Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:27]1([S:33]([NH:1][CH2:2][C:3]([N:5]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:9](=[O:15])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=3)=[O:4])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CNS(=O)(=O)c2ccccc2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of (3aR*,10aS*)-4-aminoacetyl-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (0.2 g, 0.57 mmol) and benzenesulfonyl chloride (0.12 g, 0.69 mmol) in dichloromethane (10 mL) was added triethylamine (70 mg, 0.69 mmol). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with dichloromethane. The extract was washed with water and dried, then, the solvent was distilled off. The residue was purified by silica-gel column chromatography (dichloromethane), which was crystallized from diethyl ether to give 170 mg (yield 61%) of the titled compound, m.p. 185°-187° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:21]([C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22](=[O:27])[C:23]([F:26])([F:24])[F:25]
Reactant: COC(=O)CBr
Reactant: O=C(Nc1ccc(Cl)cc1Cc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1Cc1ccccc1
Yield: 89.2 %

Procedure:
Powdered potassium carbonate (1.10 g, 7.97 mmol) is added to a stirred solution of N-(2-benzyl-4-chloro-phenyl)-2,2,2-trifluoro-acetamide (1.25 g, 3.98 mmol) and methyl bromoacetate (1.34 g, 8.76 mmol) in anhydrous DMF (5 mL). The resultant mixture is stirred at ambient temperature under nitrogen for 2 hours. After dilution with EtOAc (60 mL), the mixture is washed with water (25 mL×3), dried over MgSO4, filtered, concentrated and chromatographed on-silica (gradient 0-15% EtOAc in hexane) to give 1.37 g (3.55 mmol, 89% yield) of the title compound as oil. ESIMS: m/z 386 [(M+H)+, 35Cl], 388 [(M+H)+, 37Cl].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (384.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (85.6 mg, 21.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 407.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(N(CC)CC)C>[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]([F:33])([F:32])[F:34])[C:19]5[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:45][CH2:44]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Reactant: COCCN1CCNCC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 1-(2-methoxyethyl)piperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=139-140° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.75 (m, 3 H), 7.56 (t, 1 H), 7.49-7.40 (m, 3 H), 7.27 (d, J=8.0 Hz, 1 H), 7.18-7.15 (m, 2 H), 6.76 (d, J=7.2 Hz, 1 H), 4.64 (t, J=7.6 Hz, 1 H), 3.43-3.37 (m, 2 H), 3.34 (s, 3 H), 3.21-3.11 (m, 2 H), 2.69-2.65 (m, 2 H), 2.50-2.43 (m, 12). LCMS 588 (M+H).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])(=O)C.N>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([OH:5])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Agent: Cl
Agent: N
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50° C. with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3×200 ml), and dried in vacuo at 60° C. over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%);
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH2:30][CH3:31])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1)=[C:8]2[CH2:30][CH3:31]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(CC)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(CC)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [8-chloro-2,4-diethyl-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.20 g), methanol (4.0 mL) and 1.0 M aqueous sodium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient of acetonitrile in water (40% to 85% of organic modifier) gave title compound as a pale yellow solid, 0.034 g.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])O)=[CH:5][CH:4]=1.[NH3:12]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[NH:9])=[CH:5][CH:4]=1
Reactant: N=C(O)c1ccc(Br)cc1
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
86 g (0.32) of 4-bromobenzimidate hydrogen chloride was added to 240 cm3 of ethanol saturated with gaseous ammonia and stirred at room temperature overnight. Approximately one-half of the volume of the ethanol was distilled off and the residual solution was recrystallized to yield 57 g (0.24 mol) of 4-bromobenzamidine hydrogen chloride.
Reaction SMILES: [N+]([O-])(O)=O.C(O)C.[C:8](=[O:10])=O.[Cl:11][C:12]1[C:17](C)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>>[Cl:11][C:12]1[C:17]([CH3:16])=[C:8]([OH:10])[CH:15]=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cccc(C)c1Cl
Reactant: O=C=O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1ccc(O)c(C)c1Cl
Reaction time: 0.17 h

