Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]3[CH2:62][CH2:61][CH2:60][C@H:59]3[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([NH:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]5[CH2:62][CH2:61][CH2:60][C@H:59]5[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=4)=[CH:48][CH:49]=3)=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.25 g, 1 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.47 g, 1 mmol) in methylene chloride was added racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclopentanecarboxylic acid (0.20 g, 0.78 mmol) and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated and the residue was re-dissolved in DMSO and acetonitrile. HPLC reverse phase purification with acetonitrile and water afforded 44 mg of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid as a white solid. LCMS calcd for C30H23F3N2O5 (m/e) 548, obsd 549 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1C#N)c1ccc(Cl)cc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)O)ccc1C#N)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.5 mg (33 μmol) of tert-butyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-cyanophenyl)propanoate were dissolved in 1.1 ml of dichloromethane, and 275 μl of trifluoroacetic acid were added. The reaction mixture was stirred at RT for 1.5 h, then diluted with 20 ml of dichloromethane and concentrated under reduced pressure. The residue was dried under high vacuum overnight. This gave 14.8 mg (97% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][N:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]([CH3:40])=[N:33]1>O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:36]5[N:32]([CH3:31])[N:33]=[C:34]([CH3:40])[CH:35]=5)=[O:38])=[CH:3][CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)n(C)n1
Yield: 27.4 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (220 mg, 0.71 mmol), triethylamine (0.30 mL, 2.13 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (230 mg, 1.42 mmol) and tetrahydrofuran (6.6 mL) as starting materials and in the same manner as in Example 96, the title compound (84 mg, 27%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.BrN1C(=[O:17])CCC1=O>C(Cl)(Cl)(Cl)Cl>[N:7]1[C:6]2[C:2]([CH:1]=[O:17])=[CH:3][S:4][C:5]=2[CH:10]=[N:9][CH:8]=1
Reactant: Cc1csc2cncnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2cncnc12
Yield: 61 %

Procedure:
A mixture of 7-methyl-thieno[3,2-d]pyrimidine (1.2 g) and N-bromosuccinimide (2.9 g) in carbon tetrachloride (50 mL) was heated at reflux for 1 hour. The reaction mixture was then cooled, the solid formed was filtered off and the filtrate was concentrated under reduced pressure. The residue was suspended in water (10 mL) and the suspension was heated at reflux for 1 hour. The resulting mixture was basified by addition of a saturated aqueous solution of sodium bicarbonate and extracted twice with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solid residue was triturated with ethyl acetate and hexane and then collected by filtration to give 0.8 g of thieno[3,2-d]pyrimidine-7-carbaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24](=[O:31])[N:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[CH3:26])[CH:18]=1)=[C:10]([CH3:32])[CH:9]=2)=[O:5])C.[OH-].[K+]>CO.O>[CH:27]1([N:25]([CH3:26])[C:24]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[OH:23])[O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:32])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(=O)N(C)C4CCC4)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a solution of 5-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (102 mg, 0.23 mmol) in methanol (2 mL) at room temperature was added 3N potassium hydroxide (0.44 mL) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (10 mL) and washed with EtOAc/Et2O (1/1, 3 times 5 mL). The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl acetate (3 times 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford the title compound (81 mg) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ11.08 (s, 1H), 7.15-7.14 (d, 2H), 6.76 (s+m, 2H), 6.33 (br s, 1H), 4.25-4.16 (m, 1H), 2.90 (s, 3H), 2.25 (s, 3H), 2.22-2.19 (m, 2H), 2.15 (s, 3H), 1.95-1.85 (m, 2H), 1.60-1.48 (m, 2H). MS (APCI+) Calc: 408.2, Found: 409.2 (M+1).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][S:8]2)=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:13][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][S:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2sccc2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccsn1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
Catalytic amount of benzoyl peroxide (4 mg) was added to a solution of 2-p-tolylisothiazol-3-one 30 (123 mg, 0.643 mmol), and N-bromosuccinimide (121 mg, 0.673 mmol) in carbon tetrachloride (8 mL), which was refluxed for 2 h and then cooled to room temperature. Solvent was evaporated under low pressure and the residue was purified by flash silica gel column chromatography (methylene chloride:methanol=50:1 to 20:1), afforded the compound 31 (182 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ 4.50 (s, 2H), 6.33 (d, J=6.3 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 8.16 (d, J=6.3 Hz, 1H). HRMS: calculated for C10H9NOSBr (M+H)+269.9588. Found 269.9593.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: [Br-]
Reactant: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Yield: 105.4 %

Procedure:
1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (O2.007; 1.63 g) was dissolved in THF (150 ml), and phenyltrimethylammonium tribromide (2.2 g) was added at RT while stirring. After stirring at RT for 2 h, the mixture was admixed with water, neutralized with sodium hydrogencarbonate solution and extracted three times with EA. The alkaline water phase was extracted 3× with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, neutralized with sodium hydrogencarbonate and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 1.27 g of the title compound were isolated. LC-MS rt: 1.65 min [M+H]+: 354.9 (met. b)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>CO.O>[Cl:14][C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)s1

