Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O)=CC=1>CN(C)C=O>[F:28][C:27]([F:30])([F:29])[CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Combine 3-hydroxybenzaldehyde (134.3 g), potassium carbonate (304.0 g), 2,2,2-trifluoroethyl p-toluenesulfonate (293.6 g) and dimethylformamide (2 L). Heat the mixture at 90° C. After 15 hours, cool to room temperature, pour on ice-water, and extract with dichloromethane. Combine the organic layers, wash with 1N sodium hydroxide, and then with water. Dry the organic phase over magnesium sulfate, filter, and concentrate to a residue. Dissolve residue in toluene (200 ml), Chromatograph on silica gel eluting sequentially with toluene and then ethyl acetate to give a residue. Distill the reside under reduced pressure using a Claisen flask equipped with a Vigreux column gives title compound: bp 0.8 mm Hg, 84-85° C. Redistilling some fractions using a Claisen flask equipped with a Vigreux column and subsequently an adiabatic column filled with Rasching rings gives title compound: bp 0.9-1.0 mm Hg, 74-76° C.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1>C(O)(C)C>[CH:13]([O:23][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1)([CH3:14])[CH3:12]
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na]
Solvent: CC(C)O
Product: COc1cc(Nc2nc(C)cc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 47.2 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under heating and stirring under an atmosphere of nitrogen in isopropanol (1 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to reflux over night. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent. The fraction containing the product was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as an off-white solid (25 mg, 24%). MS ISP (m/e): 354.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.73 (s, 1H), 7.63 (s, 1H), 7.18 (d, 1H), 7.04 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.06 (s, 1H), 5.36 (sept, 1H), 3.86 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([OH:19])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A suspension of 4.0 g (0.0165 mmol) methyl 3-(benzyloxy)-5-hydroxybenzoate (160), 6.84 g (0.0495 mmol) potassium carbonate, and 11.71 g (0.0825 mmol) iodomethane in the 200 mL of acetone was stirred at room temperature for 24 h. After the mixture was filtered and evaporated, the residue was washed with water. The methyl 3-(benzyloxy)-5-methoxybenzoate (161) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[CH:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([OH:24])[CH:18]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11](=[O:13])[NH:23][C:22]1[CH:17]=[CH:18][C:19]([OH:24])=[CH:20][CH:21]=1)[C:9]#[N:10]
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc(O)cc1

Procedure:
The mixture of 5.7 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 3,6 g of p-aminophenol and 300 ml of xylene is refluxed for 2 hours and filtered hot. The filtrate is chilled, the crystals formed collected and recrystallized from methanol, to yield the 1-methyl-β-oxo-α-(p-hydroxyphenylcarbamoyl)-2-pyrrolpropionitrile melting at 182°-184°.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[N:24]([CH3:25])[CH2:23][CH2:22][N:21]([CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: CNCCN(C)Cc1ccccc1
Solvent: CCO
Product: CN(CCN(C)C1=C(O)C(=O)c2ccccc2C1=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 2.61 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 2.67 g of N-benzyl-N,N'-dimethylethylene-diamine and 150 ml of absolute ethanol was stirred for 20 hours, then concentrated to one-half its original volume and refrigerated overnight. The solvent was removed, the residue dissolved in dichloromethane and passed through a pad of hydrous magnesium silicate and silica, eluting first with dichloromethane, then with 1% methanol in dichloromethane. The active fraction was flash chromatographed eluting with dichloromethane followed by 2% methanol in dichloromethane. The active fraction was evaporated and the residue triturated in dichloromethane/-hexane giving 900 mg of the desired product, mp 121°-123° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCCl)cccc2c1=O
Reaction time: 1.5 h

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to a boiling solution of 3.37 g of Intermediate XXXVI in 20 ml of chloroform. After stirring for 90 minutes under reflux, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give 3 g of pure title compound, m.p. (188) 193°-194° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20]C(=O)C3C=CC=CC=3)=[O:19])[CH2:13][CH2:12]2)=[CH:2]1.[OH-].[Na+]>O.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18]([NH2:20])=[O:19])[CH2:15][CH2:16]2)=[CH:2]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)NC1CCN(Cc2c[nH]c3ccccc23)CC1
Reaction time: 3 h

