Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].CO>ClCCl>[C:1]([O:5][C:6](=[O:31])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:39](=[O:41])[CH3:40])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)C(CCCCN)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)OC(C)(C)C
Yield: 88.7 %

Procedure:
2-(4-Aminobutyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (280 mg, 0.64 mmole) was dissolved in dichloromethane (30 ml) and treated with triethylamine (152 mg, 1.51 mmole) and acetic anhydride (78 mg, 0.76 mmole). After 20 minutes at room temperature the solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with 1N hydrochloric acid (50 ml) and water (2×50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give a colourless foam. Chromatography on silica gel eluting with a mixture of methanol and dichloromethane (1:19-1:4 by volume) and evaporation of the appropriate fractions gave the title product as a colourless foam (273 mg, 89%). Found: C,60.09; H,8.68; N,4.99. C26H44N2O5,0.6 CH2Cl2 requires, C,60.10; H,8.57; N,5.27%.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH:23]C(=O)O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CNC(=O)O)cs2)c1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1ncc(-c2nc(CN)cs2)c1-c1ccc(F)cc1
Yield: 73.3 %

Procedure:
A solution of the compound (13.6 mg, 0.03 mmol) obtained in step 1 in TFA (1.0 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure to give (2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)methanamine (7.2 mg, 0.022 mmol, 69.0%) as a pale-yellow oil.
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:53]([N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>CN(C=O)C>[C:1]([S:5][S:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:9]([NH:66][CH:63]1[CH2:62][CH2:61][N:60]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:65][CH2:64]1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the acid from Example 59 (6.98 g, 22.6 mmol) in DMF (50 ml was added HATU (8.58 g, 22.6 mmol). After 30 min, Hunig base (4.71 ml, 27.1 mmol) and 1-Boc-4-amino piperidine (5.43 g, 27.1 mmol) were added to the mixture. The reaction was continued stirring at RT for another 3 h. DMF was removed at high vacuum, the crude residue was dissolved in EtAc (300 ml), washed with H2O (50 ml×3). The title compound was obtained after ISCO purification (5% MeOH/DCM).
Reaction SMILES: [F:1][C:2]1([F:17])[C:10](=[O:11])[C:9]2[C:8]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl.Cl>[CH2:31]([O:30][C:28]([N:14]1[CH2:15][CH2:16][C:7]2=[CH:6][CH:5]=[C:4]3[C:9]([C:10](=[O:11])[C:2]([F:1])([F:17])[CH2:3]3)=[C:8]2[CH2:12][CH2:13]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1c2c(ccc3c2CCNCC3)CC1(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCc2ccc3c(c2CC1)C(=O)C(F)(F)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a stirred solution of the product from step (a) (0.13 g, 0.56 mmol) dissolved in DCM (5 ml) at 0° C. was added DIEA (0.12 ml, 0.67 mmol) and benzyl chloroformate (0.095 ml, 0.67 mmol). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was diluted with 1N HCl and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the crude product which was purified by flash silica-gel chromatography (gradient elution: 0-40% EtOAc in hexanes) to give the sub-title compound as a colorless oil (180 mg). MS: ESI (positive): 372 (M+H).
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[C:13]([CH3:16])=[CH:14][S:15][C:5]=12)[CH3:3].[CH3:17][O-:18].[Na+]>CO>[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6](/[C:13](/[CH3:16])=[CH:14]\[S:15][CH3:5])[C:17]1=[O:18])[CH3:3]
Reactant: CC[n+]1c2ccccc2n2c(C)csc21
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)n(/C(C)=C\SC)c2ccccc21
Temperature: 25 °C
Yield: 65.7 %

