Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH2:12]2)=[CH:7][C:6]=1[Br:29])=[N+]=[N-].C1(C)C=CC=CC=1.CP(C)C.O>O1CCCC1>[Br:29][C:6]1[CH:7]=[C:8]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:18])([F:17])[F:19])[CH2:12]2)[CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: CP(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
1-[4-(Azidomethyl)-3-bromophenyl]-3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-pyrrolidine (0.634 g) was dissolved in tetrahydrofuran (10 ml), to the solution was added a 1 M toluene solution (1.37 ml) of trimethylphosphine, and stirred for 10 minutes. To the reaction solution, water (0.09 ml) was added and stirred overnight at room temperature. The volatile compound was distilled off under reduced pressure to obtain almost pure 1-{2-bromo-4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.520 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([I:10](=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:13][C:14]([F:19])([F:18])[C:15]([O-])=[O:16].F[P-](F)(F)(F)(F)F.[K+]>O>[F:13][C:14]([F:19])([F:18])[C:15]([O:11][I:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:12])=[O:16]
Reactant: CC(C)c1ccc(I(=O)=O)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: CC(C)c1ccc(I(=O)(OC(=O)C(F)(F)F)c2ccc(C(C)C)cc2)cc1

Procedure:
Bis(4-isopropylphenyl)iodosyl trifluoroacetate is prepared by a similar method to that described by F. M. Beringer and P. Boedlander, loc. cit.) using 4-isopropyliodoxybenzene (8.3 g) as starting material. The trifluoroacetate is dissolved in boiling water. Potassium hexafluorophosphate (2 molar excess) in water is added and the solution is allowed to cool. The crystals which form are collected by filtration and dried in air to afford bis(4-isopropylphenyl)iodosyl hexafluorophosphate (0.4 g) m.pt. 84° C. Spectroscopic analysis shows:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[O:6]=O.[BH4-].[Na+]>CO>[CH3:1][C:2](=[CH2:3])[CH:4]([OH:6])[CH3:5].[CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3]
Reactant: O=O
Reactant: CC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=C(C)C(C)O
Product: C=CC(C)(C)O

Procedure:
A mixture of 1.0 g (14.3 mmol) of 2-methyl-2-butene and 500 mg. of photosensitizing resin in 150 ml of methanol was irradiated as described above. The volume of oxygen uptake was measured. To the solution was added sodium borohydride, and after 5 min. the solution was extracted with ether (20 ml.) The ether solution was analyzed by gas chromatography to give 3-methylbut-3-ene-2-ol and 2-methylbut-3-ene-2-ol, in a 50:50 ratio, within experimental error. The ratio of these two products is the same as that observed when rose bengal or methylene blue are dissolved in methanol. Hence the same intermediate, singlet oxygen is involved in both processes. Radical oxidation leads to different products.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([N:48]2[N:52]=[CH:51][CH:50]=[N:49]2)=[C:43]([CH:47]=1)[C:44](O)=[O:45].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:44]([C:43]4[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=4[N:48]4[N:52]=[CH:51][CH:50]=[N:49]4)=[O:45])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.17-7.73 (m, 2H), 7.44-7.09 (m, 2H), 7.07-6.58 (m, 1H), 5.87-5.54 (m, 1H), 4.51-3.30 (m, 7H), 3.20-2.75 (m, 7H), 2.28-1.87 (m, 2H).
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.[CH3:90][C:91]([N:95]1[CH2:100][CH2:99][O:98][CH2:97][CH2:96]1)([CH3:94])[CH2:92][NH2:93]>>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:4]1([NH:1][C:2]([NH:93][CH2:92][C:91]([CH3:90])([N:95]1[CH2:96][CH2:97][O:98][CH2:99][CH2:100]1)[CH3:94])=[O:3])[CH2:21][CH2:20]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(CN)N1CCOCC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCC(C)(C)N3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-methyl-2-morpholinopropan-1-amine was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 714.3 (M+H)+, 3.95 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, d, J=6.1 Hz), 4.8 (1H, s), 4.7 (1H, s), 4.1 (2H, d, J=12.2 Hz), 3.7-3.9 (2H, m), 3.5-3.6 (2H, m), 3.4-3.5 (2H, m), 3.2 (2H, t, J=11.9 Hz), 2.6-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2 (1H, dd, J=17.1, 6.1 Hz), 2.0 (1H, t, J=10.8 Hz), 1.8-1.9 (1H, m), 1.8 (1H, br. s.), 1.7 (3H, s), 1.7 (1H, td, J=13.3, 3.4 Hz), 1.6-1.6 (2H, m), 1.5-1.6 (4H, m), 1.4-1.5 (3H, m), 1.4-1.4 (6H, m), 1.3 (1H, d, J=9.5 Hz), 1.1 (3H, s), 1.1 (3H, br. s.), 1.1 (3H, br. s.), 1.0 (3H, s), 1.0 (3H, s).
Reaction SMILES: [OH-].[Li+].C([O:11][CH:12]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=O)C1C=CC=CC=1.Cl>O1CCCC1.CO.O.O>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][CH:12]([OH:11])[CH:13]([CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)C(CCNS(=O)(=O)c1ccc(F)cc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCNS(=O)(=O)c1ccc(F)cc1)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 112.5 %

