Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[C:11](C1NC=CN=1)(C1NC=CN=1)=[O:12].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>CC#N.N1C=CN=C1.[Na]>[C:11](=[O:12])([O:31][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:33][CH:32]=1)[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CSc1ccc(CO)cc1
Agent: [Na]
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CSc1ccc(COC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 24 h
Yield: 98.6 %

Procedure:
A solution of p-(methylthio)benzyl alcohol (1.0 g, 6.48 mmol), carbonyl diimidazole (1.16 g, 7.13 mmol) and sodium imidazole (0.010 g) in CH3CN (25 mL) was stirred at 20° C. for 30 min, followed by addition of p-nitrobenzyl alcohol (1.09 g, 7.13 mmol). Stirring was continued for an additional 24 h and then the reaction mixture was evaporated to dryness. The crude carbonate was purified by silica gel chromatography (eluted with CH2Cl2) to afford 2.13 g (98.6%) of the title compound as a white solid, melting at 84°-86° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CC=CC=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(C)=O>[C:18]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([OH:3])[C:1]([OH:11])=[O:10])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=C(O)C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCC(=O)c1ccccc1C(O)C(=O)O
Yield: 84.2 %

Procedure:
15.2 gm (0.10 mole) dl-mandelic acid was dissolved in 50 ml acetone and placed in one of two 125 ml additional funnels attached to a 250 ml three-necked round bottom flask charged with 8.0 gm (0.10 mole) pyridine in 50 ml acetone cooled in an ice water bath. The other addition funnel was charged with 16.3 gm (0.10 mole) octanoyl chloride. The contents of the two addition funnels were simultaneously added dropwise over 20 minutes to the stirred/cooled pyridine solution. The reaction was removed by rotary evaporation. The residue was dissolved in 200 ml diethyl ether and this solution was extracted with 5×150 ml 5% HCl, and then washed with 1×200 ml deionized water. The organic layer was dried over Na2SO4, filtered and the solvent removed by rotary evaporation. After drying in vacuo there remained 28.2 gm of oil. GC and 13C NMR determined this material to be 83.1% of the desired product, for an overall 84.2% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.P(Cl)(Cl)(Cl)=O.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C1C=CC=CC=1.CO>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(CCOC(=O)c2ccccc2)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(CCOC(=O)c2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 133, 1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinone (8.8 g) in benzene (30 ml) was reacted with 4-(2-aminophenyl)morpholine (5.2 g) in benzene (20 ml) in the presence of phosphorus oxychloride (3.3 ml) for 35 hours at 80°-85° C. to yield an oil. The oil was dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g). The solvent was removed by evaporation and the residue washed with ether and then dissolved in water. The aqueous solution was basified with aqueous sodium carbonate solution to pH 9-10 and extracted with ether to yield an oil which was purified by chromatography on an alumina column using dichloromethane as eluant. The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4-((2-[1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinylideneamino]phenyl))morpholine monofumarate (m.p. 132°-133° C.) which was recrystallised from 1:2 mixture of methanol and ether.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[S:15][C:16]([CH3:30])=[C:17]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]3)[N:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](O)=[O:38].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:30][C:16]1[S:15][C:14]([C:6]2[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=[C:4]([CH2:3][NH:2][C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[O:38])[CH:5]=2)=[N:18][C:17]=1[CH2:19][N:20]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1
Reactant: O=C(O)c1ccccn1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(CN)cc(C(F)(F)F)c3)sc2C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(CNC(=O)c4ccccn4)cc(C(F)(F)F)c3)sc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution (3 mL) of the compound (200 mg, 0.43 mmol) obtained in Example 95f in N,N-dimethylformamide were added 2-pyridinecarboxylic acid (64 mg, 0.52 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (80 mg, 0.52 mmol) and triethylamine (0.12 mL, 0.86 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=30/70) to give the title compound (79 mg, 35%) as a pale-orange oil.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[CH3:16][CH2:17]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:16][C:17]1[O:15][N:14]=[C:2]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:6]2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CC(/C(N)=N/O)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc(C2CN(C(=O)OC(C)(C)C)C2)no1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
In a 16 mL vial, tert-butyl 3-[(Z)-amino(hydroxyimino)methyl]azetidine-1-carboxylate (170 mg, 0.74 mmol; which may be prepared as described in Step 3) was dissolved in acetonitrile (7.4 mL) and cooled to 0° C. under nitrogen. DIPEA (387 μL, 2.22 mmol) and acetyl chloride (105 μL, 1.48 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 80° C. overnight, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was taken up in o-xylene (8.4 mL) and heated to 150° C. for 2 h and concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the title compound (97 mg, 55%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][CH:22]([CH3:26])[C:23](O)=[O:24]>C(OCC)(=O)C.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[CH:22]([O:21][CH3:20])[CH3:26])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: COC(C)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-methoxypropionic acid. m.p.: 169-171° C. (ethyl acetate/hexane)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=Cc2ccc(OC)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 1-bromo-4-methoxy-2-nitrobenzene (2.3 g) in acetonitrile (20 ml) was sequentially added 4-methoxystyrene (1.5 g), N,N-diisopropylethylamine (3.9 g), 2-(di-tert-butylphosphino)biphenyl (145 mg) and palladium(II) acetate (112 mg), and the solution was stirred for 15 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:3]2[C:2]([Cl:1])=[CH:10][C:6]([C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:5][N:4]=2)[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)c(Cl)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 5,6-dichloronicotinic acid (7.0 g, 35 mmol) in DMF were added iodoethane (6.0 g, 38.5 mmol) and K2CO3 (5.8 g, 42 mmol) at ambient temperature and the mixture was stirred at 45° C. for 5 hrs. To the reaction mixture were added (3R)-1-benzyl-3-piperidinamine dihydrochloride (10.1 g, 38.5 mmol) and K2CO3 (16.9 g, 122 mmol) and the reaction mixture was stirred at 90° C. for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc-hexane/1-4˜1-3) to give ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 52%) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:26][C:25]3[CH:24]=[C:23]([CH:30]=[CH:29][CH:28]=3)[C:21]#[N:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloroquinaldine (17.7 g) in THF (80 mL) at -78° was added a solution of 100 mL lithium diisopropylamide (LDA) (1M) dropwise. After addition the solution was warmed to -20° and added dropwise to 3-cyanobenzyl bromide (20 g) in THF (80 mL) at 0°. The reaction mixture was stirred 1 hr at 0° and warmed to room temperature (30 min). The mixture was partitioned between pH 7 buffer (25% NH4OAc) and ethyl acetate. The organic layer was dried and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH:9][C@H:10]([C:12]([N:14]2[C:20](=[O:21])[CH:19]([CH3:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[C:16]3[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]2=3)=[O:13])[CH3:11])=[O:8])[CH2:2]1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=C(O)C1CCOC1
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCOC2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-3-furoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 408 (M+H).
Reaction SMILES: [CH:1](=[C:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].S(=O)(=O)(O)O>CCCCCC>[C:13]([O:18][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)O
Reactant: CC=C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 80 °C

