Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.N1C=CC=CC=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(=O)NC(=O)CCC1>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([O:8][S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([F:18])([F:17])[F:19])[CH2:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(O)c(Cl)cc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C1CCCC(=O)N1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(OS(=O)(=O)c2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (1.64 g, 5.05 mmol, Compound 19) in about 20 ml of methylene chloride was added via syringe nearly 2.5 eq. of pyridine (1 ml) which had been freshly distilled from CaH2. Then a solution of benzenesulfonyl chloride (0.64 ml, 5.0 mmol) in 4.5 ml of methylene chloride was slowly added dropwise to the reaction mixture with ice bath cooling. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Then there was added 0.17 g of additional glutarimide and the reaction mixture was stirred at room temperature for an additional 12 hours. The reaction mixture was poured into 50 ml of water and the layers were separated. The organic layer was evaporated in vacuo and the residue was dried in the vacuum oven (20-50 Torr, 50° C.). The resulting brown solid was rinsed with approximately 5 ml of methylene chloride and suction filtered to yield 1.9 g (82% yield) of the desired product as an off-white powder (m.p. 214°-215° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.CCCCC.C([Li])(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)=[O:24].[Cl-].[NH4+]>C(OCC)C>[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[O:4][CH2:3][O:2][CH3:1])[OH:30])=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COCOc1cccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1cnccc1C(O)c1ccc(C(=O)OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
Next, to a mixture of 3-(methoxymethoxy)pyridine (10.0 g, 71.9 mmol) and diethyl ether (1000 ml), a 1.47 mol/L t-butyllithium n-pentane solution (62 ml, 86.2 mmol) was added dropwise at −70° C. over 25 minutes. After stirring at −70° C. for 1 hour, a solution of 4-methoxycarbonylbenzaldehyde (14.0 g, 90.5 mmol) in diethyl ether (80 mL) was added over 30 minutes and stirred at −70° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give (4-methoxycarbonylphenyl)-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.06 g, 9.4%) as a yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.CS(O[CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1)(=O)=O>>[O:37]1[CH2:38][CH2:39][CH:35]([CH2:34][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:28])[CH2:14][CH2:15]3)=[CH:20]2)[CH2:36]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)OCC1CCOC1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CC3CCOC3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.1 g (0.26 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester and 0.067 g (0.37 mmol) of freshly prepared tetrahydro-furan-3-ylmethyl methanesulfonate. After standard purification, 0.045 g (39% of yield) of the expected acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:12]1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][O:18][C:16]([C:13]1[N:14]=[CH:15][N:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)=[O:17]
Reactant: COC(=O)c1nc[nH]n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.1 g (77.1 mmol) 3-chlorophenylboronic acid and 10.0 g (77.1 mmol) methyl 1,2,4-triazole-3-carboxylate in 200 mL DCM was added 19.0 mL (235 mmol) pyridine followed by 14.0 g (77.1 mmol) copper (II) acetate. The reaction mixture was stirred at RT for 3 days, and then filtered over celite. The filtrate was washed with 1M aqueous KHSO4 solution and saturated aqueous bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated in vacuo and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (325 mg, 78%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 13 using 3-iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1) and pyridin-3-ylboronic acid to afford a yellow oil. UPLC-MS (Condition 1) tR=2.27 min, m/z=373.0 [M+H]+, m/z=371.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.36 (d, J=8.6 Hz, 2H) 7.49-7.55 (m, 2H) 7.83-7.92 (m, 2H) 7.83-7.92 (m, 2H) 7.94 (dd, J=7.8, 1.7 Hz, 1H) 8.63 (dd, J=4.8, 1.3 Hz, 1H) 8.67 (d, J=1.7 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH2:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH:15][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@](C)(Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
