Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:36])([F:35])[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:34]=[CH:33][C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([C:9]([F:8])([F:35])[F:36])=[CH:11][CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:29]1
Reactant: Clc1ncccn1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2ncccn2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A mixture of 1.30 g (0.0114 mol) of 2-chloropyrimidine, 3.50 g (0.00875 mol) of 1-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, and 1.2 g of triethylamine in 50 ml of ethanol is stirred at 50° C. for 15 hours and at reflux for 8 hours. The mixture is partitioned between methylene chloride and aqueous 1 N sodium hydroxide. The organic phase is dried and concentrated. The residue is re-crystallized from methylene chloride and ethanol to yield 4.00 g of 4-(2-pyrimidinyl)-1-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, of melting point 246°-247.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][S:14]([O-:17])(=[O:16])=[O:15]>CC(N(C)C)=O>[CH3:12][O:13][S:14]([O-:17])(=[O:16])=[O:15].[CH3:12][N+:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[OH:1])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2cccnc12
Agent: COS(=O)(=O)[O-]
Solvent: CC(=O)N(C)C
Product: C[n+]1cccc2cccc(O)c21
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Into a 2-liter three-neck flask provided with a mechanical agitator, with a reflux-condenser and calcium chloride tube, and with a dropping funnel, one introduces 145 g of 8-hydroxyquinoline (i.e. 1 mole) and 200 ml of dimethyl acetamide. After dissolution of the 8-hydroxyquinoline, one cools the reaction mixture with a bath of ice water and one adds, drop by drop, by means of the dropping funnel, 126 g of freshly distilled methylsulfate (i.e. 1 mole). Shortly after the completion of the addition, a light yellow compound crystallizes little by little. One continues the agitation for 2 hours after the introduction of the methylsulfate and then leaves the mixture to rest overnight in a brine bath. The quaternary salt which is formed is dried, washed with anhydrous ether and recrystallized in methanol. Weight obtained = 219 g; Melting point = 158°C; Yield = 81%.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:32])[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)[CH3:16].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([O:42][C:43](=[O:58])[NH:44][C:45]1[C:46]([CH3:57])=[N:47][O:48][C:49]=1[C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[CH3:41]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([O:42][C:43](=[O:58])[NH:44][C:45]1[C:46]([CH3:57])=[N:47][O:48][C:49]=1[C:50]1[CH:55]=[CH:54][C:53]([C:20]2[CH:19]=[CH:18][C:17]([CH:15]([CH3:16])[C:14]([N:3]3[C@H:2]([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:5][C:4]3=[O:13])=[O:32])=[CH:22][CH:21]=2)=[CH:52][CH:51]=1)[CH3:41]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CC(C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: Cc1noc(-c2ccc(-c3ccc(C(C)C(=O)N4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Diastereomer B—Prepared as described in Example 36, Step 6 using (4R,5S)-4-methyl-5-phenyl-3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionyl}-oxazolidin-2-one (Diastereomer B) and [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester.
Reaction SMILES: IC1C=C(NC(C)C(O)=O)C=CC=1.C([Si](C)(C)O[C@@H]1CN(CCCNCC(OC)OC)CCC21CC2)(C)(C)C.C([Si](C)(C)[O:45][C@@H:46]1[CH2:53][N:52]([CH2:54][CH2:55][CH2:56][N:57]([CH2:70][CH:71](OC)OC)[C:58](=[O:69])[CH:59]([NH:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([I:68])[CH:63]=2)[CH3:60])[CH2:51][CH2:50][C:47]21[CH2:49][CH2:48]2)(C)(C)C.C([Si](C)(C)O[C@@H]1CN(CCCN2CCN(C3C=CC=C(I)C=3)C(C)C2=O)CCC21CC2)(C)(C)C>>[OH:45][C@@H:46]1[CH2:53][N:52]([CH2:54][CH2:55][CH2:56][N:57]2[CH2:70][CH2:71][N:61]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([I:68])[CH:63]=3)[CH:59]([CH3:60])[C:58]2=[O:69])[CH2:51][CH2:50][C:47]21[CH2:49][CH2:48]2
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)C(=O)C(C)Nc1cccc(I)c1)OC
Agent: CC(Nc1cccc(I)c1)C(=O)O
Agent: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)CCN1c1cccc(I)c1
Agent: COC(CNCCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)OC
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(I)c1

