Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C=O)C>[N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([O:10][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
5.9 g (25 mmol) of methyl 3-azido-3-phenyl-2-hydroxybutyrate (Ex. 1) are dissolved in 80 ml of DMF, treated with 1.7 g (12.5 mmol) of potassium carbonate and 5.5 g (25 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and stirred for 6 hours at 50° C. and 12 hours at room temperature. The mixture is then poured onto 400 ml of water, and the precipitate formed is filtered off with suction, washed with water and dried. 6.3 g of a white powder are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
The above general procedure was followed using bromobenzene (157 mg, 1.00 mmol) and aniline (93 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After one hour, the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 145 mg (86%) of diphenylamine as a grey solid. 1H NMR (500 MHz, C6D6) δ 7.11-7.08 (m, 4H), 6.85-6.80 (m, 6H), 4.97 (br s, 1H). 13C NMR (125 MHz, C6D6) δ 143.6, 129.5, 121.1, 118.2. In addition, 21 mg (8%) of triphenylamine was isolated.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C-]#N.[Na+].CS(C)=[O:24].C(Cl)(Cl)Cl>O>[OH:24][C:7]1[CH:6]=[CH:5][C:4]([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:3][CH:8]=1
Reactant: COc1ccccc1C=CC(=O)c1ccccc1
Reactant: CS(C)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(C=Cc1ccc(O)cc1)c1ccccc1

Procedure:
10 g of methoxy chalcone and 2.05 g of sodium cyanide are dissolved into 100 ml of dimethyl-sulfoxide, and then reacted during 24 hours. After the reaction, the reacted solution is mixed with chloroform and stirred together with distilled water so as to extract impurities. After removing the solution phase, the solution is decompressed at a room temperature in order to eliminate chloroform. After recrystallizing the remained solid phase in methanol, the solution is dried under vacuum, thus obtaining side chain 4-hydroxychalcone for photoreaction.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]#[C:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:23]([O:22][C:16]1[N:15]2[N:14]=[C:32]([CH3:33])[C:31]([C:30]([O:35][CH2:36][CH3:37])=[O:34])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cc[n+](N)c(OCc2ccccc2)c1
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
11.7 g (28.2 mmol, 1.0 eq.) of 1-amino-2-(benzyloxy)-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 6A were dissolved in 280 ml of DMF, and 6.6 ml (56 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 7.8 g (56 mmol, 2.0 eq.) of potassium carbonate were added and the mixture was stirred at RT for 1 h. Subsequently, 3.9 g (28 mmol, 1 eq.) of potassium carbonate were added and the mixture was stirred at RT for a further 16 h. Then the mixture was poured onto 540 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with 220 ml of water and dried. 3.1 g of the title compound were obtained (34% of theory; 87% purity).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:18][CH2:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:22][CH:21]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:8]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:30][CH:31]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC(C)C)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 4.1 g (16 mmol) of 3-tert-butyl-4-isopropyloxybenzoyl chloride with 3.1 g (16 mmol) of allyl 4-hydroxymethylbenzoate, 5.1 g (77%) of allyl ester, melting point 63°-4° C., are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20]([O-:22])=O)[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:80][CH2:79][C:78]3[CH:81]=[CH:82][CH:83]=[CH:84][C:77]=3[NH:76][C:75]2=[O:85])[CH2:70][CH2:69]1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[CH:11][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:22])[N:68]2[CH2:69][CH2:70][CH:71]([N:74]3[CH2:80][CH2:79][C:78]4[CH:81]=[CH:82][CH:83]=[CH:84][C:77]=4[NH:76][C:75]3=[O:85])[CH2:72][CH2:73]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:23][C:24]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(C)c(OCc2ccccc2)c(C)c1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.69 g (4.74 mmol) 1-methyl (S)-2-(4-benzyloxy-3,5-dimethyl-benzyl)-succinate, 1.55 g (4.83 mmol) TBTU, 0.69 g (5.10 mmol) HOBt and 1.34 mL (7.71 mmol) ethyldiisopropylamine in 40 mL THF and 5 mL DMF was stirred for 16 h at RT. Then 1.16 g (4.74 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one was added to the reaction mixture, which was then stirred for a further 2.5 h at RT. The reaction solution was combined with 40 mL EtOAc, the organic phase was washed twice with 30 mL semisaturated NaHCO3 and once with 40 mL saturated NaCl solution washed and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc/Cyc 3:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:12]1([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C.O>[C:12]1([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(C2=CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
1.34 g (9.72 mmol) of potassium carbonate was added to a DMF (10 mL) solution comprising 564 mg (3.24 mmol) of 3-(cyclohex-1-en-1-yl)phenol and 541 mg (3.82 mmol) of ethyl bromoacetate. The mixture was heated while stirring at 80° C. for 3 hours, and then cooled to room temperature. Water and ethyl acetate were added thereto, and extraction was performed. The organic layer was then separated, washed with water 3 times, and washed with saturated saline once. The organic layer was dried over sodium sulfate, and filtered. Thereafter, the filtrate was condensed, followed by drying under reduced pressure, thereby giving 777 mg of ethyl [3-(cyclohex-1-en-1-yl)phenoxy]acetate (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]2[S:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][S:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(C2CNCCS2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCSC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
5.632 g of 4-Bromobenzyl bromide and 2.694 g of 2-Phenylthiomorpholine (Array) in 50 mL of acetonitrile were stirred at room temperature and 6.229 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification was done by flash chromatography to afford product. Wt: 0.859 g, 53% yield. ES MS m/z 348/350
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[Cl-].[NH4+]>CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:9]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Cc1ccccn1
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To 22.44 g of potassium tert-butoxide in 500 ml of dimethyl sulfoxide are slowly added 8.66 g of 4-chloronitrobenzene and 8.2 g of 2-chloromethylpyridine dissolved in 100 ml of dimethyl sulfoxide. After 18 hours at room temperature, the mixture is hydrolysed with saturated ammonium chloride solution and extracted three times with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica H, eluting with dichloromethane, to give 10.695 g of the expected product.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:30])[N:24]([CH2:26][CH2:27][O:28][NH2:29])[CH3:25])([CH3:21])([CH3:20])[CH3:19].Cl>CCO.C(OCC)C>[CH3:25][N:24]([CH2:26][CH2:27][O:28][N:29]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:23](=[O:30])[O:22][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CN(CCON)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN(CCON=C(c1ccccc1)c1cc2ccncc2[nH]1)C(=O)OC(C)(C)C
Reaction time: 15.5 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (200 mg, 90 mmol) and tert-butyl[2-(aminooxy)ethyl]methylcarbamate (Reference Example 14) (180 mg, 94 mmol) in EtOH (20 mL) was adjusted to pH 4-5 with HCl (1.2 mL of a 1 N HCl solution in diethyl ether, 1.2 mmol). The reaction mixture was heated to reflux. After 15.5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (2×10 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 99:1 CH2Cl2/MeOH to 95:5 CH2Cl2/MeOH) gave tert-butyl methyl[2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethyl]carbamate (geometry of the oxime double bond undefined).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Temperature: 0 °C
Yield: 66.1 %

