Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[K+].I[CH:15]([CH3:17])[CH3:16]>C1COCC1.CC(OC)(C)C>[CH:15]([O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C=O)cc(C)c1OC(C)C

Procedure:
4-Hydroxy-3,5-dimethylbenzaldehyde (2.5 g, 16.6 mmol) in THF (100 mL) was treated with KOH (1.5 eq. of 1 N aq. solution, 25 mL) and 2-iodopropane (2.0 eq.) and heated at reflux for 5 days. The reaction was then cooled, transferred to a separatory funnel, diluted with MTBE, washed with H2O, 1 N NaOH (twice), 0.5 N HCl (aq.), brine, dried over MgSO4 and concentrated. The product was purified over silica gel on an ISCO combiflash to yield 1.99 g (10.34 mmol) 4-isopropoxy-3,5-dimethylbenzaldehyde as a colorless liquid. H1 NMR (300 MHz, CDCl3) 9.89 (s, 1H), 7.55 (s, 2H), 4.41-4.26 (m, 1H), 2.32 (s, 6H), 1.32 (d, J=6 Hz, 6H).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].O1CCCC1.[C:13](Cl)([Cl:15])=[O:14]>C1(C)C=CC=CC=1>[Cl:15][C:13]([NH:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: NN1CCNC1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)NN1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.01 g. (0.01 mol.) of 1-amino-2-imidazolidinone are dissolved in 20 ml. of anhydrous tetrahydrofuran and 20 ml. of a 1M solution of phosgene in toluene are added at 0°. The solution is stirred overnight at room temperature. The almost clear solution is filtered and evaporated to dryness. The 1-(chlorocarbonylamino)-2-oxoimidazolidine is obtained as an oily residue which is used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[CH3:33][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH:25]=[CH:24][C:23]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1ccccc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CN4CCOCC4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide (63 mg; 0.12 mmol) in toluene (10 ml) was added 3 equivalents of morpholine (31 mg) and the mixture heated at reflux overnight. The reaction was cooled to room temperature and the morpholine salts were filtered out and the solvent removed from the filtrate. The residue was redissolved in CH2Cl2 with a small amount of methanol and HCl gas was bubbled through the solution for 2-3 minutes, The solution was then concentrated to 2-3 ml, diluted with ethyl acetate and filtered to obtain N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamide as a yellow/brown solid (65 mg; 94%). 1H NMR (400 MHz; CD3OD) δ 2.27 (3H, s), 3.21 (2H, m), 3.56 (2H, m), 3.87 (2H, m), 4.04 (2H, m), 4.09 (2H, s), 4.36 (2H, s), 6.93 (3H, d, J=8.4), 7.09 (1H, t, J=7.4 Hz), 7.34 (2H, t, J=8 Hz), 7.54 (1H, dd), 7.65 (1H, s), 7.82 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.4 Hz), 8.76 (1H, s), 8.80 (1H, s). Irms(M+): 508.0; (M−): 506.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[C:4]([Cl:19])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[Cl:19][C:4]1[C:5]([O:8][Si:9]([CH:13]([CH3:15])[CH3:14])([CH:16]([CH3:18])[CH3:17])[CH:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(Cl)cc1Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(Cl)ccc(O[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 1,3-dichloro-4-triisopropylsilyloxybenzene (6.00 g) in tetrahydrofuran (50 ml) at -60° C. was added dropwise n-butyllithium, 1.6M solution of hexane (12.9 ml) over 30 minutes under nitrogen and the mixture was stirred for 1 hour at the same temperature. A solution of ethyl chloroformate in tetrahydrofuran (20 ml) was added dropwise to the mixture over 20 minutes at -60° C. The resulting mixture is stirred for 1 hour at -60° C., the cooling bath was removed, and temperature was allowed to rise to 20° C. A solution of ammonium chloride (2 g) in water (37 ml) was then added over 5 minutes followed by ethyl acetate (40 ml) and brine (40 ml). The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10 to 1:6) to give ethyl 2,6-dichloro-3-triisopropylsilyloxybenzoate (1.59 g) as an oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[F:26][C:12]([F:11])([F:25])[C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:17]1
Reactant: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Reactant: COC(=O)c1cnc(Br)s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (2.101 g, 9.46 mmol), (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine (2 g, 8.7 mmol) and DBU (2.7 mL, 17.9 mmol) in dioxane (30 mL) was heated at 80° C. for 24 h. After cooling, the mixture was diluted with water and extracted twice with EtOAc. The combined EtOAc extracts were washed with water, dried and concentrated. Combi-Flash chromatography (120 g, 40-80% EtOAc in hexanes in 20 min, 70 mL/min, 25 mL/fraction) gave the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.51 (s, 1 H), 3.95 (m, 1 H), 3.80-3.65 (m, 6 H), 2.60-2.46 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[Cl:12].C([BH3-])#N.[Na+]>>[Cl:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(F)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)cc1Cl

