Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]#N)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:30])C>ClCCl>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]=[O:30])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of Example 31A (4.82 g, 0.02 mol) in dry dichloromethane (100 mL) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (24 mL, 1M solution in toluene). The reaction mixture was stirred at the same temperature for 1 hour and then quenched by dropwise addition of potassium sodium tartrate (10% solution in water). The resulting mixture was warmed to room temperature, stirred vigorously for 40 minutes and then diluted with dichloromethane. The organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 100% petroleum ether to petroleum ether: ethyl acetate=50:1 to 30:1) to give title compound as a viscous oil (2.7 g, yield 55.3%). LC-MS: m/z (M+H)+ 245.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:12]2[CH2:13][CH:14]3[CH:10]([CH2:9][NH:8][CH2:15]3)[CH2:11]2)[N:17]=1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Yield: 96.4 %

Procedure:
5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (0.92 g, 2.9 mmol), DCM (10 mL) and TFA (5 mL) were stirred at 23° C. for 2 h. The mixture was concentrated to remove the volatiles, diluted with EtOAc and 1N aq. NaOH, and extracted with EtOAc (3×). The organic fractions were dried and concentrated to give the title compound (0.61 g, 96%) that contained a small amount of DCM and was used as is. MS (ESI) mass calcd. for C12H18N4, 218.30; m/z found, 219.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.27 (s, 1H), 3.81-3.70 (m, 2H), 3.55-3.48 (m, 2H), 3.16-3.07 (m, 2H), 2.94-2.78 (m, 4H), 2.29 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].C(#N)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C>[CH3:37][O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)=[CH:6][CH:7]=1)=[O:35]
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
3-Phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether (3.0 g), 0.36 g of sodium hydride and 20 ml of acetonitrile were heated under reflux for about 20 minutes, followed by the dropwise addition of 2 ml of methyl bromoacetate at room temperature. The resulting mixture was stirred at 60° C. for 20 minutes. After concentration of the reaction mixture, about 50 ml of ethyl acetate were added to the concentrate, followed by washing with water, drying and concentration. The resulting concentrate was fractionated and purified by chromatography on a silica gel column, whereby 3.0 g of 3-phenoxybenzyl 2-{4-(methoxycarbonylmethyloxy)phenyl}-2-methylpropyl ether were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[NH:8][C:9](=[O:31])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21]C)[CH:19]=2)[N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:13]=1)=[O:11].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[NH:8][C:9](=[O:31])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=2)[N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:13]=1)=[O:11]
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)Nc1c(Cl)cncc1Cl)cn2Cc1ccc(F)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cncc1Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(O)cc12

Procedure:
1.4 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2-oxoacetamide (3 mmol) is dissolved in 100 ml of dichloromethane. The solution is heated to reflux and treated with a solution of 14 mmol of BBr3 in 15 ml of dichloromethane with stirring. The reaction mixture is refluxed for 3 hours. After cooling, the solution is intensively stirred for 3 hours at 20° C. with 200 ml of an aqueous sodium hydrogencarbonate solution. The product crystallizes out, it is isolated, dried at 60° C. and recrystallized from 80 ml of ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[C:13]([CH3:16])=[N:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:9]2[C:13]([CH3:16])=[N:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: CCOC(=O)c1cc(O)n2c(C)nnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cc(Cl)n2c(C)nnc2n1
Temperature: 80 °C