Procedure:
A suspension of 4-[3-(4-acetylaminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (963 mg) in 3N hydrochloric acid (25 ml) was stirred under reflux for 3 hours. Then the mixture was poured into ice-water and alkalinized with sodium bicarbonate. The resultant solid was collected and washed with water to give 4-[3-(4-aminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (577 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[OH-].[Na+]>ClCCl>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75 liters) and the resulting solution was cooled to −78° C. Dimethyl sulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20 minutes while maintaining internal temperature of the reaction below −70° C. during addition. 1-Benzhydrylazetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to the −78° C. solution of DMSO/oxalyl chloride over a duration of 40 minutes (note—internal temperature maintained below −70° C. during addition). The solution was stirred for 1 hour at −78° C. followed by the addition of triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintained internal temperature below −70° C. during addition). The reaction mixture was then allowed to come to room temperature slowly and stir for 20 hours. 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to the crude reaction solution over 30 minutes, followed by stirring for 10 minutes at room temperature. The heavy dichloromethane layer (clear yellow in color) was then separated and discarded. The remaining acidic aqueous phase (clear, colorless) was treated with 50% sodium hydroxide (150 ml, 2.1 mol) with stirring over a 30-minute period. The final aqueous solution had a pH=9. At this pH, the desired product precipitated from solution as a colorless solid. The pH=9 solution was stirred for 30 minutes and then the precipitated product was collected by filtration. The collected solid was washed with 1.0 liter of water and then air dried for 36 hr to give 1-benzhydrylazetidin-3-one (184.1 g, 74%) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H), 7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(O)C.[I-].[Na+]>[CH2:19]([O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCC)cc2)cc1
Yield: 84.9 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was dissolved in ethanol (50 mL) and 4,4′-dihydroxybenzophenone (1.0 g, 4.67 mmol) was added followed by 1-bromooctadecane (7.8 g, 23.4 mmol) and a catalytic amount of sodium iodide (approximately 30 mg) and the reaction mixture was refluxed for 48 hours. The resulting suspension was cooled and filtered. The solid was washed with dichloromethane followed by hexane and the white solid was dried to afford compound 22 (2.85 g, 84.8% yield). 1H NMR (300 MHz, pyridine-d5) δ 7.95 (d, J=8.7 Hz, 4 H, aryl), 7.09 (d, J=8.7 Hz, 4 H, aryl), 4.05 (t, J=6.6 Hz, 4 H, 2×OCH2), 1.80 (tt, J=6.6 and 7.5 Hz, 4 H), 1.48 (m, 4 H), 1.33 (brS, 60 H), 0.87 (t, J=6.6 Hz, 6 H, 2×CH3).
Reaction SMILES: Br[CH2:2][C:3]1[C:21]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:20][C:19]([O:30][CH3:31])=[CH:18][C:4]=1[C:5](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:6].[OH:32][C@@H:33]([C:45]([O:47][CH3:48])=[O:46])[CH2:34][C:35]([NH:37][C@@H:38]([CH2:43][SH:44])[C:39]([O:41][CH3:42])=[O:40])=[O:36]>>[Si:23]([O:22][C:21]1[C:3]2[CH2:2][S:44][CH2:43][C@@H:38]([C:39]([O:41][CH3:42])=[O:40])[NH:37][C:35](=[O:36])[CH2:34][C@@H:33]([C:45]([O:47][CH3:48])=[O:46])[O:32][C:5](=[O:6])[C:4]=2[CH:18]=[C:19]([O:30][CH3:31])[CH:20]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c(CBr)c(C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: COC(=O)[C@H](O)CC(=O)N[C@@H](CS)C(=O)OC
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)cc2C(=O)O[C@H](C(=O)OC)CC(=O)N1

