Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:59])[C:17]1[CH:22]=[C:21]([NH:23][C:24](=[O:40])[CH:25]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:20]=[C:19]([NH:41][C:42](=[O:58])[CH:43]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:18]=1.[C:60](Cl)(=[O:62])[CH3:61]>C(Cl)Cl>[C:60]([C:11]1[C:10]([O:13][CH3:14])=[CH:9][C:8]([NH:15][C:16](=[O:59])[C:17]2[CH:18]=[C:19]([NH:41][C:42](=[O:58])[CH:43]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:20]=[C:21]([NH:23][C:24](=[O:40])[CH:25]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:22]=2)=[C:7]([O:6][CH3:5])[CH:12]=1)(=[O:62])[CH3:61]
Reactant: CCCCCCCCC(CCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCC)CCCCCCCC)cc(C(=O)Nc2cc(OC)ccc2OC)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCC)CCCCCCCC)cc(C(=O)Nc2cc(OC)c(C(C)=O)cc2OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In 1.6 l of methylene chloride were dissolved 168 ml of acetyl chloride and 315 g of aluminum chloride. While cooling the resulting solution with ice, 400 g of the compound (7-C) obtained above was added thereto. The mixture was stirred at room temperature for one hour. The reaction mixture was then poured into 10 l of ice water, and the mixture was stirred for one hour. The methylene chloride layer was separated, washed twice with water and concentrated under reduced pressure. To the concentrate, there was added 2 of acetonitrile. The mixture was heated under reflux for one hour and then left to stand to cool it to room temperature. The resulting crystal was recovered by filtration to obtain 383 g of the compound (7-D). Yield: 93%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 80 °C
Yield: 17 %

Procedure:
Stirring a solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1395 g) in dried pyridine (10 ml) at room temperature, a solution of p-toluenesulfonyl chloride (629.1 mg) in dried pyridine (10 ml) was dropwise added gradually thereto. The resultant mixture was stirred at room temperature for 1.5 hours and then heated at 80° C. for 4.5 hours with stirring. After removal of the pyridine, water was added to the residue and the resultant aqueous mixture was acidified with dil. hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with dil. hydrochloric acid and then water, and dried. The resultant brown viscous oil was purified by column chromatography on silica-gel using an eluent (benzene:diethyl ether=1:1) to give an orange oil, which was crystallized by treating with diethyl ether. The resultant crystals were collected by filtration and recrystallized from a mixture of diethyl ether and n-hexane to give orange-yellowish prisms (0.1926 g) of diethyl 2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 87° to 88° C., which was identified with an authentic sample.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.[CH2:13]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>>[CH2:13]([N:16]1[CH2:21][CH2:20][C:19]2[NH:2][C:4]3[C:12]([C:18]=2[CH2:17]1)=[C:8]1[CH:9]=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH2:14][CH3:15]
Reactant: CCCN1CCC(=O)CC1
Reactant: NNc1ccc2sccc2c1
Agent: Cl
Product: CCCN1CCc2[nH]c3ccc4sccc4c3c2C1

Procedure:
This compound is formed analogously to that described in Example 15, from 2 g of 5-hydrazinobenzothiophene hydrochloride and 1.7 g of 1-propyl-4-piperidone. Melting point: 143°-144° C.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:9]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:9]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:32])=[O:31])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 97.8%) of the title compound.
Reaction SMILES: C1(S)C=CC=CC=1.C(N(CC)CC)C.[N:15]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1)=[N+]=[N-]>C(#N)C>[NH2:15][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1F
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(CN)cc1F
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a suspension of stannous chloride dihydrate (0.45 g, 2.4 mmol) in 20 mL of acetonitrile under stirring was added thiophenol (1.07 g, 9.7 mmol) and triethylamine (0.726 g, 7.17 mmol). Thereafter was added a solution of 4-azidomethyl-2-fluorobenzonitrile (0.279 g, 1.58 mmol; see step (iv) above) in a few mLs of acetonitrile. After 1.5 h, the azide was consumed and the solvent was evaporated. The residue was dissolved in methylene chloride and washed three times with 2M NaOH. The organic phase was extracted twice with 1M HCl. The combined acidic aqueous phase washed with methylene chloride and then made alkaline with 2M NaOH and extracted three times with methylene chloride. The organic phase was dried (Na2SO4) and evaporated to give 0.172 g (72%) of the desired sub-title compound which could be used without purification.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH2:59][CH2:60][CH3:61]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH3:61])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
32 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 5 mg of sodium hydride under cooling with ice. After 15 minutes, 25.6 μl of butyl bromide was added, and the reaction solution was stirred for 50 minutes. The reaction solution was allowed to react at room temperature further for 13 hours under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×22 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 26 mg of compound (36) as a colorless oily substance.
Reaction SMILES: O.[NH2:2][C:3]1[C:4]([CH2:14]SC)=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1Cl>C(O)(=O)C>[NH2:2][C:3]1[C:4]([CH3:14])=[C:5]([C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(N)cccc1C(F)(F)F

