Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COc1cccc(OCCBr)c1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(OCCn2cc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (220 mg, 1.90 mmol) in MeCN (9.5 mL), 1-(2-bromoethoxy)-3-methoxybenzene (495 mg, 2.14 mmol) dissolved in MeCN (1.5 mL) and Cs2CO3 (697 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1-(2-(3-methoxyphenoxy)ethyl)-4-nitro-1H-pyrazole which was used in the next step without further purification. LC-MS conditions A: tR=0.85 min, [M+H]+=no ionization.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[N:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=4)[C:14]=3[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1>C1COCC1>[CH3:7][C:8]1[N:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=4)[C:14]=3[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: COC(=O)c1ccc(Cn2c(C)cc3c2ccc2nnc(C)n23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
1.0 M LiAlH4 in THF (1.6 mL, 1.6 mmol, Aldrich) was added dropwise to a solution of the crude product of Step 1 in THF (27 mL) at 0° C. After 30 minutes, the reaction was quenched at 0° C. by the dropwise addition of a small amount of water, followed by excess amount of Rochelle's salt. After 10 minutes, sodium sulfate was added and enough DCM to afford a transparent yellow solution. The mixture was then filtered through celite and the solvent was removed in vacuo. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM afforded product as a light yellow solid (0.11 g, 44% for two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 69.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 96 mg, 0.28 mmol), 2-aminobenzothiazole (42 mg, 0.28 mmol) and N,N-diisopropylethylamine (145 μL, 0.83 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (93 mg, 70%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C21H20ClN3O4S2 [M+] 477.06, found 478 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.35 (ddd, Jo=7.9, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.48 (ddd, Jo=8.2, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.61 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.72 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.21 (s, 1 H, NH).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1.[F:12][C:13]([F:25])([F:24])[C:14]1[C:22]2[NH:21][C:20]([SH:23])=[N:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C.[OH-].[Na+]>[F:25][C:13]([F:12])([F:24])[C:14]1[C:22]2[N:21]=[C:20]([S:23][CH2:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=3)[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccnc(CCl)c1
Reactant: FC(F)(F)c1cccc2nc(S)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccnc(CSc2nc3c(C(F)(F)F)cccc3[nH]2)c1

Procedure:
4.5 g (0.023 mole) of 2-chloromethyl-4-methoxypyridine hydrochloride are added to 5.0 g (0.023 mole) of 4-trifluoromethyl-2-mercaptobenzimidazole, dissolved in 100 ml of ethanol and 23 ml of 2N sodium hydroxide solution, and the obtained mixture is stirred at room temperature for 6 hours. After most of the solvent is stripped off, the residue is extracted with three 50 ml portions of ethyl acetate, the extract is washed with distilled water and dried over sodium sulfate and the solvent is stripped off in vacuo. The solid residue is recrystallized from acetonitrile. Yield: 5.9 g (76%) of title compound, m.p. 146° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[OH:19]>CN(C=O)C>[O:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][C:4]([CH:18]=[O:19])=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=C([O-])O
Reactant: c1ccc(N2CCOCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 22 h

Procedure:
N-Phenylmorpholine (77.2 g) was dissolved in DMF (150 ml) and phosphorus oxychloride (67.1 ml) was dropwise added in an ice bath. After the dropwise addition, the mixture was stirred at 60° C. for 22 hr. Ice water was added portionwise to the reaction mixture in an ice bath and the mixture was neutralized with a saturated aqueous hydrogencarbonate solution. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the objective 4-morpholinobenzaldehyde (70.7 g), melting point 55° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:30])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]4[N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:14][CH:13]=3)=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:39]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:30])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]4[N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:16][CH:17]=3)=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:39]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCCC3N3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc(OC2CCCCC2N2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 92.6 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[2-pyrrolidin-1-ylcyclohexoxy]benzoyl)benzo[b]thiophene (610 mg, 1.10 mmol), ethane thiol (5.50 mmol), and aluminum chloride (880 mg, 6.60 mmol) were converted to 523 mg (90%) of the title compound by the procedure of Example 16. MS(FD) 528(M+). IR (CHCl3) ν max 3377, 2934, 2857, 1595, 1467, 1258, 1164.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](OCC)=[O:13])[CH:6]=[CH:5]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 111.9 %

