Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[S:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[S:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCSc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCSc1ccccc1-3
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate (186 mg, 0.470 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at room temperature for 13 hr. 2N hydrochloric acid and water were added to the reaction mixture. The precipitated solid was collected by filtration and dried in vacuo to give 12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic acid (157 mg, yield 87.7%).
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14]CC(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CCCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a stirred solution of Meldrum's Acid (3.0 g, 20.8 mmol) in 100 mL of CH2Cl2, 4-trifluoromethyl butyric acid (2.96 g, 20.8 mmol) was added followed by DMAP (5.08 g, 41.6 mmol) and finally DCC (4.30 g, 20.8 mmol). The reaction stirred overnight at room temperature. The mixture was then filtered and the filtrate washed with 1M HCl, H2O and Brine. The organics were then dried over sodium sulfate, filtered and concentrated to a yellow oil. The material was then dissolved in 100 mL of EtOH and refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate/hexanes (1:4)) to yield 1.88 g (43%) of a clear oil.: 1H NMR (CDCl3, 400 MHz) δ 4.24–4.10 (q, 2H, J=7.14), 3.45 (s, 2H), 2.93–2.73 (t, 2H, J=7.88), 2.52–2.28 (m, 2H), 1.31–1.20 (t, 3H, J=7.14)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:22]([OH:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:22]([OH:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(Br)cc1)c1cc2ccccc2cc1O
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1cc2ccccc2cc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound N-2-(4-Bromophenyl)ethyl-3 hydroxyl-2-naphthamide in 2.0 mL of DME were added 36.6 mg (0.3 mmol) of phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 22 mg (60%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23](C2C=CN=CC=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]CCl>[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([Cl:33])[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Product: COc1nnc(Cl)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
2.7 g 6-Hydroxymethyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-car-boxylic acid tert-butyl ester is dissolved in 80 mL dichloromethane. After addition of 3.61 g activated manganese (IV) oxide the reaction mixture is heated to reflux for 1 hour. Then every two hours additional manganese (IV) oxide is added until the conversion is complete. The reaction mixture is diluted with dichloromethane and filtered over celite. 2.68 g (100%) crude product is obtained, which is directly used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[N:19]=[CH:18][N:17]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccsc1-c1nnc[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccsc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500 mL, round bottomed flask, (4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone (16.89 g, 58.29 mmol) was dissolved in tetrahydrofuran (500.0 mL, 6164 mmol). To the solution were added dihydropyran (31.9 mL, 3.50E2 mmol) and p-toluenesulfonic acid monohydrate (16.6 g, 87.4 mmol). The mixture was stirred for 3 h at rt. The reaction was quenched by the addition of saturated aqueous solution of sodium bicarbonate (200 mL). The aqueous phase was separated and then extracted with EtOAc (300 mL). The combined organic phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to afford (4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)methanone as an oil which was dried under high vacuum overnight (19.4, 89.1%). LCMS: (FA) ES+ 374.2, 376.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([N:13]([CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])[CH3:14])=[O:12]>>[OH:9][CH2:10][C:11]([N:13]([CH3:14])[CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])=[O:12]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1OCc1ccccn1
Yield: 17 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide to give the title compound as a light yellow solid in 17% yield; NMR spectrum (DMSO-d6 373K) 1.43 (d, 3H), 2.29 (s, 3H), 2.97 (s, 3H), 3.58 (m, 1H), 4.08 (m, 3H), 5.11 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.21 (d, 1H), 7.32 (m, 2H), 7.57 (m, 3H), 7.67 (t, 1H), 8.83 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 488.
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:4][CH3:5])[CH3:2].[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[C:22](=[O:23])[CH2:21][O:20][CH2:18][CH3:19])[CH3:2]
Reactant: CCN(C=Cc1cccc(C(F)(F)F)c1)CC
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC(=O)C(=CN(CC)CC)c1cccc(C(F)(F)F)c1