To a suspension of (S)-2-amino-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester hydrochloride in ethyl acetate (25 mL) was added 1N NaHCO3 solution (12.5 ml.) and the mixture was stirred rapidly at ambient temperature for the addition of neat benzyl chloroformate (0.859 g, 1.01 eq., 5.05 mmol). Following addition, the reaction mixture was stirred for an additional hour; TLC and LC-MS analysis showed the reaction to be complete. The mixture was partitioned and the organic phase was separated and dried over Na2SO4 and concentrated. The crude product was used directly in the subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][O:28]1>>[C:34]([O:33][CH2:32][C@@H:30]1[CH2:29][O:28][C:27](=[O:26])[N:31]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3C#N)CC2)c(C)c1
Yield: 68.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.68 g) described in Preparation Example 193 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.02 g), the title compound (1.56 g) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH2:23]=O.Cl>C(O)=O>[CH3:23][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1
Reactant: C=O
Reactant: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Agent: Cl
Solvent: O=CO
Product: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (200 mg), formic acid (600 mg) and 37% formalin (0.25 ml) was stirred at 80° C for 2 hours. 4N Hydrochloric acid was added to the cooled reaction mixture, and the reaction mixture was evaporated to dryness. The residue was diluted with water, basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-methyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 136° - 137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2[C@@H]1CCCNC1
Yield: 76.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (340 mg, 0.65 mmol, 1.00 equiv) in dichloromethane (50 mL), followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring. The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The resulting solution was diluted with 20 mL of water. The pH value of the solution was adjusted to >7 with sodium carbonate and then extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 210 mg (76%) of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][NH2:18].CC(O)=O>C(O)C>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[N:17][NH2:18])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Yield: 47.3 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone (0.2 g, 0.85 mmol), anhydrous hydrazine (0.13 mL, 4.26 mmol) and AcOH (0.008 mL, 0.142 mmol) in ethanol (10 mL) was heated at reflux for about 20 h. During this time, water was distilled from the reaction mixture via the use of a Dean-Stark trap. The volatiles were removed under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (20 mL). The organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by chromatography over silica gel using a 10 to 50% gradient of EtOAc in heptane as the eluent to provide 5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (0.10 g, 49%): LC/MS (Table 2, Method o) Rt=2.22 min; m/z: 249 and 251 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:16][C@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O[C@H]1CCOC1
Product: O=[N+]([O-])c1cccnc1O[C@H]1CCOC1

Procedure:
Prepared analogously to I.1 from 2-chlor-3-nitropyridine and (S)-tetrahydro-furan-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:16]([O:18]C)=O)[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][NH2:21].[H][H]>C1C=CC=CC=1.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:10][CH:11]([N:21]([CH3:20])[C:16]2=[O:18])[CH2:12][CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: [H][H]
Reactant: COC(=O)C1(c2cccc(OC)c2)CCCC(=O)C1
Agent: O=[Pt]
Solvent: c1ccccc1
Product: COc1cccc(C23CCCC(C2)N(C)C3=O)c1

Procedure:
A mixture of 9.29 g of methyl 1-(3-methoxyphenyl)-3-oxo-cyclohexane-1-carboxylate, 5.5 ml of 40 % aqueous methylamine and 0.13 g of platinum oxide is shaken at room temperature for 5 hours in a hydrogen atmosphere under atmospheric pressure. The mixture absorbs about 790 ml of hydrogen. After the reaction, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure. The residue thus obtained is heated at 100° to 110°C for 2 hours under reduced pressure, and then dissolved in benzene. The benzene solution is washed with 10 % hydrochloric acid and water, successively. Then, the benzene solution is evaporated to remove solvent. The residue thus obtained is recrystallized from isopropylether. 5.8 g of 1-(3-methoxyphenyl)-6-methyl-6azabicyclo[3,2,1]octane-7-one are obtained. M.p. 68° - 70°C.
