Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: Cc1cccc(Br)n1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cccc(C)n3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (79 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 11) (324 mg, 0.69 mmol), 2-bromo-6-methylpyridine (118 mg, 0.69 mmol) and hexamethylditin (225 mg, 0.69 mmol) in 1,4-dioxane (15 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]([CH:12]=[N+](C)C)=[C:5]2[CH:4]=1.C(=O)(O)[O-:25].[K+]>CO>[Br:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]([CH:12]=[O:25])=[C:5]2[CH:4]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2C=[N+](C)C)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2nn3ccc(Br)cc3c2C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred solution of N-((5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)methylene)-N-methylmethanaminium chloride (260 mg, 0.66 mmol) in methanol (3 mL) was added a 3% solution of potassium bicarbonate (3.1 mL) and the mixture was stirred at room temperature for 2 h. The solids were collected by filtration and dried under reduced pressure to afford the title compound as a solid (201 mg, 92%). LCMS m/z 331.0, 333.0 (M+H)+, ret. time=2.13 min.
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12](=[O:16])N(C)C)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:1]([OH:3])=[CH:2][C:12](=[O:16])[S:11]2
Reactant: CC(=O)c1c(F)cccc1SC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2c(F)cccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Dimethyl-thiocarbamic acid S-(2-acetyl-3-fluoro-phenyl) ester (2.1 g, 8.7 mmol) was dissolved in anhydrous THF (25 mL.) This solution was slowly added to a rapidly stirring solution potassium tert-butoxide (22 mL, 1M, 22 mmol) via cannula. Upon complete addition, the reaction was permitted to stir overnight at ambient temperature. The reaction was concentrated in vacuo and the residue dissolved in water and extracted three times with an equal volume of 5:1 hexanes: ethyl acetate. The organic portions were discarded and the aqueous phase acidified with 1N HCl to precipitate the product. The product was isolated via filtration and dried to provide the title compound (1.59 g.) 1H NMR (200 MHz, DMSO-d6): δ (ppm)=12.192 (br s, 1H), 7.651-7.546 (m, 1H), 7.421 (d, 1H), 6.036 (s, 1H).
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2ncccc2c1

Procedure:
0.2 g (1.27 mmol) of 2-formylquinoline is dissolved in 10 ml of anhydrous toluene, in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.46 g (1.52 mmol) of (triphenylphosphoranylidene)acetaldehyde is added to this solution. The mixture is brought back to the reflux temperature of toluene for 90 minutes, and the solution is then slowly brought back to ambient temperature and hydrolyzed with 10 ml of water. After separation of the two phases, the aqueous phase is extracted with ethyl acetate (4×50 ml).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Yield: 54.8 %

Procedure:
1-(4-(benzyloxy)benzyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one was prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate (400 mg; 1.38 mmol) with commercially available 4-(benzyloxy)benzaldehyde (293 mg; 1.38 mmol). Subsequent purification by preparative HPLC afforded 1-(4-(benzyloxy)benzyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one (316 mg; 55%). LC-MS (conditions A): tR=0.91 min.; [M+H]+: 417.76 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:23]2[CH2:22][CH2:21][CH2:20][CH:19]=[C:18]2[N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[S:10])=[C:4]([F:11])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1N=C=S
Reactant: C1=C(N2CCOCC2)CCCC1
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1NC(=S)C1CCCC=C1N1CCOCC1
Reaction time: 10 h
Yield: 87.9 %

Procedure:
In 400 ml of chloroform was dissolved 78.9 g of 4-chloro-2-fluorophenyl isothiocyanate, and 68.6 g of 1-morpholino-1-cyclohexene was added dropwise to the solution with stirring over a 10-minute period. After stirring was continued at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure, and the residue was treated with a small amount of cold ethanol. The resulting crystals were collected by filtration, and there was obtained 127.9 g (yield of 86%) of the subject compound, m.p. 86°-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[O:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:16]2[O:17][C:18]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: Clc1ccc2nc(Cl)oc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 220 mg (1.1 mmol) 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available), 188 mg (1 mmol) 2,6-dichloro-benzooxazole (commercially available) and 303 mg (3 mmol) NEt3 in 4 mL DCM was stirred at room temperature over night. After evaporation to dryness the residue was purified with flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 351 mg (99%) of the title compound. MS (m/e): 352.4 (MH+).
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[CH3:14][C:15]1(CC)OCC[O:16]1.C(O)CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[CH2:15][O:16][C:12]2([CH2:11][CH2:10][CH2:9][C:8]3[C:2]2([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=3)[O:13]1
Reactant: CC12CCC(=O)C=C1CCCC2=O
Reactant: CCC1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Product: CC12CCC(=O)C=C1CCCC21OCCO1
Temperature: 25 °C
Reaction time: 30 h
Yield: 93.6 %

