Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:30]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:37])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
A mixture of N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine (2.02 g, 5.01 mmol) and nicotinic acid (0.80 g, 6.51 mmol, 1.3 equiv) in DMF (139 mL) was treated with PyBOP (3.39 g, 6.51 mmol, 1.3 equiv.) followed by N,N-diisopropylethylamine (3.50 mL, 20.0 mmol, 4.0 equiv.) slowly leading to a clear solution. The mixture was stirred at room temperature for 24 h. The resulting solids were filtered and washed with DMF, H2O, and MeOH, then dried at 60° C. under reduced pressure to give N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide (1.64 g, 64%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.40; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.15 (d, J=9.5 Hz, 3H), 1.16 (d, J=9.5 Hz, 3H), 2.76 (t, J=11.2 Hz, 1H), 2.83 (t, J=11.4 Hz, 1H), 3.26-3.38 (m, 2H), 3.50-3.58 (m, 2H), 3.86-3.93 (m, 1H), 3.95-4.02 (m, 1H), 4.08 (s, 3H), 4.26-4.33 (m, 4H), 4.50 (br s, 1H), 4.61 (app t, J=10.7 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.96 (dd, J=5.7, 7.6 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H), 8.92 (d, J=7.9 Hz, 1H), 9.01 (d, J=4.1 Hz, 1H), 9.53 (s, 1H); mass spectrum m/z 507 ((M−1)−, 100%), 509 ((M+1)+, 24%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:54]=[CH:55][C:56]=1[O:57][CH3:58])CN1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:54]=[CH:55][C:56]=1[O:57][CH3:58])[CH2:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(SC)ncnc3s2)cc1OC
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1OC
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to a procedure similar to the one described for intermediate 17 above but starting from 6-[1-(3,4-dimethoxybenzyl)-4-phenyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (example 9) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7);
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H-].[Na+].O>C1COCC1>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[C:2]=[S:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ccc(N=C=S)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Isothiocyanato-benzenesulfonamide (750 mg, 3.5 mmol), and tert-butyldimethylsilyl chloride (528 mg, 3.5 mmol) stirred in dry THF (20 mL) at 0° C. Sodium hydride (210 mg, 60% in mineral oil, 5.25 mmol) was added, and the reaction stirred for 1 h before it was poured over H2O (50 mL) and extracted with ether (2×50 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 920 mg (80%) of 4-isothiocyanato-N-(TBDMS)-benzenesulfonamide as a white solid. 1H NMR (300 MHz, CDCl3) δ7.86 (d, 2H, J=6.9 Hz), 7.31 (d, 2 H, J=6.9 Hz), 4.40 (s, 1H), 0.90 (s, 9H), 0.22 (s, 6H). Anal. (C13H20N2O2S2Si) C, H, N, S. Calculated C=47.53; H=6.14; N=8.53; S=19.52; found C=47.47; H=6.25; N=8.46; S=19.49.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>CCOCC>[C:31](=[O:32])([O:33][CH:34]=[CH2:35])[O:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:9][Si:10]([CH3:11])([CH3:12])[CH3:13])([O:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)O[Si](CCCNCCO)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=COC(=O)OCCNCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, nitrogen blanket, dropping funnel, ice-water bath and thermometer was added 6.3 g (15.8 mmol) N-(2-hydroxyethyl)-3-aminopropyltris(trimethylsiloxy) silane, 1.37 g (17.4 mmol) of pyridine and 100 mL ether. To the reaction mixture was added 1.68 g (15.8 mmol) of vinyl chloroformate so that the temperature remained below 5° C. After stirring at room temperature for 24 hours the reaction mixture was washed with 100 mL 2N HCl, 100 mL 2N NaOH and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil, 4.3 g, chromatographed (silica gel, ethyl acetate 20% methylene chloride 80%). The oil recovered weighed 2.99 g (6.4 mmol, 25.4% yield). FTIR (neat, capillary) 2957.62, 2899.00, 1720.60, 1702.33, 1648.16, 1470.55, 1420.23, 1373.91, 1291.12, 1249.88, 1196.62, 1152.74, 1039.27, 951.52, 833.44, 753.18, 715.26, 686.53, 658.78. NMR (CDCl 3) 6.85-7.20 (1H,dd), 4.20-4.69 (2H,m), 3.36-3.71 (2H,bd), 3.00-3.36 (4H,m), 1.00-1.65 (2H,m), 0.09-0.40 (2H,m), 0.00 (27H,s). ##STR39##
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[C:36]=1[F:47])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:37]2[O:42][CH2:41][CH2:40][O:39][C:38]=2[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 105 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (58 mg) as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:27][CH:28]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(Cc2ccccc2N2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h
Yield: 2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (8.15 g), 4,4′-difluorobenzophenone (13.1 g) and powdered potassium carbonate (9.12 g) was stirred at 95° C. in DMSO (100 ml) overnight. The solution was poured into water (1500 ml) to give a precipitate which was filtered, washed with water and dried. The solid (7.82 g) was stirred in trifluoroacetic acid (25 ml) under argon with triethylsilane (10 ml) for 18 hours. The solution was poured into water (315 ml), taken to pH 12 with sodium hydroxide solution and extracted with dichloromethane (2×300 ml). The combined dichloromethane extracts were washed with water, dried (Na2SO4) and evaporated to give a residue which was purified by chromatography on alumina (ICN Alumina N 32-63) using 0.5% methanol in dichloromethane as eluant. The solid obtained was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-fluorobenzylphenyl)-4-(4-pyridyl)piperazine (350 mg) as a solid, m.p. 110-111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]=C)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:31]1CCOCC1>O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH2:29][OH:31])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C
Reactant: C1COCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1c(CO)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 56.7 %