Procedure:
184 mg of 9-ethyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (0.533 mmol) were solubilised in methanol (35 mL), then 231 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-ethyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a white powder (87 mg, 65%). Mp 74° C.; Rf=0.48 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=1.35 (3H, t, J=7.2, CH3), 2.13 (3H, d, J=1.1, CH3), 2.22 (3H, s, SCH3), 3.94 (2H, q, J=7.2, CH2), 6.22 (1H, q, J=1.1, H5), 6.86 (1H, m, Ar), 6.99-7.09 (3H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=13.46, 16.76, 20.28, 35.74, 107.58, 108.92, 120.81, 121.26, 126.59, 127.30, 127.50, 129.24, 151.75; HRMS m/z C13H17N2OS [M+H]+ calcd: 249.1056, found: 249.1056.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:5]1[CH:6]=[C:7]([I:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ncc(Cl)cc1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Silver sulfate (3.40 g, 10.9 mmol) and 2-amino-5-chloropyridine (1 g, 7.8 mmol) was added to a solution of iodine (2.76 g, 10.9 mmol) in ethanol (50 ml) and the reaction mixture stirred at rt for 72 h. The mixture was filtered, washed with methanol and the filtrate concentrated in vacuo. The residue was partitioned between saturated Na2S2O3 solution (50 ml) and DCM (2×50 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with DCM to give the title compound as a beige solid. δH (CDCl3): 4.95 (2H, br s), 7.84 (1H, d), 7.98 (1H, d).
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH:19]([CH3:24])[CH2:20][CH2:21]3)[CH:17]=[C:16]([C:25]([OH:27])=[O:26])[C:15](=[O:28])[C:14]4=[CH:13][C:12]=2[Cl:29])(=O)=O)=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34]>CS(C)=O>[F:42][C:32]([F:31])([F:41])[C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:11]2[C:22]3=[C:23]4[N:18]([CH:19]([CH3:24])[CH2:20][CH2:21]3)[CH:17]=[C:16]([C:25]([OH:27])=[O:26])[C:15](=[O:28])[C:14]4=[CH:13][C:12]=2[Cl:29])[CH2:37][CH2:36]1)=[O:34]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)cc1
Solvent: CS(C)=O
Product: CC1CCc2c(N3CCN(C(=O)C(F)(F)F)CC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 50 %

Procedure:
A mixture of 4.5 g of 8-(p-toluenesulfonyloxy)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoroacetylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150° to 160° C. for 17 hours under nitrogen gas flow at a pressure of 10 atms. The reaction mixture was treated in the same manner as Example 73 to obtain 2.3 g of 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: Cl[C:2](F)(F)[CH2:3][N:4]1[C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:18][CH:19]([CH3:21])[CH3:20])[CH:11]=[C:10]3[C:22]([F:25])([F:24])[F:23])[O:7][CH2:6][C@H:5]1[CH:26](C)C.[BH4-].[Na+]>ClC(F)(F)C(O)=O>[CH2:3]([N:4]1[C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:18][CH:19]([CH3:21])[CH3:20])[CH:11]=[C:10]3[C:22]([F:24])([F:25])[F:23])[O:7][CH2:6][C@H:5]1[CH3:26])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)Cl)[C@H](C(C)C)CO3
Agent: O=C(O)C(F)(F)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-4-(2-chloro-2,2-difluoroethyl)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (30 mg, 0.1 mmol) and NaBH4 pellets (large excess, >10 equiv) in 3 mL chlorodifluoroacetic acid (0.03 M) stirred at rt for 12 h, to afford 22 mg (57%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=9.3, 1H), 7.30 (d, J=9.3, 1H), 7.21 (s, 1H), 5.98 (m, 1H), 5.49 (m, 1H), 4.55 (dd, J=10.7, 2.4, 1H), 3.84 (dd, J=10.7, 2.4, 1H), 3.79 (m, 1H), 3.54 (m, 1H), 2.93 (m, 1H), 1.84 (m, 1H), 1.39 (d, J=6.3, 3H), 1.38 (d, J=6.3, 3H), 1.00 (d, J=9.8, 3H), 0.99 (d, J=9.8, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1C[CH2:23][CH2:22][C:11]2[N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:10]=2[C:9]1=[O:25])[CH2:15][CH2:14][CH2:13]3.[CH3:26]O>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1[CH2:23][CH2:22][C:11]2[N:12]3[C:21]4[C:20](=[CH:19][CH:18]=[CH:17][C:16]=4[CH2:15][CH2:14][CH2:26][CH2:13]3)[C:10]=2[C:9]1=[O:25]
Reactant: Cc1[nH]cnc1CN1CCCc2c(c3cccc4c3n2CCC4)C1=O
Reactant: CO
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc4c3n2CCCC4)C1=O