Procedure:
To a solution of ethyl 6-bromo-2-naphthoate (7.90 g, 28.30 mmol) in 200 mL toluene at −78° C. under an atmosphere of argon was added DIBAL (84.9 mL, 1.0 M in toluene, 84.91 mmol) via transfer needle over 20 minutes. After 1 hour the reaction mixture was quenched with ethyl acetate and the resulting mixture was allowed to warm to RT. The mixture was diluted with ethyl acetate and washed with 1.0 N HCl, water and brine. The organics were dried with magnesium sulfate, filtered and evaporated to give 7.51 g of 6-bromo-2-naphthylmethyl alcohol as a white solid and used without further purification in the oxidation (step c). 1H NMR (300 MHz; CDCl3): δ 4.86 (s, 2H); 7.50 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 7.57 (d, J=2.0 Hz, 1H); 7.70 (d, J=9.0 Hz, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.79 (s, 1H); 8.00 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:27]1[O:35][C:34]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:28]1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:27]1[O:35][C:34]2[CH:33]=[CH:32][C:31]([C:17]3[C:16]([CH3:19])=[N:15][N:14]4[C:9]([C:4]5[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=5)=[CH:10][C:11]([N:20]5[CH2:24][CH2:23][CH2:22][C@H:21]5[CH2:25][OH:26])=[N:12][C:13]=34)=[CH:30][C:29]=2[O:28]1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: OB(O)c1ccc2c(c1)OCO2
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: Cc1ccccc1
Solvent: CCO
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc2c(c1)OCO2
Temperature: 85 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
(S)-(1-(7-(3,5-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (40 mg), 3,4-methylenedioxyphenylboronic acid (23 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (5 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 4 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (36 mg).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:25])=[O:24])[N:19]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:25])=[O:24])[N:19]=1
Reactant: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (220 mg, 0.641 mmol) in MeOH (4.0 mL) and THF (12.0 mL) was added 10% Pd/C (13.6 mg, 0.013 mmol). The reaction mixture was stirred under hydrogen balloon for 1 h at rt, then filtered and concentrated to afford 5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (˜150 mg, 93%), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9](N)=[CH:10][C:4]=2[O:3]1.Cl.N([O-])=O.[Na+].[I-:20].[Na+].OS([O-])=O.[Na+]>ClCCl.O>[F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([I:20])=[CH:10][C:4]=2[O:3]1
Reactant: [I-]
Reactant: COc1cc2c(cc1N)OC(F)(F)O2
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1I)OC(F)(F)O2
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
2,2-Difluoro-6-methoxybenzo[d][1,3]dioxol-5-amine (1.4 g, 6.9 mmol) was dissolved in dichloromethane (5 mL) and added in portions to rapidly stirred concentrated HCl (75 mL) to form a loose white slurry. The mixture was cooled to 0-5° C. and treated in portions with sodium nitrite (710 mg, 10 mmol) in water (10 mL). After 40 min, this mixture was poured as a thin stream into a solution of sodium iodide (3.1 g, 21 mmol) in water (75 mL) rapidly stirred with dichloromethane (50 mL). After 45 min, the mixture was stirred with 15% NaHSO3 solution (20 mL) for 10 min. The separated aqueous phase was extracted with dichloromethane (30 mL), and the combined extracts were washed with saturated NaCl (15 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-15% ethyl acetate-hexane gradient to afford the title compound as a white solid (1.8 g, 83%): mp 50-51° C.; 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.69 (s, 1H), 3.86 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.81 (s); EIMS m/z 314.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:40]([F:41])=[CH:39][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:42])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:40]([F:41])=[CH:39][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)=[O:29])=[C:26]([F:42])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CCN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 110 °C
Yield: 10.8 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 98 mg, 0.34 mmol) and caesium carbonate (204 mg, 0.62 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) added and the mixture heated at 110° C. overnight. The mixture was filtered and the filtrate loaded onto an SCX-3 column was pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white crystalline solid (19 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[N:21]=[N:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:20]3[N:21]=[N:22][CH:23]=[N:19]3)=[CH:29][CH:28]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(-n2ncnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ncn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 25).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([OH:27])=[O:26])=[C:21]([CH2:23][OH:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:10].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[S:19][C:20]=1[C:25]([OH:27])=[O:26])(=[O:30])[CH3:29]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(CO)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylic acid (Example 237; 100 mg, 0.23 mmol) was dissolved in pyridine (2 ml) and cooled to 0° C. Acetic anhydride (21.8 μl, 0.230 mmol) was added and mixture was stirred at room temperature for 1 h. The mixture was diluted with
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([CH:16]([CH3:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]#[N:27])C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH:16]([CH3:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]#[N:27]
Reactant: CC(COc1ccc(F)cc1C#N)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)COc1ccc(F)cc1C#N
Yield: 82 %