Procedure:
Add 70 ml of water, 150 ml of glacial acetic acid and 100 g. of 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride to a three-necked round bottom flask fitted with mechanical stirrer and condenser. Then add 535 g. of washed and neutralized Raney active nickel catalyst (Grace no. 28 in water). Heat to reflux (98° C.-100° C.) for 20 hours. Steam distill to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22].O>C1C=CC=CC=1>[NH2:22]/[C:9](/[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10]\[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)/C=C(\N)Cc1ccc(F)cc1
Yield: 100.4 %

Procedure:
Allyl 4-(4-fluorophenyl)-3-oxobutanoate (47 g, 198.95 mmol) and ammonium acetate (46.00 g, 596.85 mmol) were refluxed in benzene (250 mL) for 2 h with azeotropic removal of H2O and then cooled and concentrated. The residue was redissolved in Et2O and the organics washed with 1N HCl (2×), H2O, brine, and then dried (Na2SO4), filtered and concentrated to give 47 g (100% yield) of the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.17 (dd, J=8.4, 5.2 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 5.28 (dd, J=17.2, 1.6 Hz, 1H), 5.18 (dd, J=10.3, 1.0 Hz, 1H), 4.61 (s, 1H), 4.55 (d, J=5.6 Hz, 2H), 3.41 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:15]([CH:18]([CH3:20])[CH3:19])[CH:16]=O)[C:3]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]1[C:3]2=[C:2]([CH3:1])[C:10]3[C:5]([N:4]2[CH2:11][CH2:12][CH2:13]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Cc1c2n(c3ccccc13)CCCC2N(C=O)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C(C)C

Procedure:
A solution of N-(6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-yl)-N-(1-methylethyl)formamide (37.1 mmol) in tetrahydrofuran (50 mL) was added dropwise at 25° C. to a suspension of lithium aluminum hydride (1,6 g, 42.1 mmol) in the same solvent (50 mL). The reaction mixture was refluxed overnight under the exclusion of moisture. The metal complex was decomposed with a solution of water (3 mL) in the (20 mL) under nitrogen. The resulting suspension was filtered and the filtrate evaporated in vacuo. The residue was dissolved in CHCl3 (100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The oily residue was chromatographed on silica gel (200 g). Elution with 2% MeOH in CHCl3 afforded the title base.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1.[Cl-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]cc(I)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of C6 (900 mg, 3.2 mmol) in N,N-dimethylformamide (3 mL) and tetrahydrofuran (70 mL) was added sodium hydride (60% in mineral oil, 168 mg, 4.2 mmol). After 5 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (592 mg, 3.55 mmol) was added to the cold mixture. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0° C. and treated with additional sodium hydride (56 mg, 1.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (197 mg, 1.18 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided the product as a yellow oil. Yield: 650 mg, 1.59 mmol, 50%. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=6.0 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 5.44 (s, 2H), 3.44-3.50 (m, 2H), 0.86-0.92 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C@H:20]3[CH2:32][CH2:31][O:30][C@H:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C@H:20]3[CH2:32][CH2:31][O:30][C@H:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OC[C@@H]1OCC[C@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
Trifluoroacetic acid (7 mL) was added to a solution of methyl cis-(3aRS,9bRS)-7-[bis-(tert-butoxycarbonyl)amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 2, 0.66 g) in DCM (15 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was treated with aqueous sodium bicarbonate and extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.255 g) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][N:8]([CH2:18][C:19]#[N:20])[C:7]=2[CH:21]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][N:8]([CH2:18][CH2:19][NH:20][C:22](=[O:24])[CH3:23])[C:7]=2[CH:21]=1
Reactant: COc1ccc2c(c1)N(CC#N)CC(c1ccccc1)O2
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(CCNC(C)=O)CC(c1ccccc1)O2
Reaction time: 16 h