Procedure:
11-{(5-methyl-1H-imidazol-4-yl)methyl}-5,6,9,10,11,12-hexahydro-4H, 8H-azepino[3',4':4,5] pyrrolo[3,2,1-ij]quinolin-12-one; melting point 215°-216° C. C-13-NMR (SLV: CDCl3, Ref.: TMS, ADT: MeOH)
Reaction SMILES: I[C:2]1[C:3](=[O:17])[N:4]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][O:6][C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)CCC.[Cl-].[Li+].O>O1CCCC1>[CH3:8][C:7]1[O:6][CH2:5][N:4]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3](=[O:17])[C:2]=1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(C)(C)N1COC(C)=C(I)C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2cccs2)C1=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (30.0 g), 2-(tributylstannyl)thiophene (33.5 ml), palladium bis-triphenylphosphine chloride (3.08 g) and lithium chloride (20.5 g) in tetrahydrofuran was heated at 50° C. for 24 hours. Further 2-(tributylstannyl)thiophene (2.8 ml) was added and the mixture heated for a further 18 hours. Palladium bis-triphenylphosphine chloride (0.62 g) was added and heating continued for 18 hours. The mixture was poured into water, extracted (ether) and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. Purification by chromatography on silica gel gave ethyl [2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazine-3-yl]-2-methylpropanoate (14.5 g), NMR 1.15(t,3H), 1.55(s,6H), 2.1(s,3H), 4.15(q,2H), 5.25(s,2H), 6.9-7.4(m,3H).
Reaction SMILES: [CH:1]1(/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH:1]1(/[C:7](/[CH3:11])=[CH:8]/[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C/C(=C\CO)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C/C(=C\C=O)C1CCCCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a solution of (E)-3-cyclohexylbut-2-enol (700 mg, 4.54 mmol) in dichloromethane (11 mL), cooled to 0° C., was added Dess-Martin periodinane (2.11 g, 4.99 mmol). The resulting suspension was warmed to 23° C. and stirred for approximately 30 minutes until the reaction was judged to be complete by TLC. The reaction mixture was poured into 50 mL of saturated aqueous NaHCO3 containing Na2S2O3 (1 g). This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound as a colorless oil (350 mg, 51% yield) that was a 5.2:1 mixture of E:Z isomers. Major isomer: IR (film) 2929, 2854, 1729, 1674, 1640, 1450, 1383, 1198, 1164, 894, 850, 522 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.05 (d, 1H, J=7.9 Hz CHO), 5.90 (dq, 1H, J=1.1, 7.9 Hz, C═CH), 2.18 (d, 3H, J=1.3 Hz, CH3), 2.09-2.02 (m, 1H, CH2CHCH2), 1.87-1.70 (m, 5H), 1.40 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 191.9, 168.8, 125.8, 48.4, 31.4, 31.2, 26.3, 26.1, 26.0, 16.1; HRMS (EI+) exact mass calculated for [M]+ (C10H16O) requires m/z 152.1201, found m/z 152.1205.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:14])[CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[F:16][CH2:17][CH2:18][O:19][C:20]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:21]=1[C:22](=N)OCC.ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:14][C:22]([C:21]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:20]=3[O:19][CH2:18][CH2:17][F:16])=[N:13][CH:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCCC(N)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OCCF
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCCC1N=C(c2ccc(OC)cc2OCCF)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4-propyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-pentane-1,2-diamine and ethyl 2-(2-fluoro-ethoxy)-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 391.1587, calculated for C21H25N2O2FCl [(M+H)+]391.1583.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[C:11]([CH3:16])=[N:12][N:13]([CH3:15])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>ClCCl>[Br:23][C:14]1[N:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=1[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1nn(C)cc1Oc1ccc(F)cc1Cl
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Temperature: -25 °C

Procedure:
To a mixture of 4-(2-chloro-4-fluorophenyoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step B) (680 mg, 2.82 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dichloromethane (12 mL) at −40° C. was added a solution of bromine (474 mg, 2.96 mmol) in dichloromethane (1 mL). After the addition was complete, the reaction mixture temperature was maintained at about −30 to −20° C. for 5 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL), aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (720 mg).
Reaction SMILES: ClC1N=C(NC2C=C(OC)NN=2)C(Cl)=CN=1.[Cl:17][C:18]1[C:19]([NH:34][C:35]2[CH:39]=[C:38]([O:40][CH:41](C)C)[NH:37][N:36]=2)=[N:20][C:21]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)[CH3:26])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:18]1[C:19]([NH:34][C:35]2[CH:39]=[C:38]([O:40][CH3:41])[NH:37][N:36]=2)=[N:20][C:21]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)[CH3:26])=[N:22][CH:23]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Agent: COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 144 %