Procedure:
The title compound was produced in analogy with examples 87/88, steps A-C. Thus, 2-(3-iodo-phenylamino)-propionic acid (intermediate 23) was coupled with {3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-(2,2-dimethoxy-ethyl)-amine (example 83C) in step A, leading to N-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-N-(2,2-dimethoxy-ethyl)-2-(3-iodo-phenylamino)-propionamide. This was cyclized to 1-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-4-(3-iodo-phenyl)-3-methyl-piperazin-2-one in step B. Finally, deprotection in step C afforded the title compound. Light yellow gum, MS: 484.3 (M+H)+)
Reaction SMILES: [C:1]([N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[CH3:31][CH:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:9]([CH3:10])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:13]=2)=[CH:23][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)C(C)Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)O
Yield: 77.4 %

Procedure:
1.25 g (3 mmol) of ethyl 3-{3′-[(benzoyl-methylamino)methyl]biphenyl-4-yl}-2-methylpropionate, 3 ml of sodium hydroxide (10N), 32 ml of THF and 2 ml of methanol are introduced into a round-bottomed flask. The reaction medium is refluxed for 8 hours, poured into water, acidified to pH 4 with 1N hydrochloric acid and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (60/40). 900 mg (90%) of 2-methyl-3-(3′-{[methyl-(1-phenylmethanoyl)-amino]methyl}biphenyl-4-yl)propionic acid, with a melting point of 60-61° C., are obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH:13]([OH:15])[CH3:14])([CH3:12])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>CN(C)C=O>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([C:13](=[O:15])[CH3:14])([CH3:12])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=CCC(C)(C(C)O)C(C)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(=O)C1(C)CC=C(CC(C)C)CC1C
Yield: 77 %

Procedure:
1-(4-Isobutyl-1,6-dimethylcyclohex-3-enyl)ethanol 4d (2 g, 9 mmol) was dissolved in dimethylformamide (50 ml) and cooled to below 5° C. under nitrogen. Pyridinium dichromate (4.5 g, 12 mmol) was added in two portions with stirring and the reaction allowed to return to room temperature. After stirring for 90 min another portion of PDC (1 g, 2.7 mmol) was added and after a further 90 min the reaction was complete. The reaction mixture was poured onto ice-water and 2M HCl added. After brief agitation the product was extracted from the aqeuous phase with MTBE. The organic phases were combined and washed with sat. NaHCO3 solution then to pH 7 with brine. After drying (Na2SO4) the solvent was removed in vacuo to give 1.8 g of a crude oil which was purified by flash chromatography (MTBE/hexane 2:8). Combination of pure fractions gave 3d as a 7:3 mixture of diastereomers (1.5 g, 77% yield, 99% pure). Subsequent distillation provided a sample for olfactory assessment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13](NC(=O)CC(F)(F)F)=[CH:12][CH:11]=2)[N:3]=1.ClC1C=C(NC2C=CC=CN=2)N=C(SC2C=CC(NC(=O)CC(F)(F)F)=CC=2)N=1.ClCS(C1C=C(S(CCl)(=O)=O)N=CN=1)(=O)=O.SC1C=CC([C:74]([NH:76][CH2:77][C:78]([F:81])([F:80])[F:79])=[O:75])=CC=1.C(N(CC)CC)C>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:74]([NH:76][CH2:77][C:78]([F:81])([F:80])[F:79])=[O:75])=[CH:14][CH:15]=2)[N:5]=1
Reactant: O=C(NCC(F)(F)F)c1ccc(S)cc1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Agent: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1
Agent: O=S(=O)(CCl)c1cc(S(=O)(=O)CCl)ncn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCC(F)(F)F)c1ccc(Sc2nc(Cl)cc(Cl)n2)cc1

Procedure:
4-(4,6-Dichloropyrimidin-2-ylthio)-N-(2,2,2-trifluoroethyl)benzamide was prepared according the procedure of 1a in Scheme 2 from 4,6-dichloromethylsulfonylpyrimidine (1.0 g, 4.4 mmol), 4-mercapto-N-(2,2,2-trifluoroethyl)benzamide (1.1 g, 4.7 mmol), and triethylamine (0.7 mL, 4.9 mmol) in acetonitrile (30 mL). Desired compound was purified by column chromatography (SiO2, ethyl acetate/heptanes=1:1-1:0, TLC: SiO2) to yield 210 mg (12%) (HPLC method A: Rf=8.508 minutes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[OH:12].[C:14](=O)([O-])[O-].[K+].[K+].IC>CC#N.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[O:12][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cccc(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(Br)c1OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (3-bromo-2-hydroxy-phenyl)-acetic acid methyl ester (866 mg, 3.5 mmol, 1 eq.) and potassium carbonate (2.44 g, 17.7 mmol, 5 eq.) in MeCN (9 mL), iodomethane (0.67 mL, 10.6 mmol, 3 eq.) was added. The resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[N:52]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=3)[N:16]=2)=[CH:18][CH:19]=1)=[N+:53]=[N-:54]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN=[N+]=[N-])cc3)n2)cc1Cl
Yield: 61.5 %

