Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].O=C1C2C(=CC=CC=2)C(=O)[N:8]1[CH2:17][C:18]1[C+:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]1[CH2:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]1[C:21]2([CH3:33])[CH3:32].O.NN>C(Cl)Cl.CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:8][CH2:17][C:18]1[C+:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]1[CH2:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]1[C:21]2([CH3:33])[CH3:32]
Reactant: CC1=CCN2C3=CC=C(CN4C(=O)c5ccccc5C4=O)[C+]=C3C(C)(C)C2=C1
Agent: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1=CCN2C3=CC=C(CN)[C+]=C3C(C)(C)C2=C1
Reaction time: 8 h

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-8,10,10-trimethyl-10H-pyrido[1,2-a]indolylium perchlorate (36 g, 0.077 mol; Sigma-Aldrich) was added to a conical 1-L flask equipped with magnetic stir bar, followed by 480 mL of CH2Cl2—CH3OH mixture (3:2). Stirring was started and hydrazine monohydrate (25 g, 0.50 mol; Aldrich) was added to the reaction mixture at once. Stirring was continued until all solid was dissolved. The flask was closed with a stopper and let to stand at room temperature overnight without stirring. After about 16 hours the precipitated solid phthalhydrazide was filtered off, washed with 100 mL of CH2Cl2—CH3OH mixture (3:2) and discarded. The combined filtrates were evaporated and the resulted solid was washed with Ether-CH3OH. The solid was filtered, washed with ether and dried. The yield was 26 g (100% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15].FC(F)(F)[C:19](O)=[O:20].C1N2CN3CN(C2)CN1C3>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:19]=[O:20])[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)C(C)(C)CC(=O)N2C
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 83 mg (0.38 mmol) 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 53 mg (0.38 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched with 30 ml of saturated aqueous bicarbonate solution and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue (64 mg; 68%) was used directly in the following step. Mass spectrum APCI m/e 248 (p+1).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (213 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.55 (brs, 1H), 8.89 (brs, 1H), 8.58 (s, 1H), 8.03 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.20 (s, 1H), 4.00 (s, 6H), 1.69 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].S(Cl)(Cl)=O.C[N:18](C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: COc1cc(Br)cc(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(Br)cc(C(N)=O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-5-(methyloxy)benzoic acid (9.6 g, 41.6 mmol) in toluene (60 mL), thionyl chloride (9.89 g, 83.1 mmol) and DMF (0.10 mL) were added and stirred at 50° C. for 4 h. The reaction was allowed to cooled to room temperature, and then the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL) and the mixture was added to a solution of ammonia (25%, 50 mL). A precipitate formed and was filtered off using Celite, and dried, to afford 3-bromo-5-(methyloxy)benzamide (8.70 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[CH2:39][C:40](OC)=[O:41]>CN(C=O)C>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]3[NH:1][C:40](=[O:41])[CH2:39][C:31]=2[CH:32]=1)([O-:38])=[O:37]
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1F
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (30 mg, 0.10 mmol) in DMF (5 mL) was added K2CO3 (28 mg, 0.20 mmol) and methyl 2-(2-fluoro-5-nitrophenyl)acetate (21 mg, 0.10 mmol). The mixture was warmed to 80° C. stirred for about 16 hr. After cooling down to RT, the mixture was concentrated under reduced pressure to remove solvent. The residue was portioned with DCM (10 mL) and water (10 mL), the aqueous was extracted with DCM (2×10 mL), the combined organic phases were washed sat. Sodium chloride (10 mL), dried over anhydrous Sodium sulfate, filtered, concentrated and purified by pre-TLC (DCM/CH3OH=20/1) got the product about 10 mg (21.9%). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (br s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.37 (dd, J=2.6, 9.2 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.65-7.53 (br s, 2H), 7.45-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.12-7.05 (m, 4H), 3.92 (s, 2H). MS (ESI) m/e [M+1]+ 456.1.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.N1CCCCC1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>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.[Cu]I>[NH2:21][C:17]1[N:16]=[C:15]([N:7]2[C:6]3[CH:22]=[C:2]([C:38]#[C:37][C:35]([C:30]4[N:29]=[CH:34][CH:33]=[CH:32][N:31]=4)([OH:39])[CH3:36])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:20]=[CH:19][N:18]=1