Procedure:
An enaminoketone was formed from 4.86 g. of N,N-diethyl-3-trifluoromethylstyrylamine and 2.44 g. of ethoxyacetyl chloride in the presence of 1.6 g. of pyridine. The desired enaminoketone, 1-diethylamino-4-ethoxy-2-(3-trifluoromethylphenyl)-1-buten-3-one was formed. To the unpurified enaminoketone in 75 ml. of anhydrous tetrahydrofuran at 0° C. was added 3.2 g. of sodium methoxide, and the mixture was stirred for 15 minutes. To this mixture was added 4.4 g. of ethyl formate dropwise. The mixture was stirred for three hours, and 50 ml. of a 40 percent methylamine solution in water was added followed by 5 g. of methylamine hydrochloride. The reaction mixture was stirred overnight at ambient temperature, and was then evaporated to dryness under vacuum. The residue was taken up in dichloromethane, and the solution was washed with water and dried over magnesium sulfate. The dry solution was filtered, and evaporated under vacuum to obtain a dark residue which was triturated in cold diisopropyl ether. The solids were removed by filtration and recrystallized from diisopropyl etherdichloromethane to obtain 1.6 g. of 3-ethoxy-1-methyl-5-(3-trifluoromethylthylphenyl)-4(1H)-pyridone, m.p. 131°-133° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccco1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccco4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with furan-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(furan-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH2:28])=[N:22][C:23]([NH2:27])=[N:24]2)=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[NH2:27][C:23]1[N:22]=[C:21]([NH2:28])[C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=1
Reactant: Nc1nc(N)c2ccc(F)cc2n1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2ccc3c(N)nc(N)nc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To 3,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.41 g, 1.2 eq) in dimethylacetamide (50 mL) is added slowly sodium hydride (69.5 mg, 1.5 eq) and the resulting mixture is stirred at RT for 0.5 h. Then 7-Fluoro-quinazolin-2,4-diamine (0.342 g, 1 eq) is added and the mixture is stirred at 150° C. for overnight. The reaction mixture is poured into sat'd NaHCO3 aq. solution (300 mL), extracted by EtOAc (3×150 mL). The combined organic layers are dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography to give 1-(2,4-Diamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.5 g, 77.6% yield). LC/MS m/z=336 [M+H]+.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]1=[O:12])C.[S:13]([NH:23]N)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CC(O)=O>CCO>[S:13]([N:23]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[C:5]=2[CH:4]=[N:2]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Yield: 51.3 %

Procedure:
A solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (55 g, 0.329 mol), 2-tosylhydrazine (61.3 g, 0.329 mol) and AcOH (33 mL) in EtOH (540 mL) was heated for 4 h at 70° C. Removed the solvent under reduced pressure and the residue was recrystallized using PE/EA=5/1 to give 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (49 g, yield 51.3%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:38](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:20]=[C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:38]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-[4-(3,4-difluoro-phenyl)-6-naphthalen-2-yl-pyridin-2-yl]-phenol; mp 165-167° C.; 1H NMR (DMSO-d6) d 6.99 (m, 2H), 7.38 (m, 1H), 7.65 (m, 4H), 8.06 (m, 4H), 8.24 (d, J=6.8 Hz, 1H), 8.42 (m, 2H), 8.49 (d, J=1.2 Hz, 1H), 8.74 (s, 1H), 14.35 (s, 1H); IR (KBr) 1602 cm−1; MS [M+H]+ m/z=410. Anal. calcd for C27H17F2NO: C, 79.21; H, 4.19; N, 3.42; Found: C, 79.33; H, 4.19; N, 3.22.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([C@@H:13]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH2:14][N+:15]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O1CCCC1.O>O1CCCC1>[NH2:15][CH2:14][C@H:13]([C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NC[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCC[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 106.6 g (0.33 mol) of rac-(2S*)-2-[(R*)-4-(benzyloxy)-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise while stirring to a suspension of 28.6 g (0.75 mol) of lithium aluminium hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 50°. The reaction mixture is stirred at 50° overnight and it is treated, after cooling to room temperature, with 300 ml of ethanol and subsequently with 100 ml of tetrahydrofuran/water (1:1). The separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The crystalline product obtained is recrystallized from methylene chloride/isopropyl ether. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-(benzyloxy)benzyl]cyclohexanol in the form of colourless crystals of m.p. 160°-161°.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8].Cl.C([O-])([O-])=O.[K+].[K+].[OH:31][CH2:32][C@@H:33]([NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:34][C:35]([OH:37])=[O:36]>CN(C=O)C.O.CCOC(C)=O.CO.C1COCC1>[CH3:6][C:7]([Si:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:31][CH2:32][C@@H:33]([NH:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH2:34][C:35]([OH:37])=[O:36])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H](CC(=O)O)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
In a 250 ml round-bottomed flask (3S)-4-hydroxy-3-({[(phenylmethyl)oxy]carbonyl}amino)butanoic acid D1 (3.75 g), was dissolved in DMF (30 ml). To the resulting solution imidazole (3.02 g, 44.4 mmol), and TBDPSCl (7.61 ml, 29.6 mmol) were added and the resulting solution left under stirring at room temperature for 15 hours. The reaction mixture was transferred into separatory funnel containing water (300 ml). The pH of the medium was lowered to pH=2 by the addition of a 2 M HCl aqueous solution, then extracted with EtOAc (5×50 mls). The collected organic phase was dried (Na2SO4) and volatiles removed under reduced pressure to give a slightly yellow oil. This crude oil was transferred into a 250 ml round bottom flask with THF (50 ml) and MeOH (10 ml) was added. To the resulting mixture a K2CO3 aqueous solution (9 g of K2CO3 dissolved in 10 ml of water) was added and the reaction left under stirring at room temperature for 3 hours. Volatiles were removed under vacuum and the thick oil obtained was diluted in water (200 ml) and EtOAc (200 ml) and charged into a separatory funnel. The phases were separated and to the organic one water (200 ml) was added and the pH of the medium adjusted to pH=2 by the addition of a 2 M HCl aqueous solution. The phases were separated and the aqueous one back extracted with EtOAc (5×50 mls). The collected organic phases were dried (Na2SO4) and solvent removed under reduced pressure to give an oil that was purified by flash chromatography on silica gel (DCM/MeOH from 100/0 to 90/10). Collected fractions gave the title compound D2 (5.2 g) as a colorless oil. MS: (ES/+) m/z: 492 (M+1). C28H33NO5Si requires 491. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.28 (m, 4 H), 7.72-8.00 (m, 11 H), 5.47-5.59 (m, 2 H), 4.64-4.80 (m, 1 H), 4.17-4.34 (m, 2 H), 3.20-3.31 (m, 1 H), 3.06-3.20 (m, 1 H), 1.41-1.58 (m, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:15]
Reactant: O=C1CCCCC1c1cc(Cl)ccc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 115.3 %