Procedure:
The product from Example 351A (1 equiv) was dissolved in a methanol/water 3/1 mixture followed by the addition of lithium hydroxide (5 equiv). The resultant solution was stirred at room temperature for 24 hours followed by the addition of 1N aqueous hydrochloric acid until the solution was a pH of 2. The mixture was then extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:25]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Benzyl 3-hydroxypropylcarbamate obtained in step 1 (15 g, 72 mmol) was treated with imidazole (10 g, 146.9 mmol) and TBSCl (12 g, 79.6 mmol) in DMF (10 ml) at 0° C. After warming up the resulting reaction mixture to room temperature, it was stirred for 30 minutes. The resulting solution was quenched with water (50 ml), and then extracted with diethyl ether twice (50 ml×2). After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAc:Hx=1:10) to afford the title compound (23 g, 98%) as colorless oil.
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(C1C=CC=CC=1)C#C>[Au].ClC(Cl)C>[C:29]1([C:35]#[C:36][P:37](=[O:41])([O:42][C:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:9])[O:38][CH2:39][CH3:40])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(Cc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylbenzene (70 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 3-phenylprop-1-en-2-yl phenylethynylphosphonate (68.9 mg, 71%) which is a title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:22]2[CH2:23][CH2:24][CH:19]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
To 5-fluoro-2-nitrophenyl methyl ether (26.0 g, 152 mmol), 1,4′-bipiperidine (25.5 g, 152 mmol) and K2CO3 (22.9 g, 166 mmol) was added DMSO (260 mL). The mixture was stirred at room temperature for 3 days. The mixture was poured into H2O (1000 mL) and the H2O washed with EtOAc (2×500 mL). The EtOAc washes were combined and washed with H2O (2×500 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (47.9 g, 150 mmol, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=9.5 Hz, 1H), 6.40 (dd, J=9.5 and 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 3.99-3.93 (m, 2H), 3.93 (s, 3H), 2.98-2.89 (m, 2H), 2.58-2.48 (m, 5H), 1.99-1.90 (m, 2H), 1.70-1.55 (m, 8H), 1.48-1.40 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:18][N:17]([C:19](=[O:21])[CH3:20])[C:16]4[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=4[CH2:14][CH2:13][C:12]=3[CH:26]=2)[CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C.[NH2:79][CH2:80][CH2:81][N:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>C1(C)C=CC=CC=1>[C:19]([N:17]1[CH2:18][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:79][CH2:80][CH2:81][N:82]4[CH2:86][CH2:85][CH2:84][CH2:83]4)[N:7]=3)=[CH:26][C:12]=2[CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]1=2)(=[O:21])[CH3:20]
Reactant: CC(=O)N1Cc2ccc(-c3cccc(Br)n3)cc2CCc2ccccc21
Reactant: NCCN1CCCC1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2ccc(-c3cccc(NCCN4CCCC4)n3)cc2CCc2ccccc21
Temperature: 95 °C
Yield: 32.9 %

Procedure:
A mixture of 1-[9-(6-Bromo-pyridin-2-yl)-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl]-ethanone (prepared according to Example 14 and Example 195 starting from Example 2) (17 mg, 0.04 mmol), BINAP (5 mg, 0.008 mmol), t-BuONa (10 mg, 0.1 mmol) and N-(2-aminoethyl)pyrrolidine (6 μl, 0.05 mmol) in toluene (2 mL) was purged with argon, then heated at 95° C. for 1 h. The reaction mixture was cooled to room temperature, concentrated and purified by preparative reversed-phased HPLC to give the title compound (5.8 mg, 33%). HPLC Rt=1.52(b) min. m/z=441 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].Cl>[OH-].[K+].C(O)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=[CH:2][CH3:3]
Reactant: C=CCc1cc(Oc2ccc(F)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC=Cc1cc(Oc2ccc(F)cc2)ccc1O
Temperature: 25 °C

Procedure:
A solution of 2-allyl-4-(4-fluorophenoxy)phenol, from above, in saturated KOH/ethanol (65 mls) was refluxed for 18 hrs. It was then cooled to r.t. and acidified to pH2 by that addition of 10% HCl The aqueous solution was then extracted with ethylacetate (3×200 mls). The organics were combined, dried with MgSO4 and concentrated to afford 17.52 g of 2-(1-propenyl)-4-(4-fluorophenoxy)phenol as a brownish oil which was used as is.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21](Cl)[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21]([O:30][CH3:29])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nn(C)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 70 %

