Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].OO.C(N(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:9][C:8]1[C:7](=[O:10])[CH:6]=[CH:5][C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: Cc1c(O)ccc(O)c1C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C=CC1=O
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A solution of 13.8 g (100 mmol) of 2,3-dimethylhydroquinone in 500 ml of acetic acid and 28.4 g (250 mmol) of 30% by weight aqueous hydrogen peroxide were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene, 2.52 g (2.0 mmol) of a 40% by weight aqueous solution of pentasodium diethylenetriaminepentaacetate and 0.5 mi of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The mixture was then stirred for 15 min and subsequently subjected to a steam distillation. The distillate was extracted three times with a total of 400 ml of methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to dryness to yield 11.8 g (87%) of 2,3-dimethylbenzoquinone in the form of a yellow powder. Melting point 57°-59° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]#[N:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:32][OH:33]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]([NH:32][OH:33])=[NH:24])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2C(C(=N)NO)CCC2c2ccc(F)cc2)cc1
Yield: 38.2 %

Procedure:
To a stirred suspension of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile (0.74 g, 2.15 mmol) in EtOH (25 ml) was added potassium carbonate (0.89 g, 6.45 mmol) and hydroxylamine hydrochloride (0.30 g, 4.30 mmol). The reaction mixture was heated under reflux conditions for 18 h, the formed precipitate collected, washed with dichloromethane/methanol. The organic solvents were evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/hexane 3:2). Crystallization from diethyl ether/methanol yielded the title compound (0.31 g, yield 38%) as a white solid, m.p. 217° C. and MS: m/e=378.3 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]1([NH:16][C:2]2[C:3]3[C:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[CH:15]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cc3ccccc3c3ccccc23)cc1
Reaction time: 12 h
Yield: 63 %

Procedure:
9-bromophenanthrene (7.00 g, 27.22 mmol), aniline (3.7 mL, 40.84 mmol), Pd2(dba)3 (499 mg, 0.544 mmol), tris-t-butylphosphine (0.123 mL, 0.544 mmol), sodium tert-butoxide (3.90 mg, 40.84 mmol) were put in a 250 mL two-neck flask and dissolved in toluene. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was extracted with DI water/methylenechloride and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (3:1) and was re-crystallized in a solution of methylene chloride and petroleum ether such that the solid compound was obtained, (4.60 g, yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@@H:15]3[CH2:17][CH2:18][O:19][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC[C@H]2C[C@H]2C2CCN(c3ncc(Cl)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
rac-cis-2-{2-[1-(5-Chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from step 2 of example 6 (338 mg, 1.2 mmol) was dissolved in DMF (0.7 ml, 0.38 M). Nat (60% in oil, 144 mg, 3.6 mmol) was added and the mixture was stirred for 10 min at RT. 2-Bromo-5-(methylsulfonyl)pyridine (340 mg, 1.44 mmol) was added and the mixture stirred at RT 2½ hours. The mixture was diluted with 75 ml water and extracted with iPrOAc (3×50 ml), adding brine to break the layers. Organic phases were combined, washed with brine, dried over Na2SO4, filtered and stripped. The product was purified by chromatography on SiO2 (40 g) eluting with 40% EtOAc:Hexanes.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:63][CH2:62]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.093 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 77.9 mg (66%) of 3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 493.12 (M+1)+, 99.22%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (dd, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.6-7.4 (m, 4H), 7.2 (t, 1H), 6.9 (d, 1H), 6.6 (t, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.7-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.0 (t, 2H), 1.6-1.5 (m, 1H), 1.4-1.3 (m, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH:7]1[C:15]2[C:10](=[CH:11][C:12](B(O)O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.CCO.[Cl:22][C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1>O.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.C1(C)C=CC=CC=1>[Cl:22][C:23]1[N:24]=[N:25][C:26]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][CH:8]=[CH:9]3)=[CH:27][CH:28]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccc3[nH]ccc3c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of Na2CO3 (0.70 g, 6.6 mmol) in H2O (5 mL) was added indole-5-boronic acid (1.0 g, 6.2 mmol) and EtOH (25 mL). After stirring at rt for 30 min, 3,6-dichloropyridazine (935 mg, 6.30 mmol), toluene (50 mL) and Pd(PPh3)4 (0.30 g) were added. The mixture was stirred at 90° C. for 30 h and then evaporated in vacuo. The residue was treated with CH2Cl2 (100 mL), washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography, eluting with (CH2Cl2-MeOH=100:5) to give 0.35 g (37% yield) of the product as a yellow solid. 1H NMR (DMSO-d6) δ 6.52 (1H, s), 7.40 (1H, s), 7.50 (1H, d, 6.3 Hz), 7.86-7.90 (2H, m), 8.27 (1H, d, 6.9 Hz), 8.32 (1H, s), 11.32 (1H, s). MS m/e 230 (M+H+); Calculated MW: 229 for C12H8ClN5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH2:24])=[CH:16][C:15]=2[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[C:30]([Cl:46])=[CH:29][N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:22])[CH3:23])[C:17]([NH:24][C:27]3[N:32]=[C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[S:40]([CH:43]([CH3:44])[CH3:45])(=[O:42])=[O:41])[C:30]([Cl:46])=[CH:29][N:28]=3)=[CH:16][C:15]=2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C