Procedure:
2,5-Dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 37; 0.25 mmol, 64 mg) and (1S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.25 mmol, 34.5 mg) were dissolved in n-BuOH (0.35 M) and DIEA (0.50 mmol, 0.08 ml) was added. The reaction was stirred at 110° C. overnight. The solvent was evaporated and the remaining material was separated between EtOAc and water, washed with brine, and dried. Evaporation of the solvent gave a brown oil (131 mg). This material was purified by Gilson (10-50% acetonitrile/H2O, 15 min). The title compound was collected by evaporation of the solvent as a white solid (2.3 mg). 1H NMR (MeOD) 8.32 (d, 1H), 7.85-8.07 (m, 1H), 7.49 (ddd, 1H), 7.29-7.41 (m, 1H), 5.80 (s, 1H), 4.92-5.19 (m, 1H), 3.82 (s, 3H), 1.50 (d, 3H); m/z 364.
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:15])[C@@H:5]2[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:15])[C@@H:5]1[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: COC(C)(C)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 95 %

Procedure:
A solution of (6R, 7S)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one (142.3 mg) in a mixture of acetic acid (2.28 ml) and water (0.57 ml) was heated at 65° C. for 1.5 hours. The mixture was cooled to ambient temperature and then evaporated in vacuo. Xylene was added to the residue and the resultant suspension was evaporated in vacuo. The residue was dissolved in a mixture of methanol and xylene, and the resultant solution was evaporated in vacuo. This operation was repeated once and the residue was chromatographed on silica gel (1.5 g) eluting with a mixture of methylene chloride and acetone (10:1 to 1:1) to give (3S, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (111.3 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:2].[CH2:26](Br)[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[N:13]([CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:25]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)n(CC(=O)c3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 15 h
Yield: 12.9 %

Procedure:
A mixture of the compound of Example 145 (300 mg, 0.821 mmol), phenacyl bromide (196 mg, 0.985 mmol), potassium carbonate (272 mg, 1.97 mmol) and DMF (5 mL) was stirred at 60° C. for 15 hr. After cooling, the mixture was diluted with water (10 mL), and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=1/9 to 10/0) to give the title compound (51.2 mg, 13%) as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.41 (td, J=8.0, 6.2 Hz, 1H), 7.21-7.26 (m, 2H), 7.10-7.14 (m, 1H), 3.81-3.83 (m, 4H), 3.71 (s, 2H), 3.08-3.11 (m, 4H); MS (ESI−) M/Z 381 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30].CN1C(=O)CCC1.Cl>O>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:30]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)cc4)nc3)cc2)CC1
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.3 g of 2-(4'-bromophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 0.9 g (0.01 mol) of CuCN were added to 30 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.4 g of FeCl3.6H2O, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was heated on a warm water bath at a temperature of 60° C. for one hour. The crystals deposited were filtered out, washed with water and treated through a silica gel column using chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from a mixture of acetone and chloroform to yield 2.2 g (0.006 mol) of 2-(4'-cyanophenyl)-5-[4'-(trans-4"-propylcyclohexyl) phenyl] pyrimidine. The phase transition temperature of this compound, measured by DSC, was: ##STR28## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18]>[OH-].[Na+].C(O)C.[Pd]>[O:15]1[CH2:14][CH2:13][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:18])[CH:4]=2)[CH2:17][CH2:16]1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(N2CCOCC2)c2ccccc2c1
Yield: 77.8 %

Procedure:
in a 0.3 l steel autoclave, 10.5 g of 1-chloro-4-morpholino-2-naphthol in 150 ml of sodium hydroxide (2N) and 30 ml of ethanol are maintained under a pressure of 3 bar and at 35° C. in the presence of 3 g of palladium on charcoal (5%) for 7 hours. The solution is then filtered to remove the catalyst. The aqueous phase is then acidified with acetic acid and then filtered. The precipitate is washed with water and then dried. 7.1 g of 4-morpholino-2-naphthol are thus obtained.