Procedure:
The compound obtained in Step D (350 mg; 1.25 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (30% by weight, 115 mg) and sodium acetate (1.5 eq.; 1.87 mmol; 154 mg) are then added. The mixture is left at 50° C. for 16 hours under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/9)). The title product is obtained in the form of white crystals and is recrystallised from an Et2O/i-PrOH (6/4) mixture.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([Si](OC)(OC)OC)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:41][C:42]1[CH:43]=[C:44](Br)[CH:45]=[CH:46][C:47]=1[F:48].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:45]3[CH:44]=[CH:43][C:42]([F:41])=[C:47]([F:48])[CH:46]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccc([Si](OC)(OC)OC)cc2)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(c2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To 0.645 g (2 mmol) of 4-(4-propylcyclohexyl)-phenyltrimethoxysilane (Ih) was added 2.1 ml of TBAF (2.1 mmol, 1M in THF) under nitrogen, and the mixture was stirred at room temperature for 30 minutes. After the solvent was removed under reduced pressure, a solution of 3,4-difluorobromobenzene (0.463 g, 2.4 mmol) in toluene (1 ml) was added, followed by the addition of a suspension of tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1 mmol) in toluene (3 ml). The resulting mixture was refluxed for 3 hours. After cooling, to the reaction mixture were added water and toluene. The organic layer was separated and the aqueous layer was extracted with toluene three times. The combined organic layer was dried over magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane) to obtain 0.594 g (40%) of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:26][CH3:27])=[O:10])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1OC1CCCCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Br)cc1OC1CCCCC1
Reaction time: 60 h
Yield: 85.6 %

Procedure:
To a solution of (4-bromo-2-cyclohexyloxyphenyl)acetic acid (1.33 g) in N,N-dimethylformamide (13 ml) were added potassium carbonate (0.88 g) and iodoethane (1.33 g) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 days. The resulting mixture was poured into water and the aqueous layer was extracted with a mixture of hexane and ethyl acetate (1:1). The organic layer was washed successively with water (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/toluene=1:1 to 1:2) to give ethyl (4-bromo-2-cyclohexyloxyphenyl)acetate (1.24 g).
Reaction SMILES: [K].[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[N+]([C:16]1[C:24](C)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])([O-])=O>[Pd].CO.O>[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [K]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(=O)O)c1Nc1ccccc1C(=O)O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The potassium salt of 3-methylanthranilic acid was generated by hydrogenation (Palladium-charcoal catalyst) of a solution of the potassium salt of 2-nitro-3-methylbenzoic acid (37.4 gm) in methanol-H2O (1:4 v/v) with following clarification and evaporation to dryness. To this potassium salt were added 2-chlorobenzoic acid (34.5 gm), K2CO3 (34.5 gm), catalytic Cu powder (0.3 gm), CuBr (0.3 gm), N-methyl-2-pyrrolidone (45 ml) and 2-ethoxyethanol (45 ml) and the mixture was heated in an oil bath at 150° C. with stirring for 21/2 hr. Water (1.5 L) was added to the cooled mixture and the whole warmed until the salts had dissolved and crude product was precipitated from the clarified solution by acidiciation with excess HOAc. The product was washed well with boiling water, then dissolved in 5% aqueous Na2CO3 (500 ml) and decolourising charcoal (5 gm) stirred in. To the boiling clarified solution EtOH (500 ml) was added and the mixture acidified by the slow addition of HOAc. The crystalline diacid which separated from the hot solution was collected, washed with boiling water and dried (48.9 gm). Crystallisation from EtOH--H2O provided homogeneous material as colourless needles of mp 258°-259° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:11]([CH2:17][CH2:18][OH:19])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C@H:11]([CH2:17][CH2:18][O:19][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[O:10][C:9]1([CH3:20])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@H]1[C@H](CCO)OC(C)(C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
200 mg of the compound obtained in Example 10 was dissolved in 2 ml of dry methylene chloride, and 115 μl of triethylamine and 152 mg of tosyl chloride were added thereto. The mixture was stirred at room temperature overnight. Then, 115 μl of triethylamine was further added, and the mixture was reacted at room temperature and then evaporated to dryness under reduced pressure. A solution mixture of benzene/ethyl acetate (30/1) was added to the residue. After filtering insolubles off, the filtrate was purified by silica gel column chromatography to obtain 281 mg of (4S,5S)-3-tert-butyloxycarbonyl-2,2-dimethyl-5-(2-p-toluenesulfonyloxyethyl)-4-isobutyloxazolidine as a syrup.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13](O)=[O:14])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.B.C1COCC1>CO>[CH:1]1([C:7]2[O:8][C:9]([CH3:16])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(C2CCCCC2)nc1CC(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(C2CCCCC2)nc1CCO
Temperature: 50 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
1.920 g of the above prepared (2-cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid (8.60 mmol) was dissolved in 56 ml of abs. THF and treated at 0° C. with 21.5 ml of 1M BH3THF (2.5 eq.). The reaction mixture was then kept over weekend at ambient temperature. 3.5 ml of MeOH was added and the mixture stirred for 3 h at ambient temperature and for 3 h at 50° C. to liberate the free alcohol. Removing of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=4/6) yielded finally 1.314 g of the title compound as colorless oil.