Procedure:
70 g of 2-ethyl-2-adamantanol was dissolved in toluene, 1 g of p-toluenesulfonic acid was added, and water was removed by distillation by use of a Dean and Stark dehydrator under heating so as to obtain 2-ethylideneadamantane. To 50 g of the obtained 2-ethylideneadamantane, 500 g of methacrylic acid and 0.1 ml of concentrated sulphuric acid were added, and the resulting mixture was heated at 80° C. for 5 hours. After hexane was added to the obtained reaction mixture, the mixture was washed with water, a 5% sodium hydroxide solution, and water in turn, and it was confirmed that the pH of an aqueous phase became 8. After the washed organic phase was concentrated, unreacted 2-ethylideneadamantane was partially removed by sublimation so as to obtain crude 2-ethyl-2-adamantyl methacrylate containing 80% by weight of 2-ethyl-2-adamantyl methacrylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@@H:25]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: N[C@@H]1CC[C@H](O)C1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1H) 1.75-1.91 (m, 2H) 1.97-2.05 (m, 1H) 2.10-2.16 (m, 1H) 2.61 (br. s., 1H) 4.03-4.18 (m, 1H) 4.39 (tt, J=4.84, 2.59 Hz, 1H) 4.55 (d, J=5.09 Hz, 2H) 5.19 (br. s., 2H) 6.41 (d, J=8.22 Hz, 1H) 6.55 (s, 1H) 6.90-7.02 (m, 2H) 7.05-7.18 (m, 2H) 7.24-7.34 (m, 1H) 7.43-7.55 (m, 1H) 8.07 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.BrC1C=CC(OC)=C(N[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])C=1.C(OCC)(=O)C.CCCCCCC.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:6][CH:7]=1
Reactant: COc1ccc(Br)cc1NC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cn1