Procedure:
In methanol (5 ml) was dissolved 1-[4-(4-chloro-benzoyl)benzyl]-4-chloro-6-methylimidazo[4,5-d]pyridazin-7(6H)-one (72 mg) followed by addition of 28% sodium methoxide/methanol (1.0 ml), and the mixture was refluxed for 5 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 50 mg (yield 70%) of the title compound. 1H-NMR (CD3OD) δ: 3.7.1(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz), 7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:45][S:46]SC>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][C:30]=2[S:46][CH3:45])[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccnc2c(-c3ccc(F)cc3)c(-c3ccncc3)n(C(=O)OC(C)(C)C)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,2,6,6-Tetramethylpiperidine (1.76 ml, 10.40 mmol) was dissolved in tetrahydrofuran (39 ml) and placed under an atmosphere of nitrogen. The solution was cooled to −78° C. and n-butyllithium (3.96 ml, 9.91 mmol, 2.5 M solution of in hexanes) was added at such a rate that the internal temperature did not exceed −70° C. The reaction mixture was warmed to −10° C. for 30 min., then re-cooled to −78° C. A solution of 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine (0.965 g, 2.47 mmol) in tetrahydrofuran (32 ml) was cooled to −78° C. and then added via cannula at such a rate that the internal temperature did not exceed −70° C. After 1 h, dimethyldisulfide (0.29 ml, 3.22 mmol) was added and the resulting solution was stirred for an additional 1 h at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude residue was purified by flash chromatography using 20% acetone/hexanes as the eluant to give 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine. MS: 435 (M).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=2[N+:23]([O-:24])=[O:22])[N:3]=1
Reactant: O=[N+]=O
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc2nc(Cl)nc(Cl)c2c([N+](=O)[O-])c1OC
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a suspension of 2,4-dichloro-6,7-dimethoxyquinazoline (30.0 g, 0.12 mol) in acetonitrile (550 ml) at 0° C. was added nitronium tetrafluoroborate (25.9 g, 0.19 mol) portionwise over 15 min. The reaction was stirred for 0.75 h and then evaporated under reduced pressure. The resulting solid was suspended in a mixture of saturated aqueous sodium bicarbonate and EtOAc and the solid filtered, dissolved in CH2Cl2, dried over MgSO4 and evaporated to give the subtitle compound as a pale yellow solid (27 g). Further material was obtained by separating the organic layer of the filtrate, washing with H2O (1×), saturated brine (1×), drying over MgSO4 and filtering through a pad of silica. Subsequent evaporation under reduced pressure, trituration with EtOAc and filtration gave the subtitle compound as a pale yellow solid (3.9 g, overall yield 88%). Rf 0.24 (ether/hexane 1/1, v/v).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OCC)(OCC)[O:6]CC.O.[C:16]([OH:29])(=[O:28])[CH2:17]CCCCCCCCCC>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][SiH2:5][O:6][CH2:17][CH:16]([OH:28])[OH:29]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Solvent: CCO
Product: NCCC[SiH2]OCC(O)O
Reaction time: 1 h

Procedure:
0.10 mol of 3-aminopropyltriethoxysilane is charged under a nitrogen atmosphere to a sulfonating flask. 0.20 mol of water and 0.10 mol of lauric acid are then added with thorough stirring, and stirring is continued at room temperature for one hour. The salt derived from lauric acid and 3-aminopropyldihydroxyethoxysilane [Compound (118)] is obtained in quantitative yield as an 80% solution in ethanol.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[NH:43]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C@H:44]([C:55]([O:57]N1C(=O)CCC1=O)=O)[C@@H:45]([CH3:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(CC)CC>C1COCC1.CN(C=O)C.CCN(CC)CC.O.CCOC(C)=O.CC(O)=O>[NH:43]([C:65]([O:67][C:68]([CH3:69])([CH3:70])[CH3:71])=[O:66])[C@H:44]([C:55]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:57])[C@@H:45]([CH3:54])[O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O)[C@@H](C)OCc1ccccc1
Reaction time: 24 h

Procedure:
Boc-Thr(Bzl)-Lys(Z)-OH (14.0 g, 24.5 mmol) was treated with 500 ml of 4.0 N HCl in THF for 30 minutes, evaporated to dryness, and re-evaporated twice with fresh THF. The oily residue solidified when treated with ether. The dried powder (11.4 g, 21.6 mmol) of the dipeptide hydrochloride salt was then dissolved in 140 ml DMF, cooled to 0°, and treated with Boc-Thr(Bzl)-OSu (8.8 g, 21.6 mmol) followed by 3.5 ml of Et3N. A few drops of Et3N was added to maintain a slightly basic condition while the mixture was stirred for an additional 24 hours at 25°. It was acidified with 5 ml of HOAc and then diluted with a large volume of water. The solid crude product precipitated was collected, dissolved in EtOAc, washed with H2O, dried over Na2SO4, and evaporated to dryness, leaving a glassy solid mass. Crystallized from EtOAc and petroleum ether: yield, 13.8 g (83.7%); mp 110°- 112°; [α]D25 =+19.45° (c 1, EtOAc).