Procedure:
Reduction of 2-chloro-4-fluoro-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution dichloromethane-ethyl acetate 95:5) (54% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.55 (3H, s, OCH3), 4.16 (2H, s, NCH2), 6.99 (1H, m, aromatic), 7.15 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.41 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic). The hydrochloride salt was obtained as a white solid: mp 159° C. Anal. calcd for C8H9ClFNO—HCl: C, 42.50; H, 4.46; N, 6.20. Found: C, 42.50; H, 4.36; N, 5.98.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:13]([O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCI
Reactant: O=Cc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2,3-difluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), iodoethane (6.679 g; 42.80 mmol), and K2CO3 (3.551 g; 25.70 mmol) in anh. DMF (60 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-ethoxy-2,3-difluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1>[Pd].C(O)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1=Cc2ccccc2OC1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of chromene (see: Chatterjea, J. Indian Chem. Soc. 1959, 35, 78.) (5.00 g, 37.8 mmol) and 10% palladium on activated carbon (250 mg) in glacial acetic acid (100 mL) is placed in a Parr bottle. The mixture is shaken under an atmosphere of hydrogen (45 psi) for 3 h at rt. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to afford 5.00 g (98%) of chromane as light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.15-7.05, 6.89, 6.80, 4.23, 2.84, 2.08-2.02.
Reaction SMILES: [OH-].[Li+].[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=1>O.C1COCC1>[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(Cc2ccccc2-c2ccccc2)nc(C(=O)O)c(O)c1=O
Reaction time: 24 h
Yield: 10.4 %

Procedure:
A solution of lithium hydroxide (8.2 mg, 342 μmol) in water was added to a stirred solution of methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) in THF. After 24 h, the reaction was quenched by addition of 1M HCl, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated. Purification by preparative HPLC gave the desired product as a white solid (0.010 g; 10%). LCMS: m/z=337 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[C:43]([C:40]1[N:41]=[CH:42][C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:38][N:39]=1)#[N:44]
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile to afford a yellow solid. UPLC-MS (condition 1) tR=2.54 min, m/z=485.0 [M+H]+, m/z=4831.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.67 (m, 1H) 1.82-1.93 (m, 1H) 2.21-2.30 (m, 1H) 2.98 (dd, J=11.00, 7.09 Hz, 1H) 3.14-3.30 (m, 4H) 3.33-3.41 (m, 1H) 4.62 (t, J=5.26 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.17 (d, J=2.20 Hz, 1H) 8.82 (d, J=2.20 Hz, 1H) 9.10 (s, 2H) 10.20 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(c1ncnc3ccc(I)cc13)CC2
Yield: 55.7 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.58 g of 7-methoxy-1,2,3,4-tetrahydroisoquinoline and 0.64 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 2 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 22 min.), giving 0.60 g of 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline as yellowish solid (yield 57%, content 93%); MS-FAB (M+H+)=418.0; Rf (polar method): 1.87 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](=[N:14]O)[CH:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1>CCO>[NH2:14][CH:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1=NO
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Yield: 72.4 %