Procedure:
Aqueous solution of lithium hydroxide (18 mg in 1 ml of water) was added to a solution of the compound (100 mg) obtained from Step 3 above in tetrahydrofuran:methanol:water (3:1:1, 5 ml). The resulting reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue thus obtained was diluted with water, acidified with dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with distilled water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound (94 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11].N12CCCN=C1CCCCC2.BrC(Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1COC(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-4,5-dihydro-4-oxazolecarboxylate (i.e. the product of Example 9, Step D) (1.09 g, 3.04 mmol) in 25 mL of dichloromethane at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (508 mg, 3.34 mmol). Bromotrichloromethane (662 mg, 3.34 mmol) was then added dropwise over 5 minutes. The reaction mixture was stirred for 6 h at 0° C. The reaction mixture was washed with saturated aqueous ammonium chloride (2×50 mL), the aqueous phase was back-extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 50-100% of ethyl acetate in hexanes as eluant to give 600 mg of the title compound as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:16]1(=[N:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCC1
Reactant: NCc1cccc(Oc2ccccc2)c1
Product: c1ccc(Oc2cccc(CN=C3CCCCC3)c2)cc1
Yield: 58.8 %

Procedure:
The procedure is carried out as described in Example 1(b) but with the use of 50 g (0.25 mol) of 3-phenoxybenzylamine and 25 g (0.255 mol) of cyclohexanone. Distillation leaves 41 g (0.147 mol) of N-cyclohexylidene(3-phenoxybenzylamine), corresponding to a yield of 58.7% of theory; b.p. 135°-136° C./4 Pa.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.B(O)(O)[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:21][CH:20]=1>>[S:21]1[CH:20]=[C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1csc2ccccc12
Product: c1ccc2c(-c3csc4ccccc34)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and thianaphthene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 343(MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[Si:22](OS(C(F)(F)F)(=O)=O)([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([CH3:25])[CH3:24]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)Cc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stir. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (MgSO4) filtered and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E133).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([NH:20][C:21](=[O:22])[C:16]=12)=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[C:17]3[C:18]([NH:20][C:21](=[O:22])[C:16]=23)=[O:19])[CH2:4][CH2:5]1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCN(CCCCc2cccc3c2C(=O)NC3=O)CC1
Yield: 21.8 %

Procedure:
A solution of 4-piperidone hydrochloride hydrate (2 gram, 13 mmol), bromobutylphthalimide (3.67 gram, 13 mmol) and triethylamine (3.4 ml, 26 mmol) in Chloroform (25 ml) was refluxed overnight. The reaction mixture was washed with sat. NaHCO3 and was dried over Na2SO4. Purification using flash chromatography gave 4-(4'-ketopiperidinyl)butylphthalimide (0.85 gram).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11](SC)=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][CH3:24]>>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][CH3:24])=[C:12]([S:15]([CH3:18])(=[O:16])=[O:17])[C:13]#[N:14])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(C)(C)N
Reactant: CSC(Nc1ccc2ncsc2c1)=C(C#N)S(C)(=O)=O
Product: CCC(C)(C)NC(Nc1ccc2ncsc2c1)=C(C#N)S(C)(=O)=O
Yield: 33 %

Procedure:
3-(Benzothiazol-6-ylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.167 g, 0.5 mmol) was stirred in 1,1-dimethylpropylamine (0.5 ml) for 17 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) without chromatography gave 60 mg (33%) of the title compound. Mp 112-114° C. 1H NMR (200 MHz, CDCl3): δ=1.00 (t, 3H), 1.39 (s, 6H), 1.65 (q, 2H), 3.12 (s, 3H) 7.29 (dd, 1H), 7.70 (d, 1H), 8.13 (d, 1H), 9.0 (s, 1H); EI SP/MS: 364 (M+).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:6]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(I)cn1CC(F)(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
4-Iodo-2-methyl-1H-imidazole (1.0 g, 4.8 mmol) was dissolved in 10 mL of DMF. Trifluoroethyl p-toluenesulfonate (4.89 g, 19.2 mmol) and cesium carbonate (1.57 g, 4.8 mmol) were added and the mixture was stirred for 18 h in a 50° C. oil bath. The reaction was cooled and taken up in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and brine, and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 0.6 g (43%) of 4-iodo-2-methyl-1-(2,2,2-trifluoro-ethyl)-1H-imidazole. (M+H)+=291.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:26])[CH:2]([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:58]([CH2:60][NH2:61])[OH:59]>CN(C=O)C.CC(=O)OCC>[OH:59][CH2:58][CH2:60][NH:61][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[N:10][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[C:6]([CH3:26])[CH:7]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cnc1CC(C)C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NCCO)cc3)no2)cnc1CC(C)C
Reaction time: 72 h
Yield: 46.4 %

