Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([OH:9])[CH3:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](O)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a solution of borane-tetrahydrofuran (0.647 mL, 0.647 mmol, Aldrich, 1 M solution in THF) and (S)-MeCBS (0.647 mL, 0.647 mmol, Aldrich, 1M solution in toluene) was added simultaneously a solution of 3-chloroacetophenone (1.00 g, 6.47 mmol) in anhydrous tetrahydrofuran (2.42 mL) and a solution of borane-tetrahydrofuran (3.24 mL, 3.24 mmol, Aldrich, 1 M solution in THF) over 30 min at ambient temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched slowly at 0° C. with methanol (0.94 mL) and then saturated HCl in ether (0.12 mL). After stirring at 0° C. for 5 min and ambient temperature for 30 min, the solution was concentrated in vacuo to an oil. The oil was twice diluted with benzene and concentrated in vacuo, diluted with ether, and concentrated in vacuo to an oil. The oil was purified by flash chromatography(silica gel, 20% EA in hexane) to give (R)-1-(3-chlorophenyl)ethanol as a clear colorless oil (0.784 g, 78%). Optical rotation in CHCl3 at 20° C. at concentration 0.220 was +40.9° (Literature, Bull. Chem. Soc. Jpn. 1996, 69(4), 1079-1085, optical rotation in CHCl3 at 21° C. at concentration 0.220 was +44°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:16](=[O:17])[C:11]=3[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:14](=[O:28])[N:13]([CH3:29])[C:12]=3[N:30]=[CH:31][C:9]=2[O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(Cl)c3)cnc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of 6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (470 mg, 1.06 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.12 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (298.8 mg, 2.12 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (120 mg, 19.4% yield) as an oil. LCMS: [MH+-THP] 503 and TR=1.508 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[Si]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][C:33](=O)[CH2:32]1)(C(C)(C)C)(C)C>O1CCCC1>[Si:39]([O:38][C@H:35]1[C:36](=[CH2:37])[C@H:31]([OH:30])[CH2:32]/[C:33](=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:34]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C1[C@H](O)C/C(=C\C(=O)OCC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of diisopropylamine (1.2 mL, 9.4 mmol) in 10 mL of tetrahydrofuran was cooled to −78° C.; n-butyllithium (2.5 M in hexanes, 3.6 mL) was added, followed after 5 minutes by ethyl trimethlysilylacetate (1.7 mL). The resultant solution was stirred at −78° C. for 30 minutes, and then a solution of the compound of Example 13E (2.0 g, 4 mmol) in 10 mL of tetrahydrofuran was added over 5 minutes. Stirring was continued for 4 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl; the mixture was warmed to ambient temperature, the partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl and brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 5% to 10% ethyl acetate in hexanes. The product (1.9 g) was dissolved in 17 mL of ethanol; 1.3 mL of concentrated HCl was added, and the resultant solution was stirred overnight at ambient temperature. The solvents were removed in vacuo, the residue was taken up in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 2% to 3% dichloromethane in acetonitrile. The title compound was isolated as the slower-eluting material (0.62 g).
Reaction SMILES: [N+]([C:4]1[CH:10]=[C:9](CCCC)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[CH2:15]([C:19]1C=C[C:22](N)=[CH:21][CH:20]=1)[CH2:16]CC.C(OC(=O)C)(=[O:28])C>>[CH3:22][CH2:21][CH2:20][CH2:19][CH2:15][C:16]([NH:6][C:5]1[CH:4]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ccc(N)cc1
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Product: CCCCCC(=O)Nc1ccccc1
Temperature: 10 °C

Procedure:
2-nitro-4-n-butylaniline intermediate compound 150 g of a 4-n-butyl-aniline were treated with 300 ml of acetic anhydride at 70° C. for 1 hour and then cooled to 10° C. After filtering the solid product on a Buchner funnel and drying at 60° C. under vacuum, 183 g of 4-n-butyl-acetanilide were obtained. 183 g of 4-n-butylacetanilide were dissolved in 300 ml of acetic acid and this solution, cooled at 5°-10° C., was added to a wellstirred mixture obtained by mixing 123 ml of nitric acid at a density of 1.4 and 325 ml of nitric acid at a density of 1.52. The temperature was kept below 5° C. during the whole addition and at the end the stirring was continued for 4 hours. The reaction mixture was then poured into 4 liters of ice and water under stirring, thus obtaining a yellow solid product that was filtered on a Buchner funnel and purified by recrystallization from ethanol. 