Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[O:21])=[CH:12][CH:11]=1)[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC2SC(=O)N(CCNC(=O)OC(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1.40 g, 9.68 mmol) was added to a solution of compound 4 (303 mg, 1.21 mmol) in 4 mL of anhydrous DMF at 0° C. After stifling the reaction mixture for 20 min, a solution of tert-butyl (2-bromoethyl)carbamate (268 mg, 1.21 mmol) in anhydrous DMF (2 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and then extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford compound 5 in 53.1% (253 mg) as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:26][CH3:27])[C:18](N1CCOCC1)=[O:19]>C1COCC1>[CH3:15][O:16][CH:17]([O:26][CH3:27])[C:18]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:19]
Reactant: c1ccc2sccc2c1
Reactant: COC(OC)C(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of benzothiophene (7.11 g., 0.053 mol) in 120 ml. dry THF was cooled to 0°. Butyl lithium (35.3 ml. of 1.5M in hexane, 0.053 mol) was added dropwise, maintaining 0°-5°, and the mixture then warmed to ambient temperature for 1.25 hours, cooled to -75° C. and N-(dimethoxyacetyl)morpholine (10.0 g., 0.053 mol) in 50 ml. dry THF added dropwise maintaining -75° to -70°. The reaction was quenched by adding to 300 ml. saturated NH4Cl and 300 ml. ether. The organic layer was separated, washed with brine, dried over MgSO4 and stripped to an oil, 14 g., which was distilled to yield purified title product, 8.00 g., bp 137°-139°/0.25 mm.; tlc Rf 0.23 (6:1 hexane:ethyl acetate), 0.47 (2:1 hexane:ethyl acetate); 1H-nmr 3.6 (s, 6H), 5.2 (s, 1H), 7.3-7.6 (m, 2H), 7.8-8.05 (m, 2H), 8.4 (s, 1H), tlc Rf 0.31 (4:1 hexane:ethyl acetate), 0.47 (2:1 hexane:ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:38]([O-])([O-])=[O:39].[Cs+].[Cs+].CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:38][O:39][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCOC2C1=NCCN1
Temperature: 130 °C

Procedure:
To a mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (200 mg), 2-(di-t-butylphosphino)biphenyl (5.31 mg), palladium(II)acetate (3.19 mg) and Cs2CO3 (348 mg) was added methanol (1 ml) and toluene (2 ml). The mixture was degassed with N2 and then heated for 40 min at 120° C. and 30 min at 130° C. Alternatively, other Pd-ligand complexes and reaction conditions can be applied in the C—O formation. The title compound was purified by using separation methods E and G. (Yield 5 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:47]([NH:46][C:32]2[CH:31]=[C:30]([Cl:29])[CH:45]=[CH:44][C:33]=2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:48])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1NC(=O)OCc1ccccc1
Yield: 82.9 %

Procedure:
834 mg (2.05 mmol) of 4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide and 783 mg (2.05 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 1.18 g (yield 83%) of benzyl 2-{[(4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.56 (9H, s), 5.22 (2H, s), 5.37 (2H, s), 7.04 (1H, dd), 7.33-7.42 (10H, m), 7.97 (1H, d), 8.14 (1H, d), 8.45 (1H, d), 8.60 (1H, d), 8.65 (1H, d), 11.01 (1H, s), 11.11 (1H, s).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][C:40](=[CH:2][O:3][CH3:4])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2cccc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC=C1CCC(c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (112.1 g) and THF (1000 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 36.7 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (35) (41.9 g) dissolved in THF (200 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 45.0 g of 1-(3-fluorophenyl)-4-methoxymethylenecyclohexane (36). The yield based on the compound (35) was 93.7%.
Reaction SMILES: [OH-].[Ca+2].[OH-].[O:4]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[P:18]([OH:22])([OH:21])([O-:20])=[O:19].[Na+:23]>>[OH-:4].[Na+:23].[P:18]([OH:22])([O-:21])([O-:20])=[O:19].[Na+:23].[Na+:23]
Reactant: O=P([O-])(O)O
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Product: O=P([O-])([O-])O