Procedure:
To a suspension of the product obtained in Step 1 (4.3 g) in 50 ml of phosphorus oxychloride was dropwise added 2.6 g of N,N-dimethylaniline at room temperature. The mixture was heated at 80° C. for one hour, excess phosphorus oxychloride was removed by distillation under reduced pressure, and the remaining reddish brown oil was shaken with 300 ml dichloromethane and 300 ml of water. The pH was adjusted to 7 to 8 with saturated sodium bicarbonate solution, the dichloromethane layer was collected, and the aqueous layer was again extracted with 200 ml of fresh dichloromethane. The chloroform layers were joined together, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried filtrate was concentrated under reduced pressure, and the oily product left was purified by silica gel chromatography, giving 4.2 g of the objective compound as faint yellow crystals.
Reaction SMILES: C(OC([N:8]([CH2:45][C:46]([OH:48])=[O:47])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19](C(OC(C)(C)C)=O)[C@@H:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:49].O1CCOCC1>>[ClH:49].[C:22]1([C@H:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH2:45][C:46]([OH:48])=[O:47])[CH2:13][CH:14]2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CN(CC(=O)O)C(=O)OC(C)(C)C)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(C(=O)CNCC(=O)O)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 138 mg of [(tert-butoxycarbonyl){2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-2-oxoethyl}amino]acetic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and to the obtained residue were added isopropanol and diisopropylether, and the precipitated solid was collected by filtration to obtain 83.9 mg of ({2-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-2-oxoethyl}amino)acetic acid hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][C:13]([CH3:16])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:11]3[CH:15]=[N:14][C:13]([CH3:16])=[N:12]3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 479 [M+1]+.
Reaction SMILES: C1CCN2C(=[N:5]CCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][CH2:21][N:20]2[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])=[C:15]([CH2:31]O)[CH:14]=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O.CO>[NH2:5][CH2:31][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=1[CH:19]1[CH2:22][CH2:21][N:20]1[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC1c1ccc(Cl)cc1CO
Reactant: C1CCC2=NCCCN2CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
DBU (0.209 mL, 1.40 mmol) was added to a stirred solution of 2,2,2-trichloroethyl 2-[4-chloro-2-(hydroxymethyl)phenyl]azetidine-1-carboxylate (0.346 g, 0.927 mmol) and DPPA (0.302 mL, 1.40 mmol) in THF (2 mL) at 0° C. After 2 h the reaction was partitioned between ether and water and the organic layer was washed with 1 M sodium hydroxide solution (2 times) and 1 M HCl solution, dried (Na2SO4) and evaporated in vacuo to an oil. Triphenylphosphine (0.262 g, 1.00 mmol) was added to a stirred solution of this oil in THF (2 mL) and water (4 drops). After 16 h methanol (2 mL), water (1 mL) and sodium hydroxide (1 pellet) were added, the mixture was stirred for a further 15 min and then was partitioned between ether and water. The organic layer was extracted into dilute aqueous acetic acid which was basicified with sodium hydroxide and extracted with ether. This organic layer was dried (Na2SO4) and evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with a chloroform/10% ammonium hydroxide in methanol gradient, 1-4% ammonium hydroxide/methanol) to give 2,2,2-trichloroethyl 2-[2-(aminomethyl)-4-chlorophenyl]azetidine-1-carboxylate (275 mg) as an oil: 1H NMR (CDCl3, 400 MHz) δ 2.11 (m, 1H), 2.78 (m, 1H), 3.77 (br d, J=14.4 Hz, 1H), 3.87 (br d, J=14.4 Hz, 1H), 4.16 (br m, 2H), 4.64 (br m, 2H), 5.63 (br s, 1H), 7.27 (obscured m, 1H), 7.35 (s, 1H), 7.50 (br s, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]2[CH2:33][CH2:32][CH2:31][CH2:30][C:10]=2[S:11][C:12]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[C:18]([C:25]([F:28])([F:27])[F:26])=[N:17]1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:28][C:25]([F:26])([F:27])[C:18]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=2[N:16]([CH2:15][C:14]([NH:13][C:12]2[S:11][C:10]3[CH2:30][CH2:31][CH2:32][CH2:33][C:9]=3[C:8]=2[C:6]([OH:7])=[O:5])=[O:29])[N:17]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid tert-butyl ester was dissolved in a solution of DCM (5 mL) and TFA (5 mL), and the resulting mixture stirred at RT for 3 h, before concentration in vacuo to afford the title compound as a pale yellow solid (870 mg). This was used directly in the next step without any further purification.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])=[CH:18][CH:17]=1)[C:20]#[CH:19]
Reactant: CC(C)=CCCC(C)Oc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OC(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethyl-4-hexenyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1,5-dimethyl-4-hexenyl)oxy]benzoic acid propargyl ester; nD22 = 1.5252.
Reaction SMILES: [Br:1]([OH:4])(=[O:3])=[O:2].[NH2:5][CH2:6][CH2:7][C@H:8](O)[CH2:9]O.C(O)(=O)C.[Br:16](O)(=O)=O>C(O)C>[Br:1]([O:4][C@@H:8]([CH2:7][CH2:6][NH2:5])[CH2:9][Br:16])(=[O:3])=[O:2]
Reactant: NCC[C@H](O)CO
Reactant: [O-][Br+2]([O-])O
Solvent: CC(=O)O
Solvent: CCO
Product: NCC[C@@H](CBr)O[Br+2]([O-])[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Amino-(S)-1,2-butandiol bromate 6 (0.537 mol, 100 g) and an acetic acid solution (185 g) with 33% bromic acid dissolved therein were added to a 500□ round-bottom flask and the mixture was agitated at 40° C. for 2 hours. After the preparation of an intermediate was confirmed by Thin Layer Chromatography (TLC), anhydrous ethanol (285 g) was added thereto. The reaction mixture was agitated under reflux for 3 hours to complete the reaction and then concentrated under reduced pressure to completely remove the solvent, thereby obtaining 115 g of crude 4-amino-1-bromo-(S)-2-butanol bromate 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.48 (silica gel, 20/1 ethyl acetate/methanol).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].CC(C)=O.C(=O)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH:15]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -68 °C
Reaction time: 0.15 h