Procedure:
To a solution of {4-[5-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid (50 mg, 142 μmol) in DMF (3 mL), EDC HCl (33 mg, 171 μmol), HOBt (23 mg, 171 μmol) and DIPEA (28 mg, 213 μmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (10 mg, 157 μmol) is added. Stirring is continued at rt for 72 h. The mixture is diluted with EA, washed with water, and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of MeOH to give N-(2-hydroxy-ethyl)-2-{4-[5-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide (26 mg) as a white solid; LC-MS: tR=0.82 min, [M+1]+=395.15; 1H NMR (CDCl3): δ1.01 (d, J=6.5 Hz, 6H), 2.19-2.29 (m, 1H), 2.46 (s, 3H), 2.53 (s br, 1H), 2.80 (d, J=7.3 Hz, 2H), 3.44 (q, J=4.8 Hz, 2H), 3.69 (s, 2H), 3.71-3.75 (m, 2H), 5.96 (s br, 1H), 7.46 (d, J=7.5 Hz, 2H), 8.18 (d, J=7.8 Hz, 2H), 8.17 (s), 8.19 (s), 8.22 (s, 1H), 9.20 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([Br:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(C(C)=O)CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCN(C(C)=O)CC2

Procedure:
A solution of 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) in acetic acid (20 ml) is treated with a solution of bromine (1.8 g, 0.011 m) in acetic acid (10 ml). The mixture is warmed to 70° for 1.5 hours, concentrated in vacuo and partitioned between water and ethyl acetate. The ethyl acetate phase is washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])=O.[NH2:27][C:28]([NH2:30])=[O:29].Cl>CCO>[O:29]=[C:28]1[NH:30][CH:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:27]1
Reactant: NC(N)=O
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cccc(C(=O)O)c2)N1
Temperature: 85 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
To a solution of 1,2-diphenylethanone (784 mg, 4.0 mmol), 3-formylbenzoic acid (500 mg, 3.33 mmol) and urea (600 mg, 10.0 mmol) in EtOH (40 mL) was added concentrated HCl (1.6 mL). The mixture was stirred at 85° C. for 3 days. The volatiles were removed under reduced pressure and standard aqueous/EtOAc workup procedure was followed. Purification by column chromatography (100% EA) gave Compound 93 as an off-white powder (186 mg, 15%). 1H NMR (DMSO-d6 500 MHz): δ 8.70 (s, 1H), 7.99 (s, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.57 (s, 2H), 7.50 (t, J=14.5 Hz, 1H), 7.21-7.25 (m, 5H), 6.79-7.02 (m, 3H), 6.78 (d, J=7.0 Hz, 2H), 5.24 (d, J=2.0 Hz, 1H); MS (ESI): m/z 371.1 [M+1]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([CH3:8])[CH2:6]O)=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[O-:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19].[N:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>C(Cl)Cl.CC#N>[O-:20][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17].[N:1]([CH2:4][C@@H:5]([CH3:8])[CH2:6][N+:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2)=[N+:2]=[N-:3]
Reactant: C[C@@H](CO)CN=[N+]=[N-]
Reactant: C1CN2CCN1CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](CN=[N+]=[N-])C[N+]12CCN(CC1)CC2
Reaction time: 0.67 h
Yield: 100.5 %

Procedure:
(R)-(−)-3-azido-2-methylpropanol (0.64 g, 5.56 mmol) was dissolved in CH2Cl2 (40 mL). 2,6-lutidine (1.9 mL, 16.3 mmol) was added at −20° C. followed by adding trifalic anhydride (1.4 mL, 8.32 mmol). The mixture was kept in −20° C. for 40 min, diluted with CH2Cl2, washed with water, 0.1 N HCl aqueous solution, water and brine, dried over Na2SO4 and concentrated to give the trifalte (1.33 g). The triflate (0.7 g, 2.83 mmol) was reacted with 1,4-diazabicyclo[2.2.2]octane (0.31 g, 2.77 mmol) in CH3CN for 3 hrs. The solvent was removed and the residue was dried under vacuum to give the product (1.0 g).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][CH:30]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH3:33]>CCCCCC.O1CCCC1>[CH3:7][O:8][CH:9]=[CH:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[CH:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)Oc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C)Oc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphonium bromide dissolved in tetrahydrofuran (THF), in an atmosphere of argon, and the mixture was stirred for one hour at room temperature. A solution of the compound (30) dissolved in THF was added thereto and stirring was continued for two hours. The reaction solution was washed with water, was dried over magnesium sulfate, and was then concentrated. The residue was purified by column chromatography to obtain 1-(2-methoxyethenyl)-4-(1-methylbutyloxy)benzene (31).