Procedure:
To the above filtrate, a slurry containing 179 g of calcium hydroxide (32%) was added at a temperature of about 55 degrees C. An amount of 241 g of dicalcium phosphate was separated (49% humidity) leaving a solution of 1960 ml. The solution had a pH of 4.75 with a P2O5 concentration of 7.6%. This filtrate consisted substantially of pure monosodium phosphate; by its neutralization with a solution of 47.5% NaOH (containing 1.2% NaCl) to a pH of about 8.7, disodium phosphate was produced. In this neutralization operation, an appreciable amount of heat evolved, being accompanied by the precipitation of small particles of CaO and MgO in the form of hydroxyphosphate salts. After the removal of the fine precipitates, the filtrate was cooled to about 5 degrees, by a controlled cooling at the rate of about 10 degrees per hour. The chloride concentration in the mother-liquor was about 2% which gave rise to an increase of crystallization, the yield depending on NaCl concentration, known as salting out effect. An amount of 920 g of very pure crystals (14% humidity) of disodium phosphate were separated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=O)[NH2:12])[C:6]=1[Cl:14].CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[C:6]=1[Cl:14]
Reactant: COC(=O)Cc1cccc(C(N)=O)c1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-carbamoylphenylacetic acid methyl ester (0.35 mmol) in 5 mL DCM were added 0.15 mL Et3N followed by trifluoromethanesulfonic acid anhydride (0.70 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at RT. After 30 min, water was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol) and ethanol (2.4 ml) was added 4-methoxybenzaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% ethyl acetate in dichloromethane, and then 3% to 6% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.015 g, 28%); 1H-NMR (500 MHz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2CO), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.89 Hz, 2H) and 8.14 (d, J=8.57 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.39 (dd, J=7.91, 5.08 Hz, 1H, pyridyl 5-H), 7.76 (d, J=7.80 Hz, 1H, pyridyl 4-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=4.76, 1.58 Hz, 1H, pyridyl 6-H), 8.56 (d, J=1.62 Hz, 1H, pyridyl 2-H), 13.37 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:27]1[CH2:31][CH2:30][C:29]([C:32](O)=[O:33])=[CH:28]1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:27]1[CH2:31][CH2:30][C:29]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])=[CH:28]1)[CH3:26]
Reactant: CCC1C=C(C(=O)O)CC1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3=CC(CC)CC3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.5 g of 3-ethyl-1-cyclopentene-1-carboxylic acid and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound.
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25](=[O:38])[CH2:26][CH2:27][C@H:28]([O:34]C(=O)C)[CH2:29][O:30]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@H:10]1[NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([NH:56][C@@H:57]3[C@@H:63]([O:64]C(=O)C)[C@H:62]([O:68]C(=O)C)[C@@H:61]([CH2:72][NH:73][C:74](=[O:87])[CH2:75][CH2:76][C@H:77]([O:83]C(=O)C)[CH2:78][O:79]C(=O)C)[O:60][C@:58]3([CH2:88][C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)[OH:59])=[O:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:41])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25](=[O:38])[CH2:26][CH2:27][C@H:28]([OH:34])[CH2:29][OH:30])[C@@H:16]([OH:17])[C@H:11]([OH:12])[C@H:10]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([NH:56][C@@H:57]3[C@@H:63]([OH:64])[C@H:62]([OH:68])[C@@H:61]([CH2:72][NH:73][C:74](=[O:87])[CH2:75][CH2:76][C@H:77]([OH:83])[CH2:78][OH:79])[O:60][C@:58]3([CH2:88][C:89]3[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=3)[OH:59])=[O:55])=[CH:50][CH:49]=2)=[CH:46][CH:47]=1)=[O:41])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H](CCC(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc(-c3ccc(C(=O)N[C@@H]4[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CNC(=O)CC[C@@H](COC(C)=O)OC(C)=O)O[C@@]4(O)Cc4ccccc4)cc3)cc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)OC(C)=O
Solvent: C1COCCO1
Product: O=C(CC[C@H](O)CO)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc(-c3ccc(C(=O)N[C@@H]4[C@@H](O)[C@H](O)[C@@H](CNC(=O)CC[C@H](O)CO)O[C@@]4(O)Cc4ccccc4)cc3)cc2)[C@@H](O)[C@@H]1O