Procedure:
A mixture of Wieland-Miescher ketone (5.086 g, 28.44 mmol), 2-methyl-2-ethyl-1,3-dioxolane (19.38 mL, 155.0 mmol), ethylene glycol (0.358 mL, 6.43 mmol) and p-toluenesulfonic acid monohydrate (0.4 g, 2.13 mmol) was stirred at room temperature for 30 hours. The reaction was quenched with dropwise addition of triethylamine, diluted with 20 mL of benzene, washed with water, dried over MgSO4, and concentrated under vacuum. The product was triturated from hexanes to yield monoacetal 201 (5.92 g, 94%). 1H NMR (CDCl3) δ 1.36 (s, 3H), 1.6-2.0 (m, 5H), 2.2-2.5 (m, 5H), 3.9-4.1 (m, 4H), 5.80 (d, J=Hz, 1H); 13C NMR (CDCl3) 198.91, 167.55, 125.38, 125.37, 112.12, 65.16, 64.84, 44.81, 33.70, 31.22, 29.81, 26.62, 21.51, 20.27.
Reaction SMILES: Cl.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[C:18](Cl)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[C:18]([O:8][CH2:7][C@H:6]1[O:9][C@@H:2]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[CH2:3][C@@H:4]1[OH:5])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O

Procedure:
5′-O-palmitoyldeoxycytidine is synthesized by reacting deoxycytidine hydrochloride with 1.1 equivalents palmitoyl chloride in dry dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[O:18]C)[CH:5]=[CH:4][C:3]=1[S:24]([NH:27][CH2:28][CH2:29]O)(=[O:26])=[O:25].[Br:31]B(Br)Br>>[Br:31][CH2:29][CH2:28][NH:27][S:24]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[OH:18])=[CH:7][C:2]=1[F:1])(=[O:26])=[O:25]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)c(F)c1
Reactant: BrB(Br)Br
Product: O=c1[nH]c2ccc(O)c(-c3ccc(S(=O)(=O)NCCBr)c(F)c3)c2c2ccsc12
Yield: 78.7 %

Procedure:
Following General Procedure F, 2-fluoro-N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (52 mg, 0.12 mmol) was reacted with tribromoborane (0.80 mL, 0.23 mmol) to afford the desired product (47 mg, 81%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.52 (s, 1H), 8.45 (t, J=5.7 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.46 (d, J=10.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.30 (dd, J=8.0, 1.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 3.53 (t, J=6.3 Hz, 2H), 3.42 (q, J=6.0 Hz, 2H); ESI MS m/z 499 [C19H14BrFN2O4S2+H]+; HPLC 98.3% (AUC), tR=15.61 min.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:7]12[CH3:8])[C@@H:20]1[C:15]([CH2:16][C:17](=[O:24])[CH2:18][CH2:19]1)=[CH:14][C@H:13]3[CH3:25]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:25][C@@H:13]1[CH:14]=[C:15]2[C@H:20]([CH2:19][CH2:18][C@H:17]([OH:24])[CH2:16]2)[C@@H:21]2[C@@H:12]1[C@H:9]1[C@@:7]([CH2:23][CH2:22]2)([CH3:8])[C@@H:6]([OH:5])[CH2:11][CH2:10]1
Reactant: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1C=C2C[C@@H](O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 17β-hydroxy-7α-methyl-estr-5-en-3-one acetate dissolved in tetrahydrofuran is purged with nitrogen and slowly added to a suspension of lithium tertiarybutoxyaluminum hydride also purged with nitrogen. The mixture is stirred at room temperature for about 16 hours and excess hydride is destroyed by cautiously adding a solution of sodium potassium tartrate. The solid which forms is removed by filtration and the filtrate is extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried and concentrated under vacuum. Recrystalization of the residue from acetone-hexane yields the desired 7α-methyl-estr-5-ene-3β,17β-diol acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[S:20])[NH2:19])[CH2:15][CH2:14][N:13]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:36]([O:40][C:41](=[O:47])[CH:42](Br)[C:43](=O)[CH3:44])([CH3:39])([CH3:38])[CH3:37]>C(#N)C>[C:36]([O:40][C:41]([C:42]1[S:20][C:18]([N:16]2[CH2:15][CH2:14][N:13]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C@@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:35][CH:34]=3)[CH2:17]2)=[N:19][C:43]=1[CH3:44])=[O:47])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Solvent: CC#N
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of the compound (250 mg) obtained in Example 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (168 mg) in acetonitrile (1.25 ml) was stirred at 80° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate:n-hexane=2:3) to give the title compound (268 mg).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[NH:19])[O:18][CH2:6][CH3:7]
Reactant: NC(=O)c1ccccc1C(F)(F)F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 39.2 g of triethyloxonium tetrafluoroborate in 325 ml of methylene chloride is treated with 32.5 g of o-trifluoromethyl-benzamide. After stirring at room temperature for 48 hours the reaction mixture is poured on to a mixture of 10% sodium carbonate solution and ice and the resulting mixture is extracted three times with methylene chloride. The combined extracts are then washed twice with 10% sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The oily, brown residue is distilled in a high vacuum. There is obtained pure ethyl o-trifluoromethyl-benzimidate, b.p. 67° C./0.15 mmHg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][NH:16]C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:3]=1.CN>CO>[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([CH3:8])[CH:5]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Agent: CN
Solvent: CO
Product: Cc1cc(OCc2ccc(CN)cc2)nc(N)n1
Temperature: 25 °C