217.4 g of 2-nitro-4-n-butyl-acetanilide were obtained and treated with 1,500 ml of toluolated ethanol and 600 ml of concentrated hydrochloric acid. The solution obtained was heated to reflux for two hours and the solvents removed under vacuum using a rotary evaporator. The oil residue, the analysis of which is reported hereinbelow, was used for the preparation of compound 1 without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:30][N:29]=1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: COc1ncc(B(O)O)cn1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (300 mg, 0.87 mmol) in DMF (20 mL) and H2O (2 mL) under nitrogen was added 2-methoxypyrimidin-5-ylboronic acid (199 mg, 1.30 mmol) and potassium carbonate (239 mg, 1.73 mmol). The resulting mixture was degassed with nitrogen for 15 min and then tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol) was added. Upon completion of addition, the reaction mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated to 90° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by preparative HPLC to afford 2-(2-methoxypyrimidin-5-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (205 mg) as an off-white solid. Preparative HPLC Conditions: Column: Sunfire C18 (250×19 mm), Mobile Phase A: 0.1% TFA in H2O, Mobile Phase B: CH3CN, Gradient: 0 to 40% B over 35 min, 100% B for 10 min., Flow Rate: 14 mL/min., Retention time: 28 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50 (s, 2H), 8.27 (d, J=4.7 Hz, 1H), 7.92 (d, J=3.6 Hz, 2H), 7.85-7.81 (t, J=8.0 Hz, 1H), 7.60-7.52 (m, 5H), 7.42-7.38 (m, 2H), 7.34-7.31 (m, 1H), 4.83 (d, J=4.2 Hz, 2H), 4.04 (s, 3H). LCMS Method O: retention time 1.45 min, [M+1]=421.2. HPLC Method B: purity 98.7%, retention time 5.53 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(OCC)(=O)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-fluoro-2-nitro-phenol (464 mg, 2.95 mmol), benzyl bromide (0.37 ml, 3.10 mmol) and cesium carbonate (1.055 g, 3.24 mmol) in MeCN (10 mL) was stirred room temperature under argon for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 2-benzyloxy-4-fluoro-1-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:14](Br)[C:15]#[CH:16].C(NC(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([C:11]([O:13][CH2:16][C:15]#[CH:14])=[O:12])=[C:5]([C:7]([F:8])([F:10])[F:9])[N:6]=1
Reactant: O=C(O)c1sc(Cl)nc1C(F)(F)F
Reactant: C#CCBr
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C#CCOC(=O)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 4.63 g (0.02 mole) of 2-chloro-4-trifluoromethyl-5-thiazolecarboxylic acid, 2.42 g (0.02 mole) of propargyl bromide, 2.59 g (0.02 mole) of diisopropylamine, and 50 ml. of methylene chloride was stirred for 16 hours. The methylene chloride solution was washed successively with diluted hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give propargyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([F:47])[C:45]=1F)[C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O.CS(C)=O>[C:18]([O:17][C:16]([N:15]([CH2:14][C@@H:9]1[C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:45]2[C:44]([F:47])=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[F:35])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)c(N2CC[C@H](c3ccccc3F)[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 191 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 118 mg of methyl 3,4,5-trifluorobenzoate, 114 mg of potassium carbonate, and 2.0 mL of THF-2.0 mL of DMSO was stirred at 100° C. overnight. After cooling, to the reaction mixture was added water, followed by extraction with ethyl acetate, and then drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 147 mg of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoate as a colorless amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[C:6](=[O:7])[CH2:8][N:2]([CH3:1])[C:3]2=[O:4])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN(C)C2=O)cc1
Reaction time: 72 h

Procedure:
To a stirring solution of 1-methylhydantoin (40.0 g, 351 mmol) in DMF (700 mL) at ambient temperature was added 4-methoxybenzyl chloride (49.4 g, 316 mmol) and cesium carbonate (171 g, 526 mmol). The resulting mixture was stirred for 3 days, then partitioned between H2O (2 L) and EtOAc (800 mL). The aqueous layer was extracted further with EtOAc (500 mL) and the combined organic extracts were washed with H2O (2×300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting white precipitate was collected by vacuum filtration and washed with MTBE (200 mL) to provide the title compound. MS: m/z=235.2 (M+1).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=C[N:59](N=C2)CCCCO1)C.