Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][N:25]=1)[N:22]=[CH:21][C:20]([C:26]#[N:27])=[C:19]2[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1.C(Cl)(=O)C#CC>O1CCCC1.N1C=CC=CC=1>[Br:35][C:31]1[CH:30]=[C:29]([NH:28][C:19]2[C:18]3[C:23](=[CH:24][N:25]=[C:16]([NH:15][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:17]=3)[N:22]=[CH:21][C:20]=2[C:26]#[N:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2cnc(N)cc2c1Nc1cccc(Br)c1
Agent: CC#CC(=O)Cl
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Reaction time: 72 h
Yield: 8.4 %

Procedure:
To 100 mg of butynoic acid in 5 mL of anhydrous tetrahydrofuran under an inert atmosphere at 0° C. was added 0.23 mL on N-methyl morpholine and 0.15 mL of isobutyl chloroformate. This solution was then added to 150 mg of 6-amino-4-(3-bromo-phenylamino)-[1,7]naphthyridine-3-carbonitrile in 3 mL of pyridine at 0° C. After standing at 0° C. for three days, a second portion of butynoyl chloride was added. After an additional 8 hours the reaction was stripped of solvents on a rotary evaporator and the crude product was purified by flash chromatograph using a gradient of 0-20% methanol/chloroform to give 15 mg of but-2-ynoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1,7]naphthyridin-6-yl]-amide: melting point 255° C. (decomposed); mass spectrum (m/e): M+H 406.1, 408.2.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:29][N:28]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:29][N:28]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(F)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the compound (23.4 g) obtained in step 1 and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (17.9 g) in toluene (238 mL) was added dropwise a solution of trifluoroacetic acid (1.07 mL) in toluene (11.7 mL) at 5° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution/water, extracted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 20→75% ethyl acetate/hexane) to give (4R)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(4-fluorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (less polar product, 17.1 g, 52%) and (4R)-4-benzyl-3-{[(3R,4S)-1-benzyl-4-(4-fluorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (more polar product, 14.5 g, 44%) each as a white powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[S:26][CH:27]=[CH:28][C:24]=3[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:19]3[S:20][CH:21]=[CH:22][C:18]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:50][Sn:51](Cl)([CH3:53])[CH3:52].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[S:26][C:27]([Sn:51]([CH3:53])([CH3:52])[CH3:50])=[CH:28][C:24]=3[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:19]3[S:20][C:21]([Sn:51]([CH3:53])([CH3:52])[CH3:50])=[CH:22][C:18]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1ccc(CCCCCCCCCCc2c3ccsc3c(CCCCCCCCCCc3ccccc3)c3ccsc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Sn](C)(C)c1cc2c(CCCCCCCCCCc3ccccc3)c3sc([Sn](C)(C)C)cc3c(CCCCCCCCCCc3ccccc3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 4,8-bis(10-phenyldecyl)benzo[1,2-b:4,5-b′]dithiophene (466 mg, 0.75 mmol) in dry tetrahydrofuran (15 mL) was added n-butyllithium (2.5 M in hexane, 0.66 mL, 1.65 mmol) at −78° C. After 1 hour, trimethyltin chloride (349 mg, 1.75 mmol) was added in one portion. The mixture was stirred at room temperature overnight, poured into water (25 mL) and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (500 mg, yield 70%). 1H NMR (CDCl3, 500 MHz) δ=7.49 (s, 2H), 7.27-7.32 (m, 4H), 7.17 (d, J=7.5 Hz, 6H), 3.19 (t, J=7.5 Hz, 4H), 2.59 (t, J=8.0 Hz, 4H), 1.75-1.84 (m, 4H), 1.56-1.66 (m, 4H), 1.42-1.50 (m, 4H), 1.17-1.41 (m, 20H), 0.45 (s, 18H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: COc1c(CBr)cccc1Oc1cccc(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1cccc(Cl)c1
Yield: 98.1 %