Procedure:
A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 minutes (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[N:41]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[C:29]1([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:27][NH:26][C:9]2[N:8]=[C:7]([CH2:6][NH:49][CH2:48][CH2:47][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN1CCCCC1
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (150 mg, 0.26 mmol) (Preparation 25) was dissolved in stirred dichloromethane (5 ml) and 2-(1-piperidinyl)ethylamine (0.2 ml, 1.3 mmol) added. The reaction mixture was stirred for 24 hr at room temperature. The solvent was removed from the reaction mixture under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (50 ml). The organic layer was separated and washed with water (50 ml), followed by removal of solvent under reduced pressure and purification of the residue by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5) increasing in polarity to dichloromethane:methanol:ammonia (90:10:1). This gave title compound (40 mg) as a gum. MS: 603 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.ClCCl.C(OC(=O)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Yield: 55 %

Procedure:
A solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (400 mg; 2.0 mmol), 2-chloro-5-trifluoromethyl-pyridine (362 mg; 2.0 mmol) and potassium carbonate (280 mg; 2.0 mmol) in dimethylsulfoxide (3 mL) is heated 10 hours at 120° C. The reaction is then cooled to room temperature, water (20 mL) is added and the pH is set to 4-5 by addition of aq. 1N hydrochloric acid. The aqueous layer is then extracted with dichloromethane (4×20 mL), the combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane and then dichloromethane:ethylacetate 8:1) to afford the desired product (380 mg; 1.10 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=O)[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]1>>[C:42]([C@H:39]1[CH2:40][CH2:41][C@H:36]([NH:35][C:24]([C@@H:14]2[NH:13][C:12]3([CH2:27][CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31]3)[C@:6]3([C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[C@H:15]2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=2[F:23])=[O:26])[CH2:37][CH2:38]1)(=[O:43])[NH2:44]
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Reactant: NC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@H]1CC[C@H](C(N)=O)CC1)[C@H](c1ccnc(Cl)c1F)[C@]21C(=O)Nc2cc(Cl)ccc21

Procedure:
The compound (200 mg, 0.41 mmol) obtained in Step 1 of Example 17 and trans-4-aminocyclohexanecarboxamide hydrochloride (WO2005/058892) (87 mg, 0.49 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 53 mg (21%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:29]1[CH:30]=[CH:31][C:32]2[S:36][CH:35]=[CH:34][C:33]=2[CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[S:36]1[C:32]2[CH:31]=[CH:30][C:29]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[CH:37][C:33]=2[CH:34]=[CH:35]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2sccc2c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate 0.12 g and cesium carbonate 0.32 g were added 5-bromobenzothiophene 0.17 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzothiophen-5-yl)amino)-4-(3-chlorophenyl)benzoate.