Procedure:
The compound was prepared from 5-bromo-2-pyridinamine in the manner described for compound (2): 1H NMR (DMSO-d6, 400 MHz) δ 9.96 (s, 1H), 8.49 (d, 1H), 7.93 (dd, 1H), 7.78 (d, 1H), 1.47 (s, 9H); TLC (ethyl acetate/heptane 5:95) Rf 0.28; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.50 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[OH-].[Na+].[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.O.O1CCC[CH2:27]1>>[CH3:27][C:18]1[CH:19]=[CH:14][C:15]([S:20]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:21])=[O:22])=[CH:16][CH:17]=1
Reactant: C1CCOC1
Reactant: COCCOCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of triethylene glycol monomethyl ether (300 g) in tetrahydrofuran (550 mL) was added dropwise over 105 minutes to a stirred aqueous sodium hydroxide solution (2M, 1.28 L) at 0–5° C. A solution of p toluenesulphonyl chloride (383 g) in tetrahydrofuran (600 mL) was then added to the reaction mixture over 150 minutes, maintaining the temperature at 0–9° C. The reaction mixture was stirred at 0–5° C. for a further 2 hours and then allowed to warm to 20° C. and stirred for 16 hours. Additional aqueous sodium hydroxide solution (2M, 90 mL) was then added slowly to the reaction mixture and stirring was continued for a further 1 hour. Water (1 L) was added to the reaction mixture which was then extracted with toluene (2×1.8 L). The combined organic extracts were washed with water (3×1.8 L) and then concentrated in vacuo to give the title compound as a colourless oil (448 g). GC retention time 11.2 mins
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[O:14]1[CH2:15][CH2:16][CH:11]([N:8]2[CH:9]=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccn(C2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(C2CCOCC2)n1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (1.14 g, 5.09 mmol) was dissolved in a mixture of THF (5.0 mL) and MeOH (5.0 mL). To this was added NaOH (20% aqueous, 5.0 mL). The reaction mixture was stirred overnight and was then diluted with EtOAc and washed with 1 M NaHSO4. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a white solid (802 mg, 80%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[OH-:14].[K+].C>O>[Br:13][C:9]1[N:10]=[C:11]([OH:14])[C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:8]=1
Reactant: Brc1cnc(NC2CCC2)c(Br)n1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Oc1nc(Br)cnc1NC1CCC1
Yield: 80 %

Procedure:
A suspension of 2-(N-cyclobutylamino)-3,5-dibromopyrazine (EX-115B) (25.03 g, 81.53 mmol) in 500.0 mL water (0.16 M) was added potassium hydroxide (22.90 g, 408.1 mmol) in 480.0 mL water. The resulting suspension was heated to reflux for approximately 18 hours. The reaction mixture was then added charcoal and refluxed for an additional 15 minutes. The mixture was then allowed to cool for 5 minutes and was filtered through Celite 545. The filtrate was cooled in an ice bath and was acidified to a pH of approximately 5 (litmus paper) upon which a white precipitate forms. The precipitate was collected by filtration, washed twice with water, and dried under vacuum to afford pure 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) in 80% yield: 1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 7.18 (br d, J=5.1 Hz, 1H), 6.87 (s, 1H), 4.29–4.19 (m, 1H), 2.16–2.09 (m, 2H), 2.03–1.93 (m, 2H), 1.63–1.51 (m, 2H); 13C NMR (100 MHz, DMSO) δ 147.0, 144.2, 119.9, 41.3, 26.0, 10.8; HRMS (EI) calcd for C8H11BrN3O 244.0085, found 244.0086.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19]Br)(=[O:3])[CH3:2].[C:21](=[S:24])([O-:23])[CH3:22].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19][S:24][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(CSC(C)=O)n(C(C)=O)c2ccccc12
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (I-4A, 640 mg, 1.9 mmol) in acetone (10 ml) was added potassium ethanethioate (1.3 g, 11.2 mmol). The solution was heated at reflux for 1 hour. The solution was cooled and then diluted with EtOAc (50 ml) and washed with NaHCO3 (aq) (2×25 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (10-30 EtOAc/hexanes) to get 533 mg (1.6 mmol, 84%) product. MS (m/z) 334 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][C:19]=3[O:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=3[O:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 80 °C

Procedure:
An amount of 830 mg (2.01 mmol) of the compound from Example 20A was dissolved in 10 ml of tetrahydrofuran/methanol (1:1) and admixed with 2 ml of a 2 N sodium hydroxide solution (4.01 mmol). The mixture was stirred at 80° C. for an hour. The reaction solution was diluted with 10 ml of water and extracted with twice 15 ml of ethyl acetate. The combined organic phases did not contain a product and were discarded. The aqueous product phase was acidified with 1 N hydrochloric acid and the resulting precipitate was isolated by filtration. The solid was dried in a high vacuum. Since the mother liquor still contained a large amount of product, it was concentrated completely on a rotary evaporator. This gave, all in all, 747 mg (93% of theory) of the target compound.