Procedure:
A solution of oxime of Example O (1.23 g, 3.99 mmol) in EtOH was hydrogenated at 1000 psi on Pd/C at 70° C. for 24 h. The solvent was removed in vacuo to give an oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (850 mg, 72%) as a solid. Anal calcd for C15H19N2O3F: C, 61.21; H, 6.51; N, 9.52; F, 6.45. Found: C, 60.87; H, 6.61; N, 9.32; F, 6.10. MS calcd for C15H19N2O3F 294, found 294. DSC=71.2°-74.9° C. at 76.6 J/g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:32][CH:33]1[CH2:35][O:34]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:32][C@@H:33]([OH:34])[CH3:35])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C[C@H](C)O)nc34)c(C)cn2)n1
Temperature: 120 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (374 mg, 1.119 mmol) and Cs2CO3 (364 mg, 1.119 mmol) were stirred in DMF (6 mL) for 10 minutes. 2-Methyloxirane (0.079 mL, 1.119 mmol) was added, the vessel sealed and the mixture was heated in a microwave at 120° C. for 30 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to separate the regioisomers which in turn were further purified using a Chiralcel AD-H (5 um, 20×150 mm) column eluting with CO2: 15% EtOH+0.1% DEA at 50 mL/min to give (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=4 Hz, 3H) 2.44 (s, 3H) 2.56 (s, 3H) 4.20-4.33 (m, 1H) 4.37 (dd, J=12, 8 Hz, 1H) 4.49 (dd, J=16, 4 Hz, 1H) 6.99 (d, J=4 Hz, 1H) 7.35 (dd, J=8, 4 Hz, 1H) 7.60 (dd, J=12, 8 Hz, 1H) 7.92 (s, 1H) 8.28 (d, J=4 Hz, 1H) 8.37 (s, 1H) 8.49 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=4 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.21-4.34 (m, 1H) 4.39 (dd, J=12, 8 Hz, 1H) 4.51 (dd, J=12, 4 Hz, 1H) 7.01 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 4 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.58 (s, 3H) 4.14-4.34 (m, 1H) 4.34-4.43 (m, 1H) 4.51 (m, 1H) 7.01 (d, J=4 Hz, 1H) 7.37 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=12, 12 Hz, 1H) 7.94 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.39 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; and (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.19-4.34 (m, 1H) 4.38 (m, 1H) 4.50 (m, 1H) 7.00 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 8 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:17]([SiH2:16][O:15][C:14]([CH3:22])([CH3:21])[CH:11]1[CH2:12][CH2:13][N:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN1CCC(C(C)(C)O[SiH2]C(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[SiH2]OC(C)(C)C1CCN(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[4-(t-Butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-carbamic acid t-butyl ester (100 mg, 290 μmol) was at 0° C. combined with dichloromethane (3 mL) and trifluoroacetic acid (3 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20]Cl)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: SCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 97.8 %

Procedure:
The procedure described in Example 1(b) was followed, using 6.1 g of thiourea, 13.8 g of 1-(4-chlorobenzyl)-4-(2-chloroethyl)piperazine dihydrochloride, 4.1 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 7.0 g of sodium hydroxide and 50 ml of water. Work-up, as described above, gave 6.7 g (62% of theory) of 2-[4-(4-chlorobenzyl)piperazin-1-yl]ethanethiol dihydrochloride as a white crystalline solid, M.p. 244°-247° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A solution containing 0.9 g (1.7 mmoles) of ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(5-phenyl-1H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate in 20 mL of dry tetrahydrofuran at 0° C. under argon was treated with triethylborane (1.74 mL, 1.0M in THF, 1.74 mmoles). The colorless solution was allowed to stir at 0° C. for 1.5 hours then cooled to -80° C. under argon. To this stirring solution was added sodium borohydride (130 mg, 3.4 mmoles) in one portion and the suspension was stirred for one hour. The crude reaction was quenched with 4.0 mL of 2M HCl followed by 20 mL of half saturated aqueous NH4Cl solution. The mixture was extracted twice with ethyl acetate (40 mL) and the organic layers were combined and evaporated. The concentrated crude product was diluted with 250 mL of methanol and the solution was allowed to stand at room temperature for 45 minutes then concentrated under reduced pressure at room temperature. Analytical TLC showed only one spot for the product. A solution of the crude product was filtered through silica gel and the filtrate was then concentrated under reduced pressure. Recrystallization from a mixture of ethyl acetate-hexanes gave 0.9 g of the title compound; m.p.=160.5°-161.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH2:31][CH2:30]1.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[OH:40][CH:37]([CH:38]=[CH2:39])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: C=CC(=O)CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(O)CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, a mixture of 4′-[(5-oxo-4-{trans-4-[(2-oxobut-3-en-1-yl)oxy]cyclohexyl}-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.21 g), cerium chloride anhydrous (0.15 g), tetrahydrofuran (4 mL) and methanol (2 mL) was stirred at 0° C. for 10 min, and the mixture was cooled to −78° C. Sodium tetrahydroborate (0.026 g) was added, and the mixture was stirred at −78° C. for 1 hr. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.035 g, 16%).