Procedure:
To a solution of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (0.100 g, 0.290 mmol) in THF (1.5 ml) was added DBU (0.048 ml, 0.319 mmol) followed by diphenyl phosphorazidate (0.069 ml, 0.319 mmol). After about 15 h the reaction mixture was poured into ether and saturated NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (0.066 g, 60%) as a colorless solid. LCMS (Table 1, Method c) Rt=3.22 min, m/z 370 (M+H)+
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[O:13])[CH2:8]2
Reactant: COCCCN
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: COCCCNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(3-Methoxy-propylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-methoxypropylamine. Mass spectrum (ES) MH+=409.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Nc1ccc(Cl)cc1
Yield: 81.7 %

Procedure:
A solution of (E)-4-fluorostyrylsulfonyl chloride (10 mmol) and 4-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 126-128° C, was obtained in 81.7% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]([F:31])([F:44])[F:43])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4OC(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-trifluoromethoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O4, 416.1; m/z found, 417.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (s, 1H), 12.95 (s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.69-7.66 (m, 1H), 7.61-7.53 (m, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8]O)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:11][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCn1ccnc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCCCn1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A mixture of 1H-imidazole-1-propanol (1.00 g, 3.65 mmol—prepared according to patent: WO 9722596 A1), carbon tetrabromide (1.80 g, 5.47 mmol) and triphenyl phosphine (1.43 g, 5.47 mmol) was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel. Elution with 10% methanol in dichloromethane yielded the title compound (425 mg, 35% yield) as a pale yellow solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Br)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a 0° C. mixture of 2-hydroxy-5-bromotoluene(48.63 g, 260 mmol), DMF (260 ml), imidazole (18.58 g, 273 mmol) is added t-butyldimethylsilyl chloride (41.15 g, 273 mol) in portions. After stirring for 30 m, the reaction is warmed to RT and stirred for 16 h. The reaction mixture is poured into ice/water (1.25 l) and extracted with Et2O. The organic layer is washed with water (2×100 ml), 1N NaOH (2×5 ml), water, brine, MgSO4 dried, concentrated, chromatographed (hex), and azeotroped with toluene to give the title compound as an oil (75.7 g, 97%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13].[O:16]=[C:17]1[CH2:22][S:21][CH2:20][CH2:19][S:18]1>CO.CC(C)=O>[SH:18][CH2:19][CH2:20][S:21][CH2:22][C:17]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13])=[O:16]
Reactant: O=C1CSCCS1
Reactant: NCCNC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(CSCCS)NCCNC(=O)Cn1ccnc1[N+](=O)[O-]
Yield: 37.5 %

Procedure:
N-(2-Aminoethyl)-(2-nitroimidazol-1-yl)acetamide (40 mg, 0.23 mmol) in methanol (0.5 cm3) was added to 2-oxo-1,4-dithiane (40 mg, 0.27 mmol) in acetone (0.2 cm3) under an atmosphere of dry nitrogen. The mixture was left at room temperature and monitored by n.m.r. spectroscopy until the reaction was complete. The bulk of the solvent was removed, and the resulting material purified by reverse phase h.p.l.c. using aqueous methanol as the eluant. The pure N-(2-[(2-mercaptoethylthio)acetylamino]ethyl)-(2-nitroimidazol -1-yl)acetamide (30 mg) was isolated as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Cl:14])[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1ccccc1Cl
Product: CNCC1Cc2cccc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.078 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 163-165° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 3 (0.125 g, 0.4 mmol) and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)-palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the title compound as a white solid, m.p. 122°-123° C.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH2:5]>>[CH2:3]=[CH:2][CH2:1][S:4](=[O:5])[S:4][CH2:1][CH:2]=[CH2:3]
Reactant: O
Reactant: C=CCS
Product: C=CCSS(=O)CC=C

Procedure:
First prepare a 1/400 dilution of allyl mercaptan by adding 1.25 ml (a quarter teaspoon) of food grade allyl mercaptan to 500 ml of distilled water.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:25](OC)(=[O:30])[CH2:26][C:27]([CH3:29])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:30])[CH2:26][C:27]([CH3:29])=[N:10][CH2:9][CH2:8]1
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[C:58]([F:66])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:63])[F:64])=[C:58]([F:66])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)c(F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(C(F)(F)F)c(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 16 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 138 mg light yellow solid (91%). MS (ISP) 497.4 (M+H)+.