Procedure:
A solution of 3-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (20 g) in dimethyl sulfoxide (50 ml) and powdered sodium cyanide (3 g) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(3-chlorophenoxy)phenyl]acetonitrile (16.4 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:22])=[C:16]([NH2:21])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:22])=[C:16]([NH:21][S:31]([C:25]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=3[F:23])(=[O:33])=[O:32])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N)c2F)n1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenylamine (1.146 g, 3.816 mmol) was dissolved in anhydrous pyridine (30 M) under nitrogen atmosphere and cooled to 0° C. 2,5-Difluoro-benzenesulfonyl chloride (0.513 mL, 3.816 mmol, 1 eq) was added and the mixture was allowed to stir at the same temperature. Further additions of sulfonyl chloride (for a total amount of 0.650 mL) were needed to drive the reaction to completion. The reaction mixture was kept at 0° C. overnight and then it was allowed to reach room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with NaHCO3 saturated aqueous solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was slurried in methanol at 50° C. for 10 minutes and the solid was filtered and washed with ethyl ether. After drying at 40° C. for 5 hours 1.13 g of the title compound were obtained as a white solid (62% yield).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:28])[CH3:31]
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(C(=O)OCC)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.48 g of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate and 1.5 ml of triethylamine in 10 ml of dry tetrahydrofuran was added dropwise 1 ml of ethyl chloroformate at 5° C. or below, and the mixture was stirred at room temperature for 2 hours. The resulting solid was removed by filtration, and the filtrate was evaporated to dryness to give crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphthoate.
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][CH2:7][CH:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI.CO>CCOCC>[CH3:2][O:6][CH2:7][CH:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(CO)Cc1ccccc1
Reactant: C1CCOC1
Solvent: CCOCC
Solvent: CI
Solvent: CO
Product: COCC(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
220 ml (1.9 mole) of KH (35% in oil) were placed, under a N2 -atmosphere, into a 4.5 l reactor and washed 4 times with pentane, in order to remove all traces of oil. 1.5 l of dry tetrahydrofurane were added before the dropwise addition of a solution of 259 g (1.73 mole) of 1-hydroxy-2-methyl-3-phenylpropane and 500 ml of dry tetrahydrofurane. The reaction was stirred for 15 hours at room temperature. Then 285 g (2.01 mole) of methyl iodide were added dropwise over a period of 2 hours, and stirring was continued at room temperature for another 2 hours. A possible excess of KH was hydrolyzed by adding 50 ml of methanol, then the reaction mixture was poured on ice. The product was taken up in ether, which was washed 3 times with a saturated NH4Cl solution and then with brine to neutrality. After drying over Na2SO4, the solution was filtered, concentrated and then distilled over a Vigreux-type column (boiling point: 100° C. at 5×102Pa).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O.Cl>N1C=CC=CC=1>[S:18]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19].[S:18]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: N#CC1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](C#N)CC2)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.20 g of the 4-(hydroxymethyl)cyclohexanecarbonitrile obtained in 5 ml of pyridine was treated portionwise at room temperature and under argon gasification with 2.46 g of p-tosyl chloride. After stirring at room temperature for 3.5 hours (formation of a white precipitate), the mixture, cooled to 0° C., was treated with about 2 ml of water, cautiously made acid with about 7 ml of concentrated hydrochloric acid and extracted three times with 30 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated, 2.31 g of semi-crystalline oil remaining behind. Low-pressure chromatography (0.5 bar) on 480 g of silica gel using 30% ethyl acetate/petroleum ether as the eluant gave 1.06 g (42%) of trans-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless cyrstallizing oil (m.p. 84°-85° C.) and 1.03 g (41%) of cis-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless viscous oil. Rf-values (30% ethyl acetate/petroleum ether): trans product 0.25, cis product 0.20.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[N:10]=[C:6]([CH2:5][O:4][CH3:3])[O:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: COCc1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)oxazol-4-yl)methanol (76 mg, 0.53 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.10 mL, 0.69 mmol) followed by DMAP (6.6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.67 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (5 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 118 mg of crude (2-(methoxymethyl)oxazol-4-yl)methyl methanesulfonate as a brown oil. LC-MS-conditions 07: tR=0.51 min, [M+H]+=222.02. A solution of this crude material (118 mg) in DMF (1.3 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (635 mg of a 9.6% solution in DMF, 0.53 mmol) in DMF (1.3 mL) pre-treated for 30 min with DIPEA (0.18 mL, 1.07 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.31. LC-MS-conditions 07: tR=0.62 min, [M+H]+=240.10.
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].O.[N:12]1[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1>ClCCl>[N+:12]1([O-:6])[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Solvent: ClCCl
Solvent: O
Product: [O-][n+]1ccnc2c3ccccc3c3ccccc3c21
Temperature: 25 °C
Yield: 51 %

Procedure:
First, to a solution in which 1.36 g of dibenzo[f,h]quinoxaline was dissolved in 20 mL of dichloromethane was added 2.04 g of 3-chlorobenzoic acid (abbreviation: MCPBA) in a nitrogen atmosphere, followed by stirring at room temperature for 1 week. Water was added to this mixture, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Then, the resulting solution was filtered. The solvent of this solution was distilled off. The resulting residue was purified by silica gel column chromatography which uses a mixed solvent of dichloromethane and ethyl acetate as a developing layer. By recrystallization from dichloromethane, the object of the synthesis was obtained (as a white powder in a yield of 51%). The synthesis scheme of Step 1 is illustrated in the following (a″′-2-1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25](=O)[C:26](OC)=[O:27])=[CH:21][NH:22]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (260 mg, 1.38 mmol) and methyl 2-(6-Methyl-1H-indol-3-yl)oxoacetate (300 mg, 1.38 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.38 mL, 1.38 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.76 mL, 2.76 mmol) was added. The resulting dark red solution was heated to 50° C. and stirred overnight. The mixture was cooled to room temperature and quenched with 1.0 N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (227 mg, 46%) as a red solid, mp 200–220° C. dec. 1H NMR (DMSO-d6) δ 11.72 (s, 1H), 11.09 (s, 1H), 7.90 (s, 1H), 7.59 (m, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 6.96 (m, 1H), 6.83 (m, 1H), 6.45 (s, 1H), 6.27 (m, 1H), 6.11 (m, 1H), 3.64 (s, 3H), 2.18 (s, 3H). MS (APCI): m/z=356 [C22H17N3O2+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C.CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reaction time: 2 h