Procedure:
4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.488 mmol) from the previous step, (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (Intermediate 2, 169 mg, 0.488 mmol, 1 equiv.), xantphos (28 mg, 0.049 mmol, 0.1 equiv.), palladium acetate (5.5 mg, 0.024 mmol, 0.05 equiv.), and Cs2CO3 (477 mg, 1.46 mmol, 3 equiv.) are dissolved in anhydrous THF (6 mL). N2 is bubbled through the reaction mixture for 5 minutes and then the reaction vessel is sealed and heated with microwave irradiation to 150° C. for 20 min. The reaction is filtered and the filtrate concentrated under vacuum. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow film: ESMS m/z 658.3 (M+H+). This product (105 mg, 0.160 mmol) is dissolved in CH2Cl2 (3 mL) and treated with TFA (3 mL). After 45 min., the reaction is concentrated under vacuum. 1 N HCl in Et2O (5 mL×2) is added causing the product HCl salt to precipitate. The solvent is removed by decantation. The resulting 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (66) is dried under high vacuum, generating an off-white powder: 1H NMR (400 MHz, DMSO-d6+trace D2O) δ 8.32 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56-4.48 (m, 1H), 3.49-3.32 (m, 3H), 3.10-2.91 (m, 3H), 2.09 (s, 3H), 1.89-1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH2:23])=[O:22].CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:23][C:2]1[CH:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:5]=[C:4]([Cl:16])[N:3]=1)=[O:22]
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: CN(c1cncnc1)c1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(c1cncnc1)c1cc(Cl)nc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 33 %

Procedure:
Compound 14 (43 mg, 0.17 mmol, 1.0 eq), 3-chlorobenzamide (39 mg, 0.25 mmol, 1.5 eq), NaOt-Bu (23 mg, 0.24 mmol, 1.4 eq), Pd(OAc)2 (1.9 mg, 0.0085 mmol, 0.050 eq) and Xantphos (10 mg, 0.017 mmol, 0.10 eq) were dissolved in toluene (1 mL) in a microwave vial. The vial was purged with argon, capped, and heated at 110° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 21 mg (33%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.95 (s, 1H), 9.12 (s, 1H), 8.89 (s, 2H), 8.00 (t, J=1.8 Hz, 1H), 7.89 (m, 1H), 7.63 (ddd, J=8.1, 1.2, 0.9 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 3.39 (s, 3H); [M+1]+: 374.1.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20]>C1(C)C=CC=CC=1>[OH:20][CH:11]1[O:10][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=C1COc2ccccc2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1COc2ccccc2O1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
The mixture is warmed at room temperature, then heated to reflux for 2 hours. The organic phase is washed with water, 5% aqueous sodium hydroxyde and then with water. After drying on Na2SO4, the solvent is evaporated to dryness under vacuum and the crude material is crytallized from cyclohexane--Et2O to give 1,4-benzodioxan-2-one (10 g) m.p. 52°-54° C. A molar solution of DIBAH in toluene (73 ml) is added dropwise to a stirred solution of 1,4-benzodioxan-2-one (8.9 g) in dry toluene (100 ml), cooled at -70° C. during 40 minutes. Stirring at this temperature is continued for 15 minutes, then the excess reagent is destroyed by adding 2N-isopropanol in toluene (75 ml), under stirring, at -70°+-60° C. The mixture is warmed at room temperature and treated with 30% NaH2PO4 aqueous solution (6 ml) and 25 g of anhydrous Na2SO4, for 4 hours, under stirring. The inorganic material is filtered out and the eluate is evaporated to dryness to give 8.2 g of 2-hydroxy-1,4-benzodioxan. A stirred solution of this δ-lactol (7.8 g) in ethanol (30 ml) is treated with a solution of cysteamine hydrochloride (7.36 g) and potassium acetate (6.5 g) in water (12 ml). Stirring is continued for 45 minutes, then a crystalline precipitate of 2-[(o-hydroxyphenoxy)methyl]thiazolidine(8.1 g) is obtained. M.p. 76°-78° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)=[O:18]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:17]([CH3:16])=[O:18])[C:11]=1[CH3:12]
Reactant: CS(=O)c1ccccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.00 mmol) and 2-(methylsulfinyl)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=352.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][C@H:27]([CH2:35][OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.N[C@@H](CC1C=CC=CC=1)C[OH:40]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][C@H:27]([CH2:35][OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:40])=[CH:31][CH:30]=2)[N:3]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (intermediate ZM), by substituting 4-((S)-2-amino-3-hydroxy-propyl)-phenol for (S)-2-amino-3-phenyl-propan-1-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([O:15][CH3:16])[CH2:11]2)=[O:9])[N:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]3[CH2:14][CH2:13][C@@H:12]([O:15][CH3:16])[CH2:11]3)=[O:9])[N:3]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CO[C@@H]1CCN(C(=O)c2cccc(Br)n2)C1
Product: CO[C@@H]1CCN(C(=O)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)C1

