Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:19][CH2:20][C@@H:21]1[CH2:29][C@@H:28]2[C@@H:24]([CH2:25][N:26]([C:30](=[O:41])[C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH3:32])[CH2:27]2)[C@@:23]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])([OH:42])[CH2:22]1>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:20][C@@H:21]2[CH2:29][C@@H:28]3[C@@H:24]([CH2:25][N:26]([C:30](=[O:41])[C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH3:32])[CH2:27]3)[C@@:23]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])([OH:42])[CH2:22]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CO)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reaction time: 18 h
Yield: 59.7 %

Procedure:
4.2 g of p-toluenesulphonyl chloride and then 3.1 cm3 of triethylamine are added at room temperature to a solution of 1.17 g of (3aS,4S,6R,7aR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 30 cm3 of dichloromethane. The reaction mixture is stirred at this temperature for 18 hours, then washed with twice 25 cm3 of water and then with 25 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 25 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting fractions of 25 cm3. Fractions 22 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.95 g of (3aS,4S,6R,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl) propionyl]perhydroisoindol-4-ol is obtained in the form of a thick white foam.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].O>CC(O)C>[S:19]([OH:23])([OH:22])(=[O:21])=[O:20].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)NCC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (10 g) is suspended in 2-propanol (60 ml) under an inert atmosphere and cooled to 0°. To the stirring slurry is added 1,1-dimethylethanamine (13 ml) and the reaction mixture permitted to warm to room temperature and stir for 50 minutes. The solution is then treated with a mixture of concentrated sulfuric acid (3.5 ml), 2-propanol (6.5 ml) and deionized water (5 ml). The reaction mixture is stirred for a further 18 hours whereupon the title compound (10.2 g) is isolated by filtration and dried in vacuo at 50°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][NH2:10]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[N:6][CH:7]=1
Reactant: NN
Reactant: Fc1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: O
Product: NNc1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To 5-bromo-2-fluoropyridine (3-1) (46 g, 261 mmol) in THF (460 mL) was added hydrazine (41.9 g, 41.0 mL, 1.31 mol). The mixture was heated to reflux and stirred vigorously for 2 h. After cooling, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (3-2) was used in the subsequent step without further purification. LC/MS: m/z (M+H)=187.9.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](=[O:31])[CH2:29]Br>CN(C=O)C>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](=[O:31])[CH2:29][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(CBr)c1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (460.5 mg) in DMF (5 mL) was added sodium hydride (103 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 1-(1-benzofuran-2-yl)-2-bromoethan-1-one (633 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1.[O:20](C(C)(C)C)[K].O=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH:7]([OH:20])[C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Reactant: CC(C)(C)O[K]
Agent: O=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)C(O)Oc1ccccc1-3

Procedure:
8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (300 mg, 1.194 mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 2.0 mL, 2.0 mmoL) under a flow of O2 for 6 hours. The reaction mixture was then partitioned between water and EtOAc. The EtOAc layer was washed with saturated NH4Cl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material was then purified by column chromatography (silica gel, hexanes:EtOAc 9:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[NH:8][C:7]1=[O:21])[CH3:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:9]=2[N:8]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[C:25]([F:24])([F:34])[F:35])[C:7]1=[O:21])[CH3:23]
Reactant: CCN(CC)CCn1c(=O)[nH]c2c(C(F)(F)F)cc(C#N)cc21
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(Cc2ccccc2C(F)(F)F)c2c(C(F)(F)F)cc(C#N)cc21
Temperature: 80 °C
Yield: 9.9 %

Procedure:
A mixture of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (19.1 mg), 2-trifluoromethylbenzyl bromide (30.4 mg) and potassium carbonate (16.5 mg) in N,N-dimethylformamide (3 ml) was stirred with heating at 80° C. for 1.5 hours. To the mixture was further added 2-trifluoromethylbenzyl bromide (46.8 mg), and the mixture was stirred with heating at 80° C. for 1 hour. 2-Trifluoromethylbenzyl bromide (160.3 mg) and potassium carbonate (43.2 mg) were further added, and the mixture was stirred with heating 80° C. for 1 hour. The reaction mixture was concentrated in vacuo. The resultant residue was purified by preparative TLC (1 mm, 20×20 cm, chloroform:methanol=25:1) to give the title compound (2.8 mg, 10%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[N:10][C:5]2=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([CH:29]4[CH2:31][CH2:30]4)[C:23]=3[C:22](=[O:32])[NH:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([CH:29]4[CH2:31][CH2:30]4)[C:23]=3[C:22](=[O:32])[N:21]2[C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[N:10][C:5]3=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)nc2c1nnn2C
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnn(C)c3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 102 using 5-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Step 109.4) and 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6). The reaction mixture was quenched with a saturated aq. NaHCO3 solution (75 mL) and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude material was first purified by silica gel chromatography (hexane/EtOAc 25-45%). tR: 5.69 min (HPLC 1); tR: 1.26 min (LC-MS 2); ESI-MS: 434 [M+H]+ (LC-MS 2); Rf=0.58 (EtOAc/hexane 1:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.11 (m, 2H) 1.19-1.27 (m, 2H) 1.91 (s, 3H) 2.68 (s, 3H) 3.78-3.87 (m, 1H) 4.08 (s, 3H) 6.58 (s, 1H) 7.31 (d, J=8.6 Hz, 2H) 7.43 (d, J=8.2 Hz, 2H) 8.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=[O:18])[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([OH:19])=[O:18])[N:12]=[C:11]1[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCCC(=O)OC(C)(C)C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reaction time: 1 h