Procedure:
1-[1-(Indol-3-ylmethyl)piperid-4-yl]-3-benzoylurea (0.5 g, 1.33 mmol) was added to a solution of sodium hydroxide (1 g, 0.025 mol) in water (4 ml) and methanol (16 ml). The resulting suspension was stirred for 3 hours until all the solid material had dissolved then allowed to stand at room temperature overnight, giving a blue solution. The solvents were evaporated in vacuo and the solid residue triturated thoroughly with water, collected and dried (0.32 g, 88.9%). The obtained title compound was then recrystallised from aqueous ethanol, mp--softens slowly from 122°-128° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:9]([O:16][CH2:17][C:18]1([CH2:32][OH:33])[O:23][C:22]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:21]=2[NH:20][C:19]1=[O:31])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:1]([O:33][CH2:32][C:18]1([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])[O:23][C:22]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:21]=2[NH:20][C:19]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
Another experiment using 3 equiv. of TBS-Cl with 1.02 g of 2,2-bis(hydroxymethyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one, gave the pure product (0.62 g, 32% yield), followed by the product with TBS-Cl (0.8 g), followed by mono-silylated material-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.56 g, 38%)
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[H-].[Na+].C(O[C:12](=O)[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.O>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:12]1[O:1][N:2]=[C:3]([CH2:4][CH3:5])[N:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCC(=N)NO
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Hydroxy-propionamidine (0.10 g, 1.15 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.05 g of a 60% dispersion in oil, 1.26 mmol) in DMF (20 ml) in the presence of molecular sieves (0.1 g). The reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min. 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.25 g, 1.15 mmol) in DMF (2 ml) is added over 5 minutes. After 3 hours at 50° C. the mixture is cooled to 0° C. and water (3 ml) is added. The mixture is allowed to warm to room temperature then filtered through Celite™ filter material, washing with ethyl acetate, and the solvent is removed. Purification by chromatography, eluting with hexane:ethyl acetate (3:1) affords the titled compound.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH:11]=2)[CH:2]=1
Reactant: COC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 20, 4.41 g of methyl 5-(3H-imidazo[4,5-b]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B5b) and 400 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)O1>>[F:41][C:38]([F:39])([F:40])[C:35]1[CH:34]=[CH:33][C:32]([N:31]2[C:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:28][CH:29]=[N:30]2)=[CH:37][CH:36]=1
Reactant: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C(F)(F)F)cc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (59 mg, 41%), MS (ISP) m/z=430.6 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from 4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (intermediate N) (0.1 g, 0.335 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(4-trifluoromethyl-phenyl)-1H-pyrazole (intermediate P) (0.15 g, 0.44 mmol).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][N:4]1[C:10](=[O:20])[CH2:11][NH:12]C(=O)OC(C)(C)C)#[N:2].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(#N)C>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:12][CH2:11][C:10]([N:4]1[CH2:5][C:6]([F:8])([F:9])[CH2:7][C@H:3]1[C:1]#[N:2])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(F)(F)C[C@H]1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CN
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of (S)-tert-butyl 2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamate (7.3 g, 25.2 mmol), obtained from step 7, in 150 mL of ACN was added trifluoroacetic acid (38.9 mL, 0.505 mol) dropwise. The mixture was stirred overnight and the volatiles were evaporated. The residue was washed with ether.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(F)cccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)cccc1Br
Reaction time: 1 h
Yield: 90.1 %

Procedure:
20.0 g (0.098 mol) of 2-bromo-6-fluorobenzaldehyde are dissolved in 500 ml of methanol and cooled in an ice bath; 3.72 g (0.098 mol) of sodium borohydride are then added portionwise thereto. The mixture is stirred under cold conditions for 1 hour and then the solid is evaporated under reduced pressure. The residue is taken up between water and dichloromethane and the organic phase is separated, dried and concentrated under reduced pressure. The residue is crystallised from pentane. 18.1 g of compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:10][N:9]2CC)[CH:5]=[CH:6][CH:7]=1.Cl.[F:24][C:25]([F:35])([F:34])C1C=C(NN)C=CC=1>CO>[Cl:20][C:16]1[CH:15]=[C:14]([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([C:25]([F:35])([F:34])[F:24])[CH:7]=[CH:6][CH:5]=3)[NH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCn1cc(-c2cccc(Cl)c2)c(=O)n1-c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: O=c1c(-c2cccc(Cl)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Yield: 37.7 %