Procedure:
The title compound was prepared as described Example 1 using 2-bromo-6-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}pyridine (53 mg, 0.19 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (55 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1sc(C(=O)O)cc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Reaction time: 4 h
Yield: 98.1 %

Procedure:
A solution of 4-chloro-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (121 mg, 0.5 mmol) and N-chlorosuccinimide (67 mg, 0.5 mmol) in THF (5 mL) was stirred in a sealed tube at 70° C. After 4 hrs, the solution was concentrated and partitioned between DCM and H2O. The aqueous layer was extracted several times with DCM. The organic fractions were combined, concentrated and azeotropically dried with toluene to give the title compound as a brown oil (136 mg, 98%): LC-MS (ES) m/z=278 (M+H)+.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:22]2[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>>[C:10]([NH:12][CH:13]1[C:22]2[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)(=[S:11])[NH2:9]
Reactant: Cc1cnc2c(c1)CCCC2NC(=S)NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(c1)CCCC2NC(N)=S
Yield: 98 %

Procedure:
8-Benzoylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.) was treated with a 10% sodium hydroxide solution (24 ml.) and the mixture heated on a steam bath for 15 minutes. The cooled reaction mixture was adjusted to pH 1.0 with conc. HCl, filtered to remove benzoic acid and the filtrate adjusted to pH 10.0 with aqueous ammonia. The resultant solid was recrystallised from ethanol to give the hydrate of the title compound as colourless needles (4 g.). m.p. 114° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccncc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The solid obtained after flash chromatography was further purified by reverse phase HPLC on a Phenomenex® Polar RP column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as a pale solid (74 mg), m/z 342 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12])C1C=CC=CC=1>CN1CCCC1=O.[Pd]>[Cl:23][C:20]1[CH:21]=[CH:22][C:9]([OH:8])=[C:10]([CH:19]=1)[C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12]
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)ccc1O
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
A solution of 2-benzyloxy-5-chloro-N-(tetrazol-5-yl)benzamide (2.7 g) in N-methylpyrrolid-2-one (50 ml) was hydrogenated at 25° C. and 5 kg/cm2 pressure using a 5% w/w palladium on charcoal catalyst. The reaction mixture was filtered and then evaporated under vacuum and the resulting solid was triturated with water and then dried. This solid was boiled with ethanol (50 ml) for 10 minutes and the undissolved material was filtered off and washed with ethanol and with diethyl ether to give 5-chloro-2-hydroxy-N-(tetrazol-5-yl)benzamide (1.5 g), m.p. 266°-269° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1.CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)Cc1ccc(I)cc1
Temperature: 70 °C
Reaction time: 55 h

Procedure:
724 mg (6.08 mmol) of 3-cyanophenol and 1.12 g (8.1 mmol) of potassium carbonate were added to 1.6 g (0.60 mmol) of t-butyl [(1R)-2-chloro-1-(4-iodobenzyl)ethyl]carbamate and 25 ml of dimethylformamide, and they were stirred at 70° C. for 55 hours. The reaction liquid was diluted with water. After extraction with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.