Procedure:
A solution of Example 173B (127 mg, 0.3 mmol) in dioxane (6 mL) and water (2 mL) was treated with OSO4 (2.5% wt in t-butanol, 0.5 mL), stirred for 8 minutes at ambient temperature, treated with NaIO4 (128 mg, 0.6 mmol), stirred for 30 minutes, diluted with brine, and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered, and concentrated. This concentrate was dissolved in absolute ethanol (5 mL) and THF (5 mL), treated with NaBH4 (7 mg), stirred for 30 minutes, treated with brine (10 mL), and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography with 45% ethyl acetate/hexanes to provide the desired product (71 mg, 56.7%). 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 4.42 (d, 2H), 5.12 (t, 1H), 5.24 (s, 2H), 6.84 (d, 1H), 7.35-7.46 (m, 8H), 7.70-7.75 (m, 2H), 9.81 (s, 1H); MS (ESI(−)) m/e 428 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:61])([C:57]([F:60])([F:59])[F:58])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:61])[C:57]([F:58])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Product: C[C@]12C[C@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10), 9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-9-decenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1.C1(S)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:1]2([S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2]2)=[CH:17][N:16]=1
Reactant: c1ccc(SC2CC2)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(OC2(Sc3ccccc3)CC2)cn1
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
Cyclopropylphenyl thioether (5.0 g, 33.3 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (25.1 mL, 39.9 mmol) was dropwisely added at 0° C. for 5 minutes under an argon atmosphere. Then, a solution of N-iodosuccinimide (8.99 g, 39.9 mmol) in tetrahydrofuran (100 mL) was dropwisely added at −78° C. The resultant mixture was stirred overnight, and gradually warmed to room temperature. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane), to obtain a crude product ((1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether (=2.4:1) (5.64 g). Next, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150 mL). The resultant mixture was added with silver carbonate (9.19 g, 33.3 mmol) and 1-iodocyclopropyl)(phenypsulfane:cyclopropylphenylthioether (=2.4:1) mixture (5.64 g, 16.7 mmol (*converted in terms of 1-iodocyclopropyl)(phenyl)sulfane), and stirred overnight at room temperature. Then, acetic acid (200 mL) was added thereto, and stirred for 10 minutes. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-methyl-5-(1-(phenylthio)cyclopropoxy)pyridine (1.88 g, yield 44%) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][C:22]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2cc(-c3ccccc3C#N)ccc2F)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccccc4C#N)ccc3F)cnc2c1F
Yield: 56 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4′-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (prepared as described in WO 02/074773) as described in Example 1 to give 4′-fluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as an off-white solid (217 mg, 56%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.15 (1H, s), 7.22 (1H, t, J 7), 7.40 (1H, t, J 9), 7.48-7.73 (5H, m), 7.79-7.81 (2H, m), 8.06 (1H, dd, J 7 and 2); m/z (ES+) 390 [MH+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([OH:20])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](OS(C)(=O)=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 126.2 %

Procedure:
Methanesulfonyl chloride (224.61 μL, 2.90 mmol) is added to di-tert-butyl (1S,2S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (400 mg, 967 μmoles) and triethylamine (472 μL, 3.39 mmol) in tetrahydrofuran (4.84 mL) at 0° C. and stirred. Cooling bath is removed and the reaction is allowed to warm to room temperature and stirred overnight. Dilute with water and saturated aqueous sodium bicarbonate then extract with ethyl acetate. The combined organics are washed with brine, dried over sodium sulfate, filtered, and concentrated to under reduced pressure to give the title compound (600 mg, 1.22 mmol, 100%).
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[NH:20][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:23][N:12]1[C:13]2[NH:20][C:19]([CH3:21])=[CH:18][C:17](=[O:22])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:25])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (100 mg, 0.286 mmol), diethyl ether (0.5 ml) and 3 M aqueous hydrochloric acid solution (5 ml) was stirred at room temperature for 18 hours. After treating with saturated aqueous sodium bicarbonate (20 ml), the mixture was extracted with diethyl ether (2×20 ml). The combined extracts were dried over sodium sulfate, and concentrated under vacuum to afford (R)-1,7-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (81 mg, 92% yield) a white powder. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.30-1.52 (m, 3H), 1.54-1.70 (m, 4H), 2.45 (s, 3H), 3.62 (s, 3H), 3.77 (m, 1H), 4.00 (t, 2H), 6.49 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH2:29]([O:31][CH2:32][CH2:33][CH:34]=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][N:23]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=3)=[CH:28][C:18]=2[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]1)[CH3:30]
Reactant: CCOCCC=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 96.9 %

Procedure:
To a solution of methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.53 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.66 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (475 mg) as yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:29])([CH:26]([F:28])[F:27])[CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:25][CH2:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][C:15]([F:29])([F:14])[CH:26]([F:28])[F:27])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(OCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.5 g of 6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridine methanol, and thereto was added 0.7 g of powdery potassium hydroxide. The reaction mixture was stirred overnight at room temperature and poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methyloxy]-3(2H)-pyridazinone, m.p. 112.0°~118.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28]CC5C=CC(OC)=CC=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: COc1ccc(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4-methoxy-benzyl)-amine (1.2 g, 2.3 mmol) was dissolved in TFA (20 mL). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated in vacuo, and dissolved in DCM (30 mL). The organic layer was washed by water, dried by Na2SO4, concentrated in vacuo, and separated by preparative TLC (DCM/EtOAc=4:1) to give 134 (800 mg, yield: 87%) 1H NMR (D2O, 400 MHz): δ8.05 (s, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.23 (t, J=2.0 Hz, 1H), 7.14 (s, 1H), 6.99-6.97 (m, 3H), 6.51 (d, J=8.8 Hz, 1H). LC-MS (ESI): m/z=398 [M+H]+