Reactant: COCCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCCOc1nc2ccc(C#CC(C)(O)c3ncccn3)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 4-[6-iodo-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (70%, 120 mg, 0.2 mmol) followed by piperidine (1.0 mL), tetrakis(triphenylphosphine)palladium(0) (23.61 mg, 0.02 mmol), copper(I) iodide (3.89 mg, 0.02 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (60.53 mg, 0.41 mmol). The reaction was capped and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash column chromatography (1-10% MeOH gradient in DCM), followed by trituration with EtOAc/heptanes/DCM to give the title compound: 1H NMR (500 MHz, DMSO) delta 1.88 (3H, s), 3.92-3.64 (2H, m), 4.84-4.59 (2H, m), 6.13 (1H, s), 6.97 (1H, d, J=5.5 Hz), 7.10 (2H, s), 7.23 (1H, dd, J=8.2, 1.5 Hz), 7.44 (1H, d, J=8.1 Hz), 7.49 (1H, t, J=4.8 Hz), 8.13 (1H, s), 8.39 (1H, d, J=5.5 Hz), 8.89 (2H, d, J=4.9 Hz); LC-MS: m/z=+432.05 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[N:8]=[C:9]=[S:10].[CH3:11][C:12]1[S:13][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][N:16]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:20][NH:19][C:17]([C:14]1[S:13][C:12]([CH3:11])=[N:16][CH:15]=1)=[O:18]
Reactant: Cc1ncc(C(=O)NN)s1
Reactant: S=C=NC1CC2C=CC1C2
Product: Cc1ncc(C(=O)NNC(=S)NC2CC3C=CC2C3)s1

Procedure:
The title compound was prepared from a mixture of bicyclo[2.2.1]hept-5-en-2-ylisothiocyanate (50 mg, 0.33 mmol) and 2-methylthiazole-5-carboxylic acid hydrazide (58 mg, 0.36 mmol) similar to Example 80 and isolated as a white solid (10 mg, 9%). 1H NMR (DMSO-d6): 10.11 (s, 1H), 9.34 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 6.07 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 3.99 (s, 1H), 2.82 (brs, J=8.8 Hz, 2H), 2.72 (s, 3H), 1.52-1.35 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:10]([N:12]1[C@@H:20]([C:21]#[C:22][Si](C)(C)C)[CH2:19][CH2:18][C@H:13]1[C:14]([O:16]C)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:10]([N:12]1[C@@H:20]([C:21]#[CH:22])[CH2:19][CH2:18][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-((trimethylsilyl)ethynyl)-L-prolinate (1.65 g, 3.66 mmol) in MeOH (10 mL) and H2O (10 mL) at room temperature was added LiOH.H2O (0.23 g, 5.49 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜4 by adding 4% KHSO4 dropwise. The clear solution was extracted with ethyl acetate (3×) and the combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/e 365 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19].C1N2CCN(CC2)C1.CC1C=CC(S(O[CH2:41][C:42]2[C:47]3[CH2:48][CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:46]=3[CH:45]=[CH:44][CH:43]=2)(=O)=O)=CC=1>O.CCCCCCC.C(#N)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:41][C:42]2[C:47]3[CH2:48][CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:13])[CH:7]=[CH:6][C:5]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Cc1ccc(S(=O)(=O)OCc2cccc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Solvent: CC#N
Product: CC(C)C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
A solution of potassium hydroxide (1.03 grams, 0.016 mole) in water (6.0 ml) was added to a stirred mixture of 2-(2-chloro-α,α,α-trifluoro-p-toluidino)-3-methylbutyric acid (4.62 grams, 0.016 mole, prepared by the method of C. A. Henrick, et al., Pest. Sci. 11, 224-41 (1980)) in n-heptane (75.0 ml). The mixture was stirred until all the acid dissolved, at which time the water was distilled from the mixture. Additional n-heptane (50.0 ml) was added, followed by a solution of 1,4-diazobicyclo[2.2.2]octane (0.12 gram, 0.00097 mole) and (6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-yl)methyl p-methylphenylsulfonate in acetonitrile (40.0 ml). After complete addition, the mixture was stirred and heated at reflux for approximately 18 hours. The mixture was cooled, then evaporated to dryness under reduced pressure to leave a residue. The residue was partitioned between diethyl ether (250 ml) and water (150 ml) and the phases separated. The organic phase was washed in succession with aqueous 2% hydrochloric acid (two 50 ml portions), water (two 25 ml portions), aqueous 10% sodium carbonate (two 25 ml portions), and saturated aqueous sodium chloride (25 ml). The washed organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel (250 grams), n-heptane:toluene (30:70) as the eluant, to yield (6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl 2-(2-chloro-α,α,α-trifluoro-p-toluidino)-3-methylbutyrate (4.95 grams) as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14])[CH3:2].[OH-].[Na+].[Br:17]Br>O>[Br:17][C:6]1([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[O:14])[NH:8][C:9](=[O:13])[NH:10][C:11]1=[O:12]
Reactant: BrBr
Reactant: CCOCCC1C(=O)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