Procedure:
Biphenyl-4,4'-dicarboxylic acid bis-[[benzyl 3,4-di-O-acetyl-6-[(S)-4,5-diacetoxy-pentanoylamino]-2,6-didesoxy-α-D-glucopyranosid-2-yl]-amide] was deacetylated as described in Ex. 11.F. and gave biphenyl-4,4'-dicarboxylic acid bis-[[benzyl 2,6-didesoxy-6-[(S)-4,5-dihydroxy-pentanoylamino]-α-D-gluco-pyranosid-2-yl]-amide], [α]+92.00 (c 0.2; dioxan), MS: m/z 997.9 ([M+Na]+).
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:32][CH:31]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[C:37][P:38](=[O:42])([O:43][C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:7])[O:39][CH2:40][CH3:41])=[CH:34][CH:35]=1
Reactant: CCOP(=O)(O)C#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen (4-chlorophenyl)ethynylphosphonate (73.4 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-phenylpent-1-en-2-yl 2-(4-chlorophenyl)ethynylphosphonate (51.2 mg, 44%) which is a title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=3[O:27][CH3:28])[N:17]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1.S(O[CH:37]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:38])(C(F)(F)F)(=O)=O.O>CCCCCC>[CH:39]1([CH2:37][CH2:38][C:15]2[S:14][C:13]([N:8]3[C:7]([CH3:6])=[CH:11][CH:10]=[C:9]3[CH3:12])=[N:17][C:16]=2[C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=2[O:27][CH3:28])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1CCCCC1
Reactant: COc1cc(C)cc(OC)c1-c1csc(-n2c(C)ccc2C)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: COc1cc(C)cc(OC)c1-c1nc(-n2c(C)ccc2C)sc1CCC1CCCCC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
10 ml of 1.6M n-butyllithium in hexane are added, at −30° C., to 4.27 g of 2-(2,5-dimethylpyrrol-1-yl)-4-(2,6-dimethoxy-4-methylphenyl) thiazole and the mixture is left stirring for 30 minutes at −30° C. 4.2 g of cyclohexylethanol triflate are added at −45° C., the mixture is then warmed to 0° C., water is added, this mixture is extracted with Et2O and the extracts are dried and evaporated. The gum formed is chromatographed on silica, eluting with cyclohexane/EtOAc (1/1; v/v). 0.52 g of the expected compound is obtained in the form of a colourless gum.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:25]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH2:25][CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2C)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-ethylimidazole (960 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (438 mg, 38%). Melting point 91-92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([OH:39])[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:40])[C@H:4]([O:39][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Yield: 69 %

Procedure:
The (2R,3S)-2-hydroxy-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenylbutanoic acid methylester obtained in Reference Example 25 2.30 g (4.06 mmol) was dissolved in tetrahydrofuran 8 mL and thereto were added 3,4-dihydro-2H-pyrane 4.80 mL and p-toluenesulfonic acid pyridinium 204 mg (0.81 mmol) and the mixture was stirred under reflux for 8 hours. After distillating tetrahydrofuran off, the residue was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on magnesium sulfate, filtered and concentrated. The concentrated residue was purified by a column chromatography on silica gel (eluted with chloroform-methanol system) and recrystallized from a mixed solvent of ethyl acetate and hexane. A precipitated material was collected by filtering and dried to give 1.81 g (2.78 mmol) of the title compound (yield: 69%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16].[H+].[B-:18]([F:22])([F:21])([F:20])[F:19]>O>[F:19][B-:18]([F:22])([F:21])[F:20].[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([N+:5]#[N:1])=[C:7]([CH3:16])[CH:8]=1)=[O:11]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)c(C)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc([N+]#N)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To an aqueous solution of NaNO2 (12.54 g, 2.0 eq) in 75 mL H2O at 0° C. was added dropwise cooled solution of methyl 4-amino-3-methylbenzoate (15 g, 1.0 eq) in HBF4(aq)(40% in water). After addition, the mixture was stirred for 15 min at ambient temperature. The precipitate was filtered, washed with ice-cold water, and dried, to give the desired product as a white solid (16 g, 90%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15]C)[C:11](=[O:17])[CH2:10][CH2:9]2.O>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[OH:15])[C:11](=[O:17])[CH2:10][CH2:9]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCc2cc(Br)c(O)cc21

Procedure:
46.7 g (0.35 mol) of aluminium chloride are added portionwise to a solution of 28.3 g (0.117 mol) of 5-bromo-6-methoxyindan-1-one in 500 ml of toluene. The reaction mixture is heated at reflux for 15 minutes and is then poured into water and the phases are separated by settling (sparingly soluble product).