Procedure:
A solution of 48 mg (117 μmol) of the compound from Example 223A in 2 ml methanol is treated with a 1 N lithium hydroxide solution in water (470 μl, 470 μmol). After 1 hr at RT, the methanol is removed on the rotary evaporator. The residue is dissolved in DMSO and purified by preparative HPLC. 41 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[NH2:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:31][C:27]3[S:26][CH:30]=[CH:29][N:28]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl

Procedure:
4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (EXAMPLE 5) was prepared in the same manner as INTERMEDIATE D, step 3, starting from 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride and using thiazol-2-amine instead of intermediate A. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (br. s., 2 H) 4.36 (t, J=4.45 Hz, 2 H) 6.32 (d, J=8.41 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.14 (dd, J=8.61, 2.15 Hz, 1 H) 7.17-7.26 (m, 2 H) 7.73 (d, J=8.31 Hz, 1 H) 7.81-7.88 (m, 1 H) 8.06 (s, 1 H) 12.58 (br. s., 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[O:14].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:26][N:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[S:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=S(c1nc2ccccc2[nH]1)c1ccccc1-c1ccccn1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(S(=O)c2ccccc2-c2ccccn2)nc2ccccc21
Yield: 75.3 %

Procedure:
2-[2-(2-Pyridyl)-phenyl sulphinyl]-1H-benzimidazole (Example 13) (0.7 g) in dry dimethylformamide (50 ml), methyl iodide (0.34 g) and anhydrous potassium carbonate (1.1 g) were stirred at room temperature for 1.75 hours. The mixture was poured onto water, extracted into ethyl acetate, washed, dried and evaporated under reduced pressure to leave the title compound as a cream solid (0.55 g).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[CH:6]=[CH:7][C:8](=[O:10])[CH:9]=1)[CH2:2][CH3:3].C[O:13][C:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH:15]=1.Cl>C1C=CC=CC=1.CO>[OH:11][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:8]2[O:10][C@H:16]3[CH2:15][C:14](=[O:13])[CH2:19][CH2:18][C@H:17]3[C:7]=2[CH:6]=1
Reactant: COC1=CC=CCC1
Reactant: CCCC1=CC(=O)C=CC1=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: CCCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@@H]1O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
A solution of 1.08 g (7.2 mmol) of 2-propyl-1,4-benzoquinone and 2.20 g (20.0 mmol) of 1-methoxy-1,3-cylcohexadiene in 20 mL of benzene was heated at reflux for 2 h. The solution was concentrated in vacuo and the residue dried under high vacuum to afford a pale yellow oil. This material was dissolved in 20 mL of methanol and to that solution was added 1 mL of 2.0M HCl. The solution was stirred at room temperature for 6 hours, then was concentrated to about 5 mL volume. This was partitioned between ethyl acetate and water and the aqueous layer was washed with two portions of ethyl acetate. The organic extracts were sequentially washed with water and NaCl solution, combined, dried over magnesium sulfate, and concentrated. The residue was crystallized from ether-hexane to afford 0.764 g white crystals, 43%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:21]([CH3:23])[CH3:22])([CH2:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:21]([CH3:23])[CH3:22])([CH2:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:27][CH2:26][CH2:24][OH:25])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccc(N)cc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: NCCO
Product: CCC(Cc1ccc(N)cc1)(C(=O)c1ccc(NCCO)cc1)N(C)C
Yield: 36.8 %

