction is concentrated and partitioned between EtOAc (100 ml) and 0.2N HCl (50 ml). The organic layer is washed with water (50 ml), dried (MgSO4), concentrated, and chromatographed (12 g SiO2, 5% EtOAc/Hex) to yield the title compound (180 mg, 27%). 1NMR (400 MHz, CDCl3) δ 7.00 (d, 1H, J=2.2 Hz), 6.92 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.46 (s, 1H), 4.17 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.14 (s, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.07-1.98 (m, 4H), 1.28 (t, 3H, J=7.0 Hz), 1.00 (s, 9H), 0.68 (t, 6H, J=7.3 Hz), 0.20 (s, 6H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([O:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: OCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
Phenol (0.098 g, 1.04 mmol) and 7-bromo-1-heptanol (0.243 g, 1.246 mmol) were dissolved in acetone (25 mL) in a 50 mL round bottomed flask. Potassium carbonate (0.86 g, 6.23 mmol) was added to this solution and the flask was fitted with a condenser and refluxed using an oil bath at 70° C. for a period of 26 hours. The reaction flask was then cooled to room temperature. The contents of the flask was then filtered through a fluted filter paper and washed with acetone (10 mL). The combined filtrate was then evaporated to dryness under reduced pressure. The residue obtained was dissolved in ethyl acetate (25 mL). The ethyl acetate solution was then washed with 1N. NaOH (3×5 mL), water (2×5 mL) and brine (2×5 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product. The product was then purified by flash chromatography (Si gel, 12×2.5 cm) using ethyl acetate: hexane (1:1) to afford the pure 7-(phenyloxy)-1-heptanol (0.22 g, quantitative yield). The product alcohol from step A was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.31-1.52 (m, 6H), 1.52-1.63 (m, 2H), 1.73-1.89 (m, 2H), 1.97 (bs, 1H), 3.61 (t, 2H, J=6.57 Hz), 3.93 (t, 2H, J=6.50 Hz), 6.80-6.97 (m, 3H) and 7.20-7.28 (m, 2H); 13C-NMR (CDCl3) δ 25.5, 25.8, 29.0, 29.1, 32.4, 62.5, 67.7, 114.3, 120.3, 129.2 and 158.8; IR (neat): 3348 cm−1; MS (ES+): 209 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.C(=O)([O-])O.[Na+:12].[N:13]1([CH2:18][C:19]([NH:21][C@@H:22]2[C:51](=[O:52])[N:24]3[C:25]([C:48]([OH:50])=[O:49])=[C:26]([CH2:29]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[N:16][N:15]=[N:14]1>P([O-])([O-])([O-])=O>[N:13]1([CH2:18][C:19]([NH:21][C@@H:22]2[C:51](=[O:52])[N:24]3[C:25]([C:48]([O-:50])=[O:49])=[C:26]([CH2:29][S:1][C:2]4[S:6][C:5]([CH3:7])=[N:4][N:3]=4)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[N:16][N:15]=[N:14]1.[Na+:12]
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1