To a mixture of 5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (27.8 g, 139 mmol) and 1.5 L of water was added 1M sodium hydroxide solution (140 mL) and bromine (7.2 mL, 22.2 g, 139 mmol) at 0° C. After warming to room temperature, the mixture was stirred for 48 hours, filtered, and the solids were washed with water, then ether, then hexanes and dried in vacuo, affording 23 g of 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.F[C:13](F)(F)[C:14](O)=O.C(Cl)Cl>>[NH2:9][CH2:7][CH2:5][CH2:4][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[C:10]1[C:14]1[CH:13]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=c1[nH]cnc2ccccc12
Solvent: ClCCl
Product: NCCCn1c(-c2ccccc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg of resin (7) is suspended in 2 ml of a 50% trifluoroacetic acid/methylen chloride solution and shaken for 1.5 hours at room temperature. Customary working up for solid-phase reactions afforded 3-(3-aminopropyl)-2-phenyl-3H-quinazolin-4-one;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1>C(O)(C)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:12][CH:13]([CH3:19])[CH3:14])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Solvent: CC(C)O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) and isopropanol (2 ml) the subtitle compound was obtained (204 mg, 84%). 1H NMR (DMSO) δ 8.85(d, 1H), 8.44(dd, 1H), 8.12(d, 1H), 7.90(d, 1H), 7.76(m, 3H), 7.54(m, 3H), 7.40(t, 1H), 4.35(m, 1H), 1.45(d, 6H).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[CH3:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[S:64](Cl)(=[O:66])=[O:65]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([NH:52][S:64]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=3[CH3:57])(=[O:66])=[O:65])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: Cc1ccccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (350 mg, 1.003 mmol) and 2-methylbenzenesulfonyl chloride (0.145 mL, 1.00 mmol) the title compound of Step A was obtained as a yellow solid (140 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 8.35-8.65 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.11-7.50 (m, 6H), 6.73 (d, J=5.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.54 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9](Cl)=[O:10].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]2[CH:27]=[CH:28][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:20]=1)=[O:10]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(Oc2ccc(Cl)cc2)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
In 20 ml of dry benzene was dissolved 2.28 g of cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride, followed by addition of 2.34 g of 3-(4-chlorophenoxy)benzyl alcohol and 1.58 g of pyridine. The mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove a low-boiling fraction, whereby an oily product was obtained as a residue. This oil was purified by preparative liquid chromatography [column: Waters Associates' Prep LC/System 500, Prep PAK® 500/SILICA; solvent system: diisopropyl ether:n-hexane=6:94, v/v]. The above procedure yielded 3.91 g of 3-(4-chlorophenoxy)benzyl cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (yield 92%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH2:32]=O>CO.C(Cl)Cl>[CH3:32][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1
Reactant: C=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 96 mg (0.23 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 3 mL methanol was treated with 0.17 mL (2.3 mmol) formaldehyde (37% in water) and 150 mg (0.70 mmol) NaBH3(CN). The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 426 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:75])[NH:64][C:65]3[CH:70]=[CH:69][C:68](Br)=[C:67]([O:72][CH2:73][CH3:74])[CH:66]=3)=[CH:59][N:58]=2)[C@H:53]([CH3:76])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].COCCOC.O.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:75])[NH:64][C:65]3[CH:70]=[CH:69][C:68]([C:24]4[CH:25]=[CH:26][C:21]([C:19]5[N:20]=[C:16]([C@@H:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:36])[CH:6]([CH3:7])[CH3:8])[NH:17][CH:18]=5)=[CH:22][CH:23]=4)=[C:67]([O:72][CH2:73][CH3:74])[CH:66]=3)=[CH:59][N:58]=2)[C@H:53]([CH3:76])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: CCOc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)nc2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)nc2)ccc1-c1ccc(-c2c[nH]c([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (253 mg, 0.52 mmol) and the TFA salt of (R)-4-[5-(4-bromo-3-ethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (324 mg, 0.52 mmol; Preparation 21) was dissolved in 1,2-dimethoxyethane (5.32 mL, 51.2 mmol) and water (0.92 mL, 51.2 mmol) and the mixture was sparged under nitrogen. Sodium bicarbonate (161 mg, 1.92 mmol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.077 mmol). The reaction mixture was further sparged with nitrogen, sealed under nitrogen and heated at 90° C. overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to produce the title intermediate as a brown oil. (m/z): [M+H]+ calcd for C44H56N8O7 809.43 found 809.6.