Procedure:
A solution of 1.0 mL trifluoroacetic acid and 1.2 g (4.08 mmol) of 1,1-dimethylethyl[2-(2-cyano-4-fluorophenoxy)-1-methylethyl]carbamate in 10 mL methylene chloride was stirred at ambient temperature for 3 days. Solvent was removed and the residue was taken up in aqueous Na2CO3 and ethyl acetate. The organic layer was separated and washed with water and brine. Drying (MgSO4) and removal of solvent gave 650 mg of 2-(2-aminopropoxy)-5-fluorobenzonitrile as an oil.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=1.S(Cl)([Cl:18])(=O)=O>C(Cl)Cl>[Cl:18][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc(OC(F)F)n(C)n1
Solvent: ClCCl
Product: COC(=O)c1nn(C)c(OC(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.1 g (10 mmol) 5-Difluoromethoxy-3-methoxycarbonyl1-methylpyrazole, dissolved in 30 ml methylene chloride, was treated with 1.35 g (10 mmol) sulfuryl chloride and the mixture stirred at room temperature for 10 minutes. It was then concentrated and the residue recrystallised from diisopropyl ether/ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([C:20]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[N:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10]1)=[O:7])(C)(C)C.Cl>CO>[CH3:1][O:5][C:6]([CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([C:20]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:16][CH2:15]2)[N:11]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)CN1CN(c2ccccc2)C2(CCN(C3(c4ccccc4)CCCCCC3)CC2)C1=O
Agent: Cl
Solvent: CO
Product: COC(=O)CN1CN(c2ccccc2)C2(CCN(C3(c4ccccc4)CCCCCC3)CC2)C1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A mixture of 3-t-butoxycarbonylmethyl-1-phenyl-8-(1-phenylcycloheptyl)-1,3,8-triazaspiro[4.5]decan-4-one (prepared in Preparation 4, 100 mg, 0.193 mmol) and HCl solution in methanol (10 ml) was stirred at 60° C for 16 h. After evaporation of the solvent, the residue was basified with 25% NH4OH and extracted with CH2Cl2. The extracts combined were dried(Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm plate×2, hex/acetone:5/2) to give 68.8 mg (75.1%)of title compound as white amorphous solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3[NH2:26])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[NH2:26][C:21]1[C:22]2[C:17](=[C:16]([O:15][C@@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cccc3c(N)nccc23)CC1
Agent: Cl
Solvent: CO
Product: Nc1nccc2c(O[C@H]3CC[C@@H](N)CC3)cccc12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 131 (76 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (52 mg).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:10]1([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:10]1([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 1 h

Procedure:
Acetic anhydride (3 ml) was added to a stirred solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (2.0 g, 9.17 mmol) in pyridine (5 ml) and stirred for 1 hr. The reaction mixture was concentrated to furnish 4-acetylamino-1-benzyl-3,3-dimethyl piperidine as an oil. Yield 1.8 g (76%), C16H24N2O, m/z 261 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.64 (m, 2H), 2.02 (s, 3H), 2.12 (m, 2H), 2.44 (d, 1H), 2.84 (d, 1H), 3.44 (d, 2H), 3.7 (m, 1H), 5.3 (bs, 1H), 7.31 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12)[NH2:5].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:5][C:4]2[CH:3]=[C:2]([F:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=34)=[C:7]([F:20])[CH:6]=2)[CH:27]=1
Reactant: Cc1c[nH]c2nccc(Oc3c(F)cc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
415 mg (1.51 mmol) of 3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 321 mg (1.96 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 8 ml of water. 1.96 ml of 1N hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:5).