Procedure:
In a phosphate buffer solution of pH 6.4(3 ml) are dissolved 5-mercapto-2-methyl-1,3,4-thiadiazole (79 mg), sodium hydrogen carbonate (92 mg) and 7β-(1H-tetrazol-1-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (298 mg) and the resultant solution is heated at 60° C. for one hour. Then, the mixture is concentrated and the residue is subjected to column chromatography on Sephadex LH-20, elution being carried out with water. The fractions containing the desired product are pooled and lyophilized. The procedure provides sodium 7β-(1H-tetrazol-1-yl)acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate. This product is in good agreement with the authentic sample in NMR spectrum.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][CH:13]1[CH2:19][CH2:18][C:17]2[C:20]([O:30][CH3:31])=[C:21]([O:28][CH3:29])[C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:16]=2[CH2:15][CH2:14]1)(=O)C.Cl>C(OCC)C.O>[CH3:25][O:24][C:23]1[C:16]2[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][OH:10])[CH2:19][CH2:18][C:17]=2[C:20]([O:30][CH3:31])=[C:21]([O:28][CH3:29])[C:22]=1[O:26][CH3:27]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOC(C)=O)CC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCO)CC2
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a suspension of lithium aluminum hydride (486 mg) in diethyl ether (20 ml) was dropwise added a solution of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl acetate (3.00 g) in diethyl ether (10 ml) with cooling with ice. After the reaction mixture stirred for 30 min, 10% hydrochloric acid was added to the reaction mixture, which was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:1) to yield the entitled compound (2.60 g) as crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C([O-])(O)=O.[Na+].[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.C(O)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCCC1.ClCCCl>[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([NH:2][C@@H:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:14]([NH2:16])=[O:15])[CH2:28][CH2:29]1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N[C@@H](Cc2c[nH]c3ccccc23)C(N)=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The hydrochloride of L-tryptophanamide (1.49 g, 6.3 mmol) was vigorously stirred with 1,2-dichloroethane (30 ml), tetrahydrofuran (20 ml) and saturated NaHCO3 solution (40 ml) for 15 min and the aqueous phase was then immediately extracted with a tetrahydrofuran/ethyl acetate mixture (1:3.5×40 ml). After drying with Na2SO4 the organic phase was concentrated to low volume. The released base (1.3 g, 6.3 mmol) and 4-(dimethylamino)-4-phenylcyclohexanone (1.3 g, 6.3 mmol) were dissolved in tetrahydrofuran (40 ml) and 1,2-dichloroethane (30 ml) in argon. Glacial acetic acid (0.37 ml, 6.3 mmol) and Na2SO4 (3.2 g) were added to the clear solution. After a reaction time of 15 min the reaction mixture was mixed with NaBH(OAc)3 (2 g, 9 mmol) and stirred for 2 d at room temperature. For work up of the batch the mixture was mixed with saturated NaHCO3 solution (60 ml) and stirred for 15 min. The aqueous phase was extracted with dichloromethane (2×40 ml). The combined organic phases were concentrated to low volume after drying, and a light brown oil was obtained. The chromatographic separation of the substance mixture on silica gel 60 (50 g) was conducted with ethyl acetate/methanol (1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([Cl:14])=[CH:4][N:3]=1.[NH3:15]>>[Cl:14][C:5]1[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)=[N:7][C:2]([NH2:15])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(OC2CCOC2)n1
Reactant: N
Product: Nc1ncc(Cl)c(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,5-dichloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine (intermediate 31,100 mg, 0.425 mmol) in NH3 (7 M in MeOH, 608 μl, 4.25 mmol) was heated to 70° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 6.78 (br. s, 2H), 5.47-5.54 (m, 1H), 3.72-3.94 (m, 4H), 2.18-2.29 (m, 1H), 1.95-2.04 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:16]([C:18]1[C:19]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][NH2:28])=[N:20][CH:21]=[N:22][C:23]=1[CH3:24])[CH3:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:16]([C:18]1[C:19]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][NH:28][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])=[N:20][CH:21]=[N:22][C:23]=1[CH3:24])[CH3:17]
Reactant: CCc1c(C)ncnc1NC(CC)CN
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(C)ncnc1NC(CC)CNC(=O)/C=C/C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15 mg, 0.11 mmol) was dissolved in DCM (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (9.5 μl, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)butane-1,2-diamine (24.5 mg, 0.1 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in DMF (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 12.7 mg (0.038 mmol, 38%).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)CC1>>[ClH:1].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)cc(F)c56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66) and amine 14 analogously to the method described in example 1.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][CH2:9][C@@H:10]([OH:34])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:11]([O:30][CH2:29][C@@H:28]([O:31][C:5](=[O:7])[CH3:6])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C@H:10]([O:34][C:25](=[O:26])[CH3:24])[CH2:9][Cl:8])=[CH:18][CH:17]=2)([CH3:21])[CH3:20])=[CH:33][CH:32]=1)(=[O:12])[CH3:10]
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](COc1ccc(C(C)(C)c2ccc(OC[C@@H](CCl)OC(C)=O)cc2)cc1)OC(C)=O
Reaction time: 8 h
Yield: 182.3 %

Procedure:
Acetic Anhydride (4.3 g, 41.7 mmol) was added to a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (2.8 g, 6.95 mmol) and DMAP (30 mg, 0.25 mmol) in anhydrous pyridine (24 mL) in a water bath. The resulting solution was stirred overnight. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL), washed subsequently with water (2×40 mL), then cold aqueous 1M HCl (40 mL), saturated NaHCO3 (40 mL) and water (40 mL). The organic layer was dried over Mg2SO4, filtered and concentrated to give light yellow oil. The crude product was purified by column chromatography (eluent: 5% ethyl acetate in hexane to 20% ethyl acetate in hexane) to afford the title compound (3.30 g, 91.5% yield) as a colorless viscous oil.
Reaction SMILES: N.C(OP(=O)(OCC)O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[C:17]([CH3:20])([CH3:19])[CH3:18])C.[Li]>CCOCC>[C:13]([C:10]1[CH:11]=[CH:12][CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOP(=O)(OCC)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Agent: N
Agent: [Li]
Solvent: CCOCC
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To NH3 (liquid, 250 mL) was added a solution of phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester (51 g, crude from last step, about 0.2 mol) in Et2O (anhydrous, 150 mL) at −78° C. under N2 atmosphere. Lithium metal was added to the solution in small pieces until a blue color persisted. The reaction mixture was stirred at −78° C. for 15 min and then quenched with sat. NH4Cl solution until the mixture turned colorless. Liquid NH3 was evaporated and the residue was dissolved in water, extracted with Et2O (300 mL×2). The combined organic phases were dried over Na2SO4 and concentrated to give crude 1,3-di-tert-butyl-benzene as a yellow oil (30.4 g, 94% over 2 steps, contaminated with some mineral oil), which was used directly in next step.
Reaction SMILES: NN.[F:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(F)cc1
Agent: NN
Solvent: CO
Product: NCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
Hydrazine solution (138 mg, 2.75 mmol) was added to a solution of 2-(2-(4-fluorophenoxy)ethyl)isoindoline-1,3-dione (713 mg, 2.5 mmol) in methanol (8 ml) and stirred at room temperature for 4 hours. The resulting solid was filtered off and concentrated in vacuo. The residue was triturated with diethyl ether (30 ml), and the resulting solid was filtered off again and concentrated in vacuo to give 2-(4-fluorophenoxy)ethanamine (280 mg, 70%) as colorless oil: LCMS: 325 [M+1]+.
Reaction SMILES: [C:1](O)(=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]C>[Ni].C1CCCCC1.C([Sn](CCCC)(CCCC)CCCC)CCC>[CH3:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [Ni]
Agent: CCCC[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCC

Procedure:
A drum provided with a distillation system is successively fed with 50 g of palmitic acid, 10 g of dry Raney nickel in cyclohexane and 870 mg of tetrabutyl tin. The mixture is slowly heated while distilling the cyclohexane and passing a hydrogen stream, the drum being brought to a temperature of 300°-310° C. A liquid product distills at 210°-230° C. At time intervals, additional amounts of palmitic acid, totalling 150 g, are injected into the drum, while distilling progressively a product which, as shown by VPC analysis, consists mainly of a mixture of differently positioned isomers of linear pentadecene, comprising about 60% of 1-pentadecene. Some pentadecane has formed. The C15 olefin weight is 63.5 g; the selectivity to C15 olefin is 69% with respect to the converted acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[C:10]([O:14][C:15](=[O:44])[NH:16][C:17]([C:19]1[S:20][C:21]([S:42][CH3:43])=[C:22]([S:24]([C:27]2[CH:28]=[C:29]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([OH:40])=[CH:35][C:34]=3[CH3:41])[CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:23]=1)=[NH:18])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:40][C:36]1[CH:35]=[C:34]([CH3:41])[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([C:22]3[CH:23]=[C:19]([C:17]([NH:16][C:15]([O:14][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:44])=[NH:18])[S:20][C:21]=3[S:42][CH3:43])(=[O:26])=[O:25])[CH:28]=2)=[C:38]([CH3:39])[CH:37]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)OC(C)(C)C)cc2C)c1
Reaction time: 18 h
Yield: 22.1 %

Procedure:
Bromo-acetic acid tert-butyl ester (0.013 mL, 0.085 mmol) was added dropwise to a solution of {[4-(4′-hydroxy-2′,6′-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.050 g, 0.077 mmol) [example 124, step b] and potassium carbonate (0.021 g, 0.154 mmol) in acetone [1 mL] at room temperature and stirred for 18 hours. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.011 g, 28%) as a solid. ESI-MS (m/z): Calcd. for C31H38N2O7S3: 646.18; found: 646.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(OC([N:29]1[C:37]2[N:32]([C:33](=[O:39])[N:34]=[C:35](Cl)[CH:36]=2)[CH2:31][C@@H:30]1[CH3:40])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:35]1[CH:36]=[C:37]2[NH:29][C@@H:30]([CH3:40])[CH2:31][N:32]2[C:33](=[O:39])[N:34]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH2:26][CH2:25][N:24]([C:35]([O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].O1CCOCC1>>[ClH:47].[F:34][C:30]1[CH:29]=[C:28]([CH:27]2[CH2:26][CH2:25][N:24]([C:35]([O:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)=[O:36])[CH2:23][CH:22]2[CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 385 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added isopropanol, followed by heating for dissolution. Diisopropylether was added dropwise thereto, and the precipitate was isolated by filtration, and dried under reduced pressure to obtain 178 mg of 4-({[4-(3-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[N:14]([CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Reactant: CCCC(Br)CCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)N1C(=O)C(C)Oc2c(-c3ccc(C)cc3C)cccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(2,4-dimethylphenyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (43 mg, 1.68 mmol). After the mixture was stirred at 80° C. for 30 min, 4-bromoheptane (804 mg, 4.49 mmol) was added. The mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 186 mg (30%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.C(OCC)C>[CH3:25][N:2]([CH2:3][C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH:9]=1)[CH3:1]
Reactant: CSc1ccc(-c2cc(C(=O)N(C)C)sc2-c2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CSc1ccc(-c2cc(CN(C)C)sc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 79.9 %

Procedure:
A solution of N,N-dimethyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide (1.95 g) in benzene (15 ml) was added dropwise to an ice-cooled mixture of lithium aluminum hydride (0.27 g) in diethyl ether (10 ml). The mixture was refluxed for 9 hours. To the mixture was added dropwise 4N sodium hydroxide solution. Ethyl acetate was added, and the mixture was filtered. The filtrate was washed with water, dried and evaporated. The oily residue (2 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (2:1) to give a yellow oil of N,N-dimethyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]-2-thenylamine (1.5 g).