Procedure:
23.5 g (0.078 mol) 2-[(4-aminophenyl)methyl]-1-(4-fluorophenyl)-2-dimethylamino-1-butanone are reacted with ethanol amine (33.4 g, 0.55 mol) under conditions as described for example 1.2. The crude product obtained is purified by first by filtration over silica gel using hexane/ethyl acetate 1:1→ethyl acetate as the eluent, followed by flash chromatography on silica gel (eluant: ethyl acetate). 10.2 g (37%) 2-[(4-aminophenyl)methyl]-1-[4-(2-hydroxyethyamino)phenyl]-2-dimethylamino-1-butanone are obtained as a viscous yellow oil.
Reaction SMILES: O1CCOCC1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:15]1([NH:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([NH:21][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCCCCC
Reactant: ONc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCC/C=C/CNc1ccccc1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12mL), 3 mL of 1-octene, 1g of 4A Molecular Sieves, and 0.051 g (0.11 mmol) of (2,6-diPicolinato)MoO2 (hexamethyl phosphoramide)is heated at reflux (ca. 100° C.) under a nitrogen atomosphere while a toluene solution (50 mL)of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 6-12 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure and the residue chromatographed over silica gel. Elution with pentane afforded phenyl trans-2-octenyl amine (>95% one isomer by NMR, GC/MS) in 20-30 % yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:20][C:21]([Br:24])=[CH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([CH2:43][CH2:42][C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=3)=[CH:41][CH:40]=2)[CH2:45][CH2:46]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=O)CC3)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=C(Br)Br)CC3)cc2)cc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A solution of 6.7 g of triphenylphosphine in 60 ml of methylene chloride was placed at -20° C. under argon gasification in a sulphonation flask equipped with a thermometer, dropping funnel and solid substance addition tube and treated within 5 minutes with 4.3 g of tetrabromomethane. The clear orange solution was stirred at -15° C. for a further 10 minutes and then a solution of 2.33 g of trans-4-[2-(4'-pentyl-4-biphenylyl)ethyl]cyclohexanecarboxaldehyde in 40 ml of methylene chloride was added dropwise at -5° C. within 10 minutes. The mixture was stirred at -5° C. for a further 10 minutes, then poured into 700 ml of hexane and freed from precipitated triphenylphosphine oxide by filtration. The concentrated filtrate was digested with 300 ml of hexane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.5 g) on silica gel with 1% ethyl acetate/petroleum ether gave 2.87 g (87%) of 4-[2-[trans-4-(2,2-dibromovinyl)cyclohexyl]ethyl]-4'-pentylbiphenyl as colourless crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][S-:22].[Na+]>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[N:3]=[C:2]([S:22][CH3:21])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: C[S-]
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(SC)nc21
Temperature: 110 °C

Procedure:
A mixture of the product from step (ii) (0.6 g) and sodium thiomethoxide (0.45 g) in dimethylsulphoxide (15 ml) was heated at 110° C. for 4 h. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. Yield 0.45 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-bromo-benzylamine (0.8 g, 2.807 mmol) in anhydrous DME (12 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol), pyridine-4-boronic acid (0.513 g, 4.211 mmol), and a 2M aqueous Na2CO3 solution (2.8 mL, 5.614 mmol). Heat the reaction overnight at 70° C. Cool the mixture to ambient temperature, dilute with EtOAc, and filter over Celite®. Wash the organic fraction with water, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give the title compound as an oil (0.295 g, 37%). GC-MS m/z: 284 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: OCC(O)CO
Reactant: Cc1cccc(C=O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C2OCC(O)CO2)c1
Yield: 64.6 %

Procedure:
A mixture of 3-methylbenzaldehyde (24.0 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2.0 ml) in 150 ml of benzene was heated under a Dean-Stark apparatus until no more water was collected (approximately 2.5 hours). The mixture was cooled, neutralized with potassium carbonate, diluted by the addition of 200 ml of ether and the ether solution washed with water (3 × 100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a residue of 25.1 g of the desired 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane nD25 1.5346.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reaction time: 0.75 h

Procedure:
Fmoc-protected tripeptide 74 (546 mg, 0.98 mmol) was treated with a 5% v/v solution of piperidine in DMF (5 mL). After stirring for 45 min, the reaction mixture was concentrated to dryness. The crude material was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]1[NH:4][CH2:5][CH2:6][CH2:7]2.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH:16]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]2([CH3:1])[CH2:14][C:13]3[C:8]([CH:3]12)=[CH:9][CH:10]=[CH:11][CH:12]=3)([CH3:18])[CH3:15]
Reactant: CC12CCCNC1c1ccccc1C2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)N1CCCC2(C)Cc3ccccc3C12
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
To a solution of (4aRS,9bRS)-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (140 mg) and acetone (217 mg) in 1,2-dichloroethane was added sodium triacetoxyborohydride (792 mg), followed by stirring at room temperature for 3 days. A 1 M aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain (4aRS,9bRS)-1-isopropyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (138 mg) as an oily substance. This was made into a salt using an equivalent amount of methanesulfonic acid by a conventional method, washed with ethyl acetate, and collected by filtration to obtain (4aRS,9bRS)-1-isopropyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine methanesulfonate (95 mg) as a colorless powder.