Procedure:
p-Nitrobenzyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate was reacted with methyl (R)-2-[(R)-3-hydroxy-3-methoxycarbonyl-propionylamino]-3-mercapto-propionate in an analogous manner to the procedure described in Example 1(f), and the product was subjected in an analogous manner to a sequence of procedures described in Example 13(f) and in Example 21 to yield dimethyl (4R, 8S)-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-12-methoxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4,8-dicarboxylate as a white solid. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, dimethyl (4R, 8S)-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4,8-dicarboxylate as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=1.[BH4-].[Na+].Cl>CS(C)=O>[CH2:8]([C:5]1[CH:4]=[C:3]([CH3:2])[O:7][N:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1cc(CBr)on1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCc1cc(C)on1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 5-(bromomethyl)-3-dodecylisoxazole (9.99 g, 0.0302 mol) in dimethylsulfoxide (100 mL) was warmed to give a cloudy solution and allowed to cool. When the temperature reached +35° C., sodium borohydride (1.2 g, 0.032 mol) was added in one portion, and the mixture was stirred for 3 days under nitrogen at room temperature. The mixture was poured into 0.1M HCl (900 mL) and extracted with ether. The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated. The residue was chromatographed on silica gel (160 g, 70-230 mesh) using petroleum ether-acetone (29:1, 10×200 mL) as eluent. Fraction 6 was rotoevaporated and dried in vacuo to give a white solid; yield 3.96 g (52%); mp 35°-38° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C1(C)C=C[C:15]([S:18](O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.CS.[OH-].[Na+]>C(=O)=O.CCOCC>[CH3:15][S:18][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH2:9][CH2:10][OH:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CCCC(C)CCO
Agent: CS
Agent: O=C=O
Agent: Oc1ccc(O)cc1
Solvent: CCOCC
Product: CSC(C)(C)CCCC(C)CCO
Reaction time: 8 h

Procedure:
A mixture of 4 g. of citronellol (3,7-dimethyloct-6-en-1-ol), 0.490 g. of p-toluenesulfonic acid and 0.290 g. of hydroquinone is placed in a stainles steel screw cap bomb having an internal volume of 45 ml. The bomb is cooled in dry ice. Methyl mercaptan (9 g.) is introduced directly into the bomb through the valve head. The bomb is sealed, left overnight at room temperature and then heated to 220° in an oil bath for about 72 hours. After cooling in dry ice, the bomb valve is opened and the reaction mixture is carefully poured into 5% aqueous sodium hydroxide solution. Ether is added and the organic layer is separated, washed with 5% NaOH, 5% HCl and water, dired over calcium sulfate and concentrated with vacuo to yield 7-methylthio-3,7-dimethyloctan-1-ol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: COc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: COc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-methoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2690.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Li+]>O1CCOCC1>[Br:16][C:11]1[C:12]([CH3:15])=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2c(C)c(Br)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(Br)ccc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.8 %

Procedure:
5.37 g (19.0 mmol) of 5-bromo-4-methyl-1H-indole-2-carboxylic acid ethyl ester were dissolved in 150 ml of dioxane; then, 38.1 ml (38.1 mmol) of a lithium hydroxide solution (1 molar in water) were added and the reaction mixture was stirred for 60 hours at room temperature. After evaporation of the solvents, the residue was dissolved in dichloromethane; water was added and the pH adjusted to pH 2-3; then, the mixture was extracted 3 times with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give 4.82 g of crude 5-bromo-4-methyl-1H-indole-2-carboxylic acid as off-white solid.