Procedure:
A mixture of 12 grams of the 3-chloroatropic acid, methyl ester (prepared in Example 9 above), 13 grams 3-(trifluoromethyl)phenylhydrazine hydrochloride and 100 ml. methanol was refluxed overnight to yield 4.6 grams of 4-(3-chlorophenyl)-1-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 190°-192° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[F:26][C:27]([F:33])([F:32])[O:28][CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][O:28][C:27]([F:33])([F:32])[F:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCOC(F)(F)F
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCOC(F)(F)F)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(trifluoromethoxy)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H) 3.55 (q, J=5.3 Hz, 2H) 4.16 (t, J=5.3 Hz, 2H) 7.59 (d, J=7.8 Hz, 1H) 7.66 (s, 1H) 7.71 (br. s., 1H) 8.14 (br. s., 1H) 8.36 (d, J=7.3 Hz, 1H) 8.84-8.88 (m, 1H) 8.93 (t, J=4.4 Hz, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 432.4.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])=[O:6]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cccc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluorobenzoic acid (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3-difluorobenzoyl)amino]acetate which was used in the next step without purification.
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,5-dichlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.BrC1C=CN2C(C(NC3[CH:23]=[C:24](C=CC=3F)[C:25]([OH:27])=[O:26])=O)=CN=C2C=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:8]=2)[CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Product: O=C(O)c1cnc2ccc(I)cn12

Procedure:
The title compound was prepared from 5-iodopyridin-2-amine analogously to 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 2 and step 3); LC-MS: Rt 1.07 mins; MS m/z 317 [M+H]+; Method 2minLC_v003
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C>[C:10]([C@H:2]([NH:1][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:11])[NH2:12]
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: NC(=O)[C@@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To a solution of D-Phenylalaninamide (1.83 g, 11.1 mmol) in acetonitrile (20 mL) was added 1,3-propane sultone (1.29 g, 10.6 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×20 mL). The solid product was suspended in EtOH (75 mL). The suspension was stirred at reflux for 1 hours. The solid material was filtered, washed with acetone (1×25 mL) and dried in vacuo, affording the title compound (2.62 g, 89%). 1H NMR (D2O, 500 MHz) δ ppm 7.28 (m, 3H), 7.19 (m, 2H), 4.05 (m, 1H), 3.19 (dd, 1H, J=5.3 Hz, 14.2 Hz), 3.04 (m, 3H), 2.86 (t, 2H, J=5.8 Hz), 2.03 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.39, 133.73, 129.62, 129.26, 128.15, 61.57, 47.99, 45.57, 36.21, 21.45. [α]D=−20.7° (c=0.0038 in water), ES-MS 285 (M−1).
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[OH:41][CH2:42][CH2:43][CH2:44]C1C=CC(B(O)O)=CC=1>>[OH:41][CH2:42][CH2:43][CH2:44][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:16])=[O:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Reactant: OCCCc1ccc(B(O)O)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using 4-(3-hydroxypropyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C33H32N3O5S+ 582.2. Found m/z=582.3 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1COCC1.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].[F:30][C:31]1[C:36](O)=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41]>O>[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][C:36]2[C:35]([F:38])=[C:34]([F:39])[C:33]([F:40])=[C:32]([F:41])[C:31]=2[F:30])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)c([N+](=O)[O-])c1
Yield: 56.8 %

Procedure:
WSC (7.9 g) was added to a THF (100 ml) solution of 4-hydroxy-3-nitrobenzoic acid (7.3 g). and pentafluorophenol (7.4 g) at 0° C., and stirred overnight at 25° C. Water (50 ml) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the organic layer was extracted with ethyl acetate. After drying the organic layer over MgSO4, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4), thereby giving 7.9 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([O:22][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC2(CC1)OCCO2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 5 °C
Yield: 78.9 %

Procedure:
4-Methyl-benzenesulfonyl chloride (5.51 g; 29 mmol; 1.0 eq.) was added portionwise to a solution of 1,4-Dioxa-spiro[4.5]decan-8-ol (4.44 g; 28 mmol; 1.0 eq.) in anhydrous Pyridine (13.5 mL) maintained at 5° C. with an ice bath. The reaction mixture was then allowed to warm to RT and stirred O/N. It was then quenched by addition of water and diluted with EtOAc. Organic phase was washed with a 1N HCl solution, saturated NaHCO3 solution and brine. It was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6.9 g of a pale yellow oil. Purification by flash chromatography on silica (heptane/EtOAc 60:40) afforded the title compound as a white powder (4.7 g, 52%). HPLC (Condition A): Rt 4.04 min (purity 100%). MS (ESI+): 330.3