[NH2:94][C:95]1[CH:104]=[CH:103][C:102]([C:105]2[CH:106]=[N:107][N:108]([C:110]([CH3:115])([CH2:112][CH2:113][OH:114])[CH3:111])[CH:109]=2)=C[C:96]=1[C:97]([NH:99][CH3:100])=[O:98]>>[OH:114][CH2:113][CH2:112][C:110]([N:108]1[CH:109]=[C:105]([C:102]2[N:59]=[C:96]([C:97](=[O:98])[NH:99][CH3:100])[C:95]([NH:94][C:22]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[CH:104][CH:103]=2)[CH:106]=[N:107]1)([CH3:111])[CH3:115]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Reactant: CNC(=O)c1cc(-c2cnn(C(C)(C)CCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C(C)(C)CCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 24 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 304 mg, 0.671 mmol) and 2-amino-5-[1-(4-hydroxy-2-methylbutan-2-yl)-1H-pyrazol-4-yl]-N-methylbenzamide (Compound 50C, 213.1 mg, 0.705 mmol) to afford 117 mg of the title compound (24%). 1H NMR (400 MHz, CD3OD) δ 9.01 (d, J=8.8 Hz, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 7.70-7.76 (m, 2H), 7.07 (s, 1H), 6.96 (dd, J=2.3, 10.6 Hz, 1H), 4.01-4.12 (m, 5H), 3.88 (s, 3H), 3.42 (t, J=7.1 Hz, 2H), 2.99 (s, 3H), 2.14-2.24 (m, 3H), 1.70 (s, 6H), 1.21-1.30 (m, 6H). MS (ESI): m/z=721.49 [M+H]+. UPLC: tR=1.33 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CC1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 4-piperidine-acetamide (Chembridge) to give the title compound. HR-MS (ES, m/z) calculated for C35H43Cl2N6O3 [(M+H)+] 665.2768, observed 665.2767.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CN(C)C1C=CC=CC=1.S(Br)([Br:40])=O>C(Cl)(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([Br:40])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=S(Br)Br
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](Br)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cholesterol, (25 g, 64.6 mmol) was dissolved in 10 mL of dimethylaniline (78.9 mmol) and 5 mL of chloroform. While stirring on ice; small quantities of thionyl bromide (6 mL, 77.6 mmol) dissolved in 20 mL of cold chloroform was added slowly over a period of 15 minutes. After the addition of thionyl bromide wa complete, the mixture was stirred for an additional 2 hours at room temperature. The resulting solution was poured into 200 mL of ice cold 95% ethanol and left on ice for 2 hour until crystallization was complete. The product was filtered and washed with 25 mL of ice cold 95% ethanol. A small amount of product was recovered from the filtrate with the addition of 75 mL distilled water followed by refrigeration. Finally, the product was recrystallized from 120 mL of acetone giving 21.8 g of cholesteryl bromide (yield, 75%) with a melting point of 93-95%C (lit 97°-98° C.). The identity of the product was confirmed with mass spectrometry (EI) which showed an intense peak with an m/z of 448, corresponding to the molecular ion (M+°) of cholesteryl bromide. Also, the bromide molecular weight pattern characteristic of the two different isotopes of bromine (79Br:81Br,l:1) was observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (4.88 g, 10 mmol), pyrazole (0.681 g, 10 mmol), Cu2O (0.143 g, 1 mmol), salicylaldoxime (0.549 g, 4 mmol), and Cs2CO3 (6.52 g, 20 mmol) in CH3CN (100 mL) was refluxed for 5 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/THF (1/2) and recrystallized from EtOH/H2O to give the title compound (1.90 g, 44% yield) as a pale yellow powder: mp 214-216° C.; 1H NMR (300 MHz, CDCl3) δ ppm 3.92 (3H, s), 6.44 (1H, t, J=9.0 Hz), 6.53 (1H, dd, J=1.9, 2.3 Hz), 7.30 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.34 (1H, d, J=1.9 Hz), 7.37-7.48 (5H, m), 7.61 (1H, dd, J=2.3, 12.4 Hz), 7.76 (1H, d, J=1.9 Hz), 7.79 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.3 Hz), 7.92 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 429 [M+H]+. Anal. Calcd for C23H17FN6O2: C, 64.48; H, 4.00; N, 19.62. Found: C, 64.41; H, 4.00; N, 19.54.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.[Cl:43]C1C=C(C=CC=1)C=O.ClC1C=C(CC(O)=O)C=CC=1.COC(C(O)=O)C1C=CC=CC=1>>[Cl:34][C:30]1[C:31]([F:33])=[CH:32][C:10]2[N:9]=[C:8]([CH:1]([O:42][CH3:41])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]([CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:43])[CH:24]=3)[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:15])[C:11]=2[CH:29]=1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Reactant: O=CC1CCCCC1
Reactant: O=Cc1cccc(Cl)c1
Agent: COC(C(=O)O)c1ccccc1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COC(c1ccccc1)c1nc2cc(F)c(Cl)cc2n1C(C(=O)NC1CCCCC1)c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with 3-chlorobenzaldehyde ([CAS RN 587-04-2]) and (3-chloro-phenyl)-acetic acid with DL-α-methoxyphenylacetic acid ([CAS RN 7021-09-2]). MS (ISP): 540.2 [M+H]+.