Procedure:
Nitration of 2-chloro-m-xylene. Nitric acid (90%, 50 mL) was cooled to −35° C. (ethanol-dry ice bath). 2-Chloro-m-xylene (10 mL) was added dropwise over 1 h keeping the temperature between −30° C. and −35° C. The reaction mixture was poured onto ice, stirred for 10 min, precipitate formed was collected by filtration, washed with water, dried. The crude product was purified on SiO2 (50 g), hexane-EtOAc (0 to 2% v/v). The product—yellow solid, 12.8 g, as a mixture of 2-chloro-1,3-dimethyl-4-nitro-benzene and chloro-1,3-dimethyl-5-nitro-benzene (4:1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1
Reactant: c1c[nH]cn1
Reactant: OC(c1cccc(Cl)c1)c1ccc2c(c1)Cc1ccccc1-2
Product: Clc1cccc(C(c2ccc3c(c2)Cc2ccccc2-3)n2ccnc2)c1

Procedure:
Using α-(9H-fluoren-2-yl)-3-chlorobenzyl alcohol and imidazole as starting compounds, the process of Example 1 was repeated to obtain 1-[3-chloro-α-(9H-fluoren-2-yl)benzyl]-1H-imidazole.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([OH:21])([CH2:17][C:18]([CH3:20])=[CH2:19])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]([CH:14]([CH3:15])[CH3:16])([CH2:17][C:18]([CH3:20])=[CH2:19])[O:21][C:30]2=[O:32])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 3-{(S)-2-[1-(4-bromophenyl)-ethylamino]-ethyl}-2,5-dimethyl-hex-5-en-3-ol (6.4 g, 16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH2Cl2 (260 mL) was added triphosgene (2.52 g, 8.5 mmol) at 0° C. under N2, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by column chromatography to give two isomers of 3-[(S)-1-(4-bromophenyl)ethyl]-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1>>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][N:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cnc(Cl)nc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-chloropyrimidine (251 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (30 mg, 6.8%). MS (ISN) 467.2 [(M)−]; mp 157-159° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH:21][C:22](=[S:25])[NH:23][NH2:24]>C(O)C>[C:7]1([C:5](=[N:24][NH:23][C:22](=[S:25])[NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: NNC(=S)NCCc1ccccn1
Solvent: CCO
Product: S=C(NCCc1ccccn1)NN=C(CCCCl)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
A mixture of 4-chlorobutyrophenone (8.5 mL, 53 mmol) and 4-(2-(2-pyridyl)ethyl)-3-thiosemicarbazide (9.5 g, 48 mmol) in 400 mL of ethanol was heated under a nitrogen atmosphere to 75° C. and then at that temperature for 24 hours (overnight). The solvent was removed under reduced pressure to give 20.3 g of a yellow oil. This oil was triturated with EtOAc to separate the desired product from the thiosemicarbazide. The ethyl acetate was removed under reduced pressure and the residue chromatographed on 1 kg of silica gel (230-400 mesh) using 10-20% EtOAc-hexane as the eluent. The material collected (2.86 g, yellow solid) was recrystallized from isopropyl alcohol to give 2.30 g (13%) of the title compound as an off-white solid, mp 126-129° C.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH2:9]([N:16]1[CH2:24][C:23]2([C:25]([O:27][CH3:28])=[O:26])[CH:18]([C:19](O)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:20][CH2:21][CH:22]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>ClCCl>[CH2:9]([N:16]1[CH2:24][C:23]2([C:25]([O:27][CH3:28])=[O:26])[C:18](=[C:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:20][CH2:21][CH:22]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccccc1C)CCC2c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C12CN(Cc3ccccc3)CC1=C(c1ccccc1C)CCC2c1ccccc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A mixture of 3.2 cm3 of trifluoromethanesulphonic acid and of 3 cm3 of dichloromethane was added dropwise to a solution of 2.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(2-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of dichloromethane maintained at a temperature in the region of 0° C. The reaction mixture was stirred for thirty minutes at a temperature in the region of 0° C. and twenty hours at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. The pH was then brought to 8 by addition of a normal aqueous sodium hydroxide solution. The aqueous phase was separated by settling and extracted with three times 50 cm3 of dichloromethane. The organic phases were combined, washed with three times 100 cm3 of distilled water and 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. 1.9 g of methyl (3aRS,4SR)-2-benzyl-7-(2-methylphenyl)-4-phenyl-1,3,3a,4,5,6-hexahydroisoindole-3a-carboxylate were thus obtained in the form of an oil, and used in the subsequent syntheses, the characteristics of which were as follows:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the intermediate obtained in Step B in 4 mL of methylene chloride was treated with 0.16 mL (1.21 mmol) of trimethylsilylbromide. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride then washed with aqueous saturated sodium chloride (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 133 mg of crude product. 1H NMR (400 Hz, CDCl3): 2.78 (s, 6H), 4.5 (s, 2H), 6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H), 8.10 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:19]1[C:26]2([C:27](Cl)=[O:28])[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:27]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[O:28])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)C12CCCN1CCC2
Reactant: Nc1ccccc1C(=O)Nc1cccnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1NC(=O)C12CCCN1CCC2
Temperature: 10 °C
Reaction time: 17 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-3-(2-aminobenzoyl)aminopyridine (15.0 g, 61.0 mmol), in 200 ml of anhydrous pyridine, pyrrolizidine-7a-carbonyl chloride hydrochloride (14.0 g, 80.5 mmol), prepared as described in Reference Example 3) was added at -20° C. The mixture was stirred for 17 hours at 10° C. and evaporated in vacuo to dryness. The remaining residue was partitioned between saturated sodium biscarbonate solution and chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. To the remaining residue, methanol was added. After stirring, the resulting crystals was obtained through filtration and washed with small amount of methanol to give 18.1 g (77.2%) of the desired compound.
Reaction SMILES: [CH2:1]([NH:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[BH3-][C:32]#N.[Na+]>>[CH3:32][N:9]([CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2)nc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CN(CCc1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 91.6 %