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in a four-necked flask, and were dissolved by adding a 1:1 mixed solvent of acetic acid/methanol thereto. Thereafter, reaction was allowed at 70° C. for 2 hr. After the reaction, the solvent was removed, and the reaction product was extracted on a silica gel column (ethyl acetate:hexane=1:1).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=O)=[CH:22][N:21]=3)[C@H:16]([CH3:33])[CH2:15]2)=[C:10]([CH3:34])[C:9]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](Cl)(=[O:40])[C:37](Cl)=O.[CH3:42][N:43](C=O)C.CN>C1COCC1.CCOC(C)=O>[OH:40][CH2:36][CH2:37][N:43]([CH3:42])[C:30]([C:23]1[C:24]([C:26]([F:28])([F:29])[F:27])=[N:25][C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[N:13][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:9]([CH3:35])[C:10]=3[CH3:34])[CH2:15][C@H:16]2[CH3:33])=[N:21][CH:22]=1)=[O:32]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)[C@H](C)C2)c1C
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3ncc(C(=O)N(C)CCO)c(C(F)(F)F)n3)[C@H](C)C2)c1C
Reaction time: 1 h

Procedure:
To a solution of 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid (45 mg, 0.1 mmol, 1 eq) in THF (2 mL) is added an excess of oxalyl chloride (100 μL, 1.2 mmol, 12 eq,) and a catalytic amount of DMF, and the resulting solution is stirred at rt for 45 min, at which time N-2-hydroxyethyl, N-methyl amine (200 μL, 2.5 mmol, 25 eq) is added, and the reaction is stirred for an additional 1 h. The reaction mixture is diluted with EtOAc (50 mL) and washed with water (2×10 mL) followed by brine (2×10 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (CH2Cl2—20% MeOH/CH2Cl2) as a white solid (43 mg, 79%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=C(/C(O)=O)\C)[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:35]=[O+][O-].CSC>CO>[CH:26]([CH:25]([N:23]([CH3:24])[C:21]([CH:16]([NH:15][C:13](=[O:14])[CH:3]([NH:2][CH3:1])[C:4]([CH3:12])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:11])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH:32]([CH3:33])[CH3:34])=[O:35]
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (1.0 g) in methanol (20 mL) is added to 100 mL of methanol at −78° C. which had been treated with ozone until the solution is blue. The resulting colorless reaction mixture is treated with ozone at −78° C. until the blue color remained. After 5 min dimethylsulfide (2 mL) is added. The reaction mixture is allowed to warm to room temperature and then concentrated in vacuo to give the title compound as an oil. MS (ES): m/z 418.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:25](=[O:27])[O:10][CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Br)cc1C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanol (0.50 g, 1.798 mmol) is dissolved in anhydrous THF (25 mL). Triethylamine (0.55 g, 5.393 mmol) is added followed by triphosgene (0.16 g, 0.539 mmol). The mixture is stirred at room temperature overnight. Water (50 mL) is added and the reaction stirred for 15 minutes then extracted with ethylacetate (3×50 mL). The organic phases is washed with 1N HCl (2×50 mL) and a saturated solution of sodium hydrogencarbonate (50 mL). The organic phase is dried over sodium sulfate and concentrated in vacuo to provide the desired product as a white solid.
Reaction SMILES: Br.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][C:18]4([C:24]5[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=5)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1.C(N(CC)CC)C.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45]>ClCCl>[CH3:42][C:43]([CH3:48])([CH3:47])[C:44]([N:21]1[CH2:20][CH2:19][C:18]([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)([CH2:17][CH2:16][N:15]2[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH2:9][CH:8]([N:7]2[C:6]4[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=4[N:4]=[C:3]2[CH3:2])[CH2:14]3)[CH2:23][CH2:22]1)=[O:45]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(O)c2)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(O)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A mixture of 3-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol hydrobromide (0.22 g, 0.42 mmol), triethylamine (0.117 mL, 0.84 mmol) and trimethylacetyl chloride (0.057 mL, 0.462 mmol) in dichloromethane (2 mL) was stirred at rt for 3 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 3-(1-(2,2-dimethyl propanoyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol as a white solid (0.070 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.05-7.15 (m, 3H), 6.77 (m, 1H), 6.73 (s, 1H), 6.59 (m, 1H), 4.51 (m, 1H), 3.74 (m, 2H), 3.24 (m, 4H), 2.47 (s, 3H), 2.36 (m, 2H), 1.97 (m, 2H), 1.86 (m, 4H), 1.75 (m, 6H), 1.58 (m, 2H), 1.15 (s, 9H). HRMS C33H44N4O2 m/z 529.3543 (M+H)Cal., 529-3542 (M+H)Obs..