Procedure:
2-(2,5-Dichloro-phenyl)-cyclohexanone (50 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.5 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (78 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]2[C:36]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(OCC)(=O)C.[ClH:52]>>[ClH:52].[ClH:52].[CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]2[C:36]=1[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27]
Reactant: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3S,5R)-3-[(2-methylpropyl){[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (290 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to give the object product (278 mg).
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][CH2:9][NH2:10])(=[O:6])=[O:5])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][NH:32][C:33](=O)[O:34]C2C=CC([N+]([O-])=O)=CC=2)[CH2:26]1.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC(C=O)=CC=1>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:24][N:25]1[CH2:30][CH2:29][O:28][C@@H:27]([CH2:31][NH:32][C:33]([NH:10][CH2:9][CH2:8][CH2:7][S:4]([CH2:2][CH3:3])(=[O:6])=[O:5])=[O:34])[CH2:26]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCS(=O)(=O)CCCN
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: CCS(=O)(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 19 h
Yield: 0.1 %

Procedure:
Intermediate 40 (0.0225 g) and N,N-diisopropylethylamine (0.021 ml) were added to a solution of Intermediate 10 (0.044 g) in dichloromethane (3 ml), and the mixture was shaken at 22° C. for 19 h. Formyl polystyrene scavenging resin (2.95 mmol/g, 0.02 g) was added and the mixture shaken for 2 h. The mixture was filtered, the resin washed with dichloromethane, and the filtrate applied directly to a sulphonic acid ion exchange cartridge (2 g Isolute SCX). Elution with methanol followed by 10% 0.880 ammonia in methanol gave the crude product (0.04 g). Purification by chromatography on silica gel (Varian Bond Elut 1 g cartridge), eluting with dichloromethane, ether, ethyl acetate, and acetone, gave the title compound (0.029 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH2:3]1.[H-].[Na+].[CH2:21](Br)[CH3:22].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:9])[CH3:10])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][O:18][CH2:21][CH3:22])[CH3:15])[CH2:3]1
Reactant: CCBr
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCN(C)CCO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 19.3 %

Procedure:
2.57 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-hyd roxyethyl)-N-methylamine were dissolved in 100 ml of tetrahydrofuran. 0.48 g of a 50% strength sodium hydride dispersion was added at room temperature, and the reaction mixture was heated under reflux for 3 hours. A solution of 1.1 g of ethyl bromide in 20 ml of tetrahydrofuran was then added dropwise to the reaction solution at boiling temperature, and the reaction solution was heated under reflux for a further 6 hours. The reaction solution was worked up by adding 2 ml of water and concentrating the mixture under reduced pressure. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 0.55 g of oily N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-etho xyethyl)-N-methylamine was obtained. [α]D20 =-51.20° (c=1; methanol)