Procedure:
15 mg (0.061 mmol) N-[4-(2-Amino-4-methylpyrimidin-6-yloxymethyl)-benzyl]-2,2,2-trifluoro-acetamide is dissolved in 1 mL methanol and treated with 2 mL methylamine (33% in ethanol). The reaction mixture is stirred at room temperature over night and all volatiles are removed in vacuo. The product is used without further purification in the next step. ESI-MS m/z 245.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH2:12](I)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6])[CH3:13]
Reactant: O=Cc1cc(O)c(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(O)c1O

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3,4,5-trihydroxybenzaldehyde with ethyl iodide in DMF using K2CO3 as base. MS (ISN): 181.1 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCCC)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butanoyl)-n-butylamino)-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:21]3[C:26]([N:27]=2)=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[N:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:21]4[C:26]([N:27]=3)=[CH:25][N:24]=[CH:23][N:22]=4)[CH2:16][CH2:17]2)=[CH:5][CH:6]=1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Reactant: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCN2CCC(Nc3nc4cncnc4n3Cc3ccccn3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 2 parts of 1-(2-chloroethyl)-4-methoxybenzene, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (50%) of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-9-(2-pyridinylmethyl)-9H-purin-8-amine; mp. 144.5° C. (compound 74).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:47])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=1[Cl:46]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:47])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=3[Cl:46])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1ccc(COC(=O)Cl)c(Cl)c1
Product: Cc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c(Cl)c1

Procedure:
2-Chloro-4-methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 2-chloro-4-methylbenzyl carbonochloridate (59.3 mg, 0.18 mmol) according to General Procedure H to give 20 mg (24.8%) of white solid. Anal. Calcd. for C27H33ClN4O2 m/z 480.2, found: 481.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.43 (d, J=8.8 Hz, 2H), 7.27 (d, J=7.72 Hz, 2H), 7.19 (bs, 1H), 7.06 (m, 1H), 6.97 (m, 2H), 5.06 (m, 2H), 3.67 (m, 1H), 3.56 (m, 1H), 3.00 (m, 1H), 2.78 (m, 2H), 2.52 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.93 (m, 2H), 1.79 (m, 3H), 1.64 (m, 1H), 1.34 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.90 (s, 2H), 7.88 (m, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 7.42 (d, 2H), 7.21 (d, 2H), 7.12 (m, 1H), 7.03 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.65 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H).
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH2:21][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1CCNCC1
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 14 and piperidine.
Reaction SMILES: [CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][NH:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(N)(C)CN.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:52]([N:60]=[C:61]=[S:62])(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH3:24][C:2]([NH:25][C:61]([NH:60][C:52](=[O:59])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[S:62])([CH3:1])[CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(N)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(N)CN
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=S)NC(=O)c1ccccc1
Yield: 44 %

Procedure:
2-Methyl-N1-tritylpropane-1,2-diamine, prepared from 2-methylpropane-1,2-diamine and trityl chloride (EP1204654) in yield of 44%, was coupled with benzoylisothiocyanate to give N-(2-methyl-1-(tritylamino)propan-2-ylcarbamothioyl)benzamide (US2008/45579) which was then reacted with lithium hydroxide to give 1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea. Yield 79%. 1H NMR (400 MHz, CDCl3) δ 7.40-7.12 (m, 16H), 6.30 (s, 1H), 2.38 (d, J=8.3, 2H), 2.15 (t, J=8.3, 1H), 1.31 (s, 6H)