Procedure:
Using a method similar to Example 13, using 6-(1-phenethylamino-indan-5-yloxy)-nicotinamide (example 18, 980 mg, 2.62 mmol), paraformaldehyde (1.03 g), and NaBH3CN (494 mg, 7.87 mmol) gives the title compound (930 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.30-7.17 (m, 6H), 6.97-6.91 (m, 3H), 5.79 (br. s, 2H), 4.45 (t, 1H), 2.96-2.74 (m, 4H), 2.68 (m, 2H), 2.33 (s, 3H), 2.09 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:20]C(=O)OC(C)(C)C)[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:20])[CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7][CH:6]=1
Reactant: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)COc1ccc(C(N)CN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of t-butyl (1R)-1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethylcarbamate (87 mg, 0.207 mmol) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (0.25 mL, 3.24 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the product was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer to afford 1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethanamine.3TFA (85.9 mg, 63% yield, 2 steps) as a colorless amorphous semi-solid: 1H NMR (400 MHz, DMSO-d6) δ 9.84 (br. s., 1H), 8.21 (br. s., 3H), 7.38 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 4.41 (dt, J=9.5, 4.7 Hz, 1H), 3.83 (dd, J=9.3, 5.8 Hz, 1H), 3.75 (dd, J=9.3, 6.5 Hz, 1H), 3.41 (d, J=11.8 Hz, 2H), 3.13 (d, J=12.6 Hz, 1H), 2.94-3.07 (m, 3H), 2.92 (d, J=13.3 Hz, 1H), 2.72-2.84 (m, 4H), 2.58 (dd, J=13.5, 4.7 Hz, 1H), 2.35 (t, J=11.1 Hz, 1H), 1.87 (dq, J=12.5, 6.3 Hz, 1H), 1.23-1.48 (m, 3H), 1.13-1.22 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.1 Hz, 3 H); LRMS (ESI) m/e 320.3 [(M+H)+, calcd for C19H34N3O 320.3].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][N:21]=1)=[O:19])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:22][N:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Yield: 43.2 %

Procedure:
To a stirred solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (570 mg, 3.01 mmol) and 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (655 mg, 3.92 mmol) in THF (15 mL) under argon was added triphenylphosphine (1.03 g, 3.93 mmol). Diethyl azodicarboxylate (1.71 mL of a 40% solution in toluene, 682 mg, 3.92 mmol) was added dropwise. After 20 h the reaction mixture was concentrated in vacuo, water was added, and the reaction mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 10 to 60% ethyl actetate in heptane) afforded the title compound (440 mg, 43%) as a pink oil. MS: m/e=339.3 [M+H]+.