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C@@H:11]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:12][C:13](N2[C@H](C3C=CC=CC=3)[C@H](C)N(C)C2=O)=[O:14])[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1>[F:10][C:8]1[CH:7]=[C:6]([C@@H:11]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH2:12][CH:13]=[O:14])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C[C@@H](c2cc(F)cc(F)c2)C2CCOCC2)C(=O)N1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CC[C@@H](c1cc(F)cc(F)c1)C1CCOCC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Lithium borohydride (1.5 ml of 2M solution in THF) was added to a solution of (4S,5R)-1-[(3R)-3-(3,5-difluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propanoyl]-3,4-dimethyl-5-phenylimidazolidin-2-one (882 mg) in anhydrous THF (20 ml) and the mixture was heated to 60° C. for 2 hours. The reaction mixture was cooled and quenched with saturated ammonium chloride and ethyl acetate and stirred for 20 minutes. The organic layer was dried and evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of ethyl acetate and isohexane (10:90 to 50:50) to give the title compound as an oil. Yield 345 mg. NMR CDCl3 1.2-1.4 (m, 2H), 1.6-1.85 (m, 4H), 2.15,(m, 1H), 2.5 (m, 1H), 3.25-3.6 (m, 4H), 3.9 (m, 1H), 4.05 (m, 1H), 6.7 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1>[NH4+]=S>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([NH2:9])=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(O)n1
Product: Nc1nc(N)c(N)c(O)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A suspension of the compound of example 46 (15 g, 96.7 mmoles) in an ammonium sulfide solution (20% in water, 200 ml) was stirred overnight at 50° C. The reaction mixture was cooled down in the refrigerator and the precipitate was filtered off, providing the title compound as a yellow powder (11.33 g, yield: 83%). The spectral data are identical with literature data (Landauer et al. cited supra).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C1CCC(N=C=NC2CCCCC2)CC1.CS([O:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:47])[NH2:46])[CH:41]=2)[CH:36]=1)(=O)=[O:32]>N1C=CC=CC=1>[C:10](=[O:11])([OH:32])[OH:12].[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:47])[NH2:46])[CH:41]=3)[CH:36]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)cc1
Product: O=C(O)O
Reaction time: 1 h
Yield: 183.7 %

Procedure:
To 100 ml of pyridine, were added 8.6 g of 4-guanidinobenzoic acid hydrochloride and 9.0 g of DCC. The mixture was stirred for one hour under cooling in ice (reaction mixture A). To 100 ml of pyridine, was added 113 g of 6amidino-2-naphthol methanesulfonate. To the mixture, while being cooled in ice and stirred, was added the reaction mixture A portionwise over a period of one hour. After completion of the addition, the resulting mixture was stirred for another hour under cooling in ice, then overnight at room temperature. The precipitated crystals were collected by filtration and washed with pyridine and acetone. The crystals were then dissolved in about 200 ml of water and the insoluble DCU was removed by filtration. A saturated aqueous sodium hydrogencarbonate solution was added to the filtrate to precipitate pale yellow crystals. The crystals were washed with water and acetone to obtain 15 g (79.8% yield) of 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate. From this carbonate other acid addition salts may be obtained by the procedure described in method A.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH2:36][CH:29]1[CH2:30][N:31]([C:37]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=1)=[O:38])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:29]2[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:37]([C:39]1[CH:40]=[N:41][C:42]([NH:45][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:43][CH:44]=1)=[O:38])[CH2:30]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 58.7 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.342 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (130 mg, 0.376 mmol, 1.1 eq) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (121 mg) in 59% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.56-1.70 (m, 3H) 1.70-1.81 (m, 3H) 1.88 (br. s., 3H) 2.05-2.24 (m, 6H) 2.50-2.67 (m, 2H) 3.18 (s, 7H) 3.55 (br. s., 1H) 3.91 (br. s., 1H) 4.25 (br. s., 1H) 4.78-4.90 (m, 1H) 6.50 (s, 1H) 7.80 (dd, J=8.84, 2.27 Hz, 1H) 8.28 (br. s., 1H) 8.41 (s, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.78 (s, 1H); MS/m/z 603.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]3[O:20][C:17](=[O:19])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: O=C1CCC(c2ccc(-c3ccc(Cl)c(Cl)c3)o2)O1

Procedure:
A mixture of 3.0 g (0.009 mole) of 4-[5-(3,4-dichlorophenyl)-2-furanyl]-4-hydroxybutanoic acid and 50 ml of 10% hydrochloric acid was heated at 55° for 21/2 hrs and then cooled. The resulting solid was filtered, dissolved in ethyl acetate and dried over MgSO4. The MgSO4 was removed by filtration and the filtrate was diluted with hexane. The resulting solid was filtered and dried in the vacuum pistol at room temperature to yield 1.2 g (45%), m.p. 89°-90°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 3.01 (s, 3H), 7.36-7.37 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.54 & 7.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.90 (m, 4H), 8.59 (d, J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz, 1.6 Hz, 1H), 9.98 (